Artículos de revistas: "Cellular immunity and chemotherapy, immune status of cancer patients"

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Schantz, S. P., H. E. Savage, T. Racz, F. J. Liu, B. W. Brown, R. D. Rossen y W. K. Hong. "Immunologic determinants of head and neck cancer response to induction chemotherapy." Journal of Clinical Oncology 7, n.º 7 (julio de 1989): 857–64. http://dx.doi.org/10.1200/jco.1989.7.7.857.

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Various measures of immune response were assessed prior to induction chemotherapy (intravenous [IV] cisplatin, fluorouracil [5-FU], and bleomycin) in 43 previously untreated head and neck cancer patients to derive a clinical response prediction model. These were parameters of functional cellular immunity (natural killer [NK] cell activity, lymphocyte blastogenesis response to mitogens), total lymphocyte and lymphocyte subset numbers and percentages, and circulating humoral immunity (total immunoglobulin, immunoglobulin classes, and C1q binding activity [C1q BA]). The C1q BA may reflect levels of circulating immune complexes within peripheral blood. The objective primary tumor response rate was 65% (16 complete responses and 12 partial responses). Univariate logistic regression analysis showed that failure to respond to therapy was significantly related to higher value (vis-à-vis response) of humoral immune parameters total immunoglobulin (Ig), P less than .01; IgG, P less than .01; and C1q BA, P less than .001. No association between cellular immune response measurements and response to chemotherapy was identified. By multivariate logistic regression analysis, only C1q BA levels were predictive of drug therapy responsiveness (P less than .001). Results extend our previous investigations regarding C1q BA measurement in head and neck cancer patients, and show that C1q BA levels add accuracy of prediction of subsequent chemotherapy response to that based solely on standard staging criteria and other parameters of immune status.

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Khakimova, G. G., A. A. Tryakin, T. N. Zabotina y Sh G. Khakimova. "Comprehensive assessment of the systemic and local immunity, inflammatory factors and clinical indicators in patients with gastric cancer". Malignant tumours 10, n.º 4 (7 de julio de 2021): 5–15. http://dx.doi.org/10.18027/2224-5057-2020-10-4-5-15.

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Objective.To study the state of cellular immunity and local immunity in patients with gastric adenocarcinoma.Materials and methods.From 2017 to 2018 45 primary patients with gastric adenocarcinoma (25 — with stages I–III, 20 — with stage IV) received surgical / combined treatment or chemotherapy at the Blokhin Scientific Research Center of Oncology, respectively. Peripheral blood and tumor tissue were collected before starting treatment. The percentage of the degree of infiltration of tumor tissue by lymphocytes (CD45 + CD14‑TILs) was assessed by flow cytometry: T‑cells (CD3 + CD19‑TILs), B‑cells (CD3‑CD19 + TILs), NK‑cells (CD3‑CD16 + CD56 + TILs), effector cells CD16 and CD8 and their cytotoxic potential (CD16 + Perforin + TILs, CD16CTPTILs), (CD8 + Perforin + TILs; CD8CTPTILs); subpopulations of regulatory T‑cells — NKT‑cells (CD3 + CD16 + CD56 + TILs), regulatory CD4‑cells (CD4 + CD25 + CD127‑TILs) and CD8 (CD8 + CD11b‑CD28‑TILs) and parameters of systemic immunity.Intratumoral and stromal subpopulations of CD4 + TILs, CD8 + TILs, CD4 + / CD8 + TILs ratios were studied by immunohistochemistry. Also, the cellular composition of peripheral blood was investigated. The prognostic significance of immune cells, inflammation factors (neutrophil‑lymphocyte index, platelet‑lymphocyte index) and clinical characteristics (patient»s age (both by years and by groups: up to 45 years, 46–60 years, over 60 years), disease stage, differentiation (G), Lauren type and MSI status were evaluated for overall survival (OS) and progression‑free survival (PFS).Results.The factor of a favorable prognosis for PFS in patients with local and locally advanced forms of gastric cancer was an increase in the number of CD3 + CD19‑TILs (HR0.865, 95 %CI 0.782–0.957, p = 0.005), and for poor prognosis — an increase in NK‑cells; HR1.382, 95 %CI 1.087–1.758, p = 0.008. There was a negative effect of the relative content of NK‑cells, an increase in the level of neutrophils in the peripheral blood on the OS of patients with metastatic GC (HR1.42, 95 %CI 1.06–1.89, p = 0.017 and HR1.64, 95 %CI 1.12–2.40, p = 0.011). At the same time, an increase in the age of patients, the level of neutrophils and platelets (HR1.106, 95 %CI 1.002–1.199, p = 0.015; HR1.714, 95 %CI 1.063–2.764, p = 0.027 and HR1.017, 95 %CI 1.006–1.029, p = 0.003) reduce PFS in patients with metastatic gastric cancer.Conclusion.Indicators of local immunity, the cellular composition of peripheral blood, characterizing the systemic inflammatory response, as well as indicators of systemic immunity can serve as additional prognostic factors in gastric cancer.

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Mantovani, Stefania, Barbara Oliviero, Stefania Varchetta, Dalila Mele y Mario U. Mondelli. "Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches". Cancers 12, n.º 4 (9 de abril de 2020): 926. http://dx.doi.org/10.3390/cancers12040926.

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Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

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Diplas, Bill, Ryan Ptashkin, Andrea Cercek, Rona Yaeger, Kelly L. Bolton, Sree Bhavani Chalasani, Avni Mukund Desai et al. "Clinical relevance of clonal hematopoiesis in metastatic gastrointestinal malignancies." Journal of Clinical Oncology 39, n.º 15_suppl (20 de mayo de 2021): e16082-e16082. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e16082.

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e16082 Background: Clonal hematopoiesis (CH) represents non-random clonal selection of bone marrow-derived cells marked by somatic mutations in certain genes. The presence of CH is associated with development of atherosclerosis and leukemia, and accelerated by toxic exposures (chemotherapy, radiation, smoking) and aging (Jaiswal et al. NEJM 2017; Abelson et al. Nature 2018). The impact of these genetic alterations on cellular function is unknown, especially in the broader context of immunity and in response to cancer therapy. To determine the contribution of CH to therapeutic response and hematologic toxicity in cancer patients, we examined the outcomes of patients treated with cytotoxic and immunotherapy in relationship to CH status. Methods: We evaluated patients with metastatic colorectal cancer (CRC) or esophagogastric cancer (EGC). DNA extracted from whole blood and tumor tissue were sequenced in tandem as part of the MSK-IMPACT hybridization capture-based sequencing assay. CH was defined as any mutation with a VAF of at least 2%, present in at least 10 reads, with at least 2:1 blood:tumor reads, or 1.5:1 blood:lymph node that was not found in gnomAD with a frequency > 0.005. Additional filtering and putative driver definitions (CH-PD) were described by Bolton et al. Nature Genetics 2020. Multivariate survival analyses were performed using a Cox Proportional Hazard model correcting for CH, CH-PD, prior smoking, prior chemotherapy, prior radiation, MSI status, and age at cancer diagnosis. Results: 654 patients with EGC (n = 348) and CRC (n = 306) who began treatment between 2006 and 2020 were included in the analysis. CH was present in 34.5% and 24.4% of each group, and 17.2% and 12.9% harbored CH-PD, respectively. CH and CH-PD were both associated with older age and smoking history, and CH was also associated with prior radiation and MSI-high status (p < 0.05). Patients with CH or CH-PD receiving first-line (1L) therapy for CRC or EGC demonstrated no difference in mPFS after multivariate analysis, though 1L EGC patients with CH-PD had inferior mOS (p = 9e-5). There was no difference in pre-1L WBC, ANC, or ALC, nor in G-CSF or PEG-G-CSF doses administered during 1L therapy between patients with CH or CH-PD versus those without. Similarly, presence of CH or CH-PD had no impact on mPFS or mOS in patients receiving immune checkpoint blockade (ICB) without concurrent chemotherapy after multivariate survival analysis. Conclusions: We confirmed that the mere presence of CH is not prognostic for overall survival, but that EGC patients with CH-PD mutations have inferior overall survival, which is consistent with previous findings. Presence of CH or CH-PD was not associated with differences in baseline leukocyte counts nor need for G-CSF support, nor did it impact PFS in either tumor type, suggesting limited utility of CH in solid tumor clinical decision-making.

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DeJoubner, Nutan Jyothi, Hyunseok Kang, Qunna Li, Wayne A. C. Harris, Rena Stewart, Alicia Price, Arshed Quyyumi et al. "Prognostic impact of circulating endothelial cell counts in patients with advanced non-small cell lung cancer." Journal of Clinical Oncology 30, n.º 15_suppl (20 de mayo de 2012): e21045-e21045. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e21045.

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e21045 Background: Blood progenitor cells expressing the stem cell marker CD34 have been associated with prognosis in cancer. We hypothesized that non-small cell lung cancer (NSCLC) patients with higher numbers of circulating CD34+ endothelial progenitor cells (CD34+/CD146+/CD45-, CEC) would have worse post-treatment outcomes and patients with more hematopoietic progenitor cells (CD34+/CD45+/CD45dim/CD133+, HPC) would have better outcomes. Methods: Blood samples from patients with advanced NSCLC were analyzed at 3 time points: prior to chemotherapy, after cycle one, and at completion of treatment or progression of disease, in an IRB-approved protocol. CEC, HPC, and immune subsets were measured by flow cytometry optimized for rare event detection. Primary outcomes were progression and death from the time of study entry. Patients were categorized and compared for progression free survival (PFS) and overall survival (OS) based on median cell counts. Differences between groups were tested using log-rank test and Cox regression. Results: A total of 62 patients were enrolled with mean age of 64 (37-87 years). There were 29 deaths after a median follow-up of 8.1 months. 40 patients progressed at a median of 5.4 months. Median numbers of CEC, HPC, and CD4+ T-cells were (0.05/uL, 0.41/uL, and 637/uL, respectively). Lower CEC at baseline was associated with a favorable PFS compared to those with higher counts (median PFS of 7.3 months versus 4.3 months, p=0.049). In a multivariate analysis after adjusting for age, gender, smoking, race, TNM stage, pathology, performance status and CD4 counts at baseline, patients with high CEC had almost 3-fold risk of death (HR=2.70, p=0.04) and disease progression (HR=3.03, p < 0.01) compared with patients with low numbers of CEC. In the same model, patients with fewer CD4+ T cells had > 3 fold risk of death compared with patients with higher numbers (HR=3.79, p=0.01). HPC content was not associated with OS or PFS. Conclusions: In patients with advanced NSCLC, higher CEC and lower CD4 counts at diagnosis are associated with worse outcomes. Higher CEC may serve as a cellular biomarker for extent of disease or tumor biology. Patients with poor T-cell immunity prior to treatment have worse survival.

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Zemskov, Vladimir M., Konstantin N. Pronko, Dmitrii A. Ionkin, Alexei V. Chzhao, Maria N. Kozlova, Alexander A. Barsukov, Nadezhda S. Shishkina, Valentina S. Demidova, Andrei M. Zemskov y Amiran Sh Revishvili. "Immune Status of Pancreatic Cancer Patients Receiving Cryosurgery". Medical Sciences 7, n.º 6 (22 de junio de 2019): 73. http://dx.doi.org/10.3390/medsci7060073.

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Cryosurgery used on patients with unresectable pancreatic cancer improved their quality of life, but mainly because of the pain relief. In postoperative patients, multifaceted changes in immunity were found, and the state of the immune system prior to surgery often was a decisive factor to indicate whether further disorders in the postoperative period would develop, or by contrast, it would boost its recovery. Some patients receiving cryosurgery showed immune system imbalance and activation, and of antitumor immunity in particular. It has been suggested that the advisability of immunotropic therapy for specific treatment algorithms should be predicted or the therapy should be suspended at some pathologic stage, and this has been immunologically confirmed. Cryosurgery should be considered as a reasonable alternative to the existing types of surgery for pancreatic cancer or as an essential component of multimodal therapy, consisting of topical cryosurgery, chemotherapy, and immunotropic therapy, to boost antitumor immunity and to discontinue cytoreductive therapy due to its toxic effects.

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Pais, Irene, Nuno Correia, Isabel Pimentel, Maria José Teles, Esmeralda Neves, Júlia Vasconcelos, Judite Guimarães et al. "Effects of Acupuncture on Leucopenia, Neutropenia, NK, and B Cells in Cancer Patients: A Randomized Pilot Study". Evidence-Based Complementary and Alternative Medicine 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/217397.

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Chemotherapy is one of most significant therapeutic approaches to cancer. Immune system functional state is considered a major prognostic and predictive impact on the success of chemotherapy and it has an important role on patients’ psychoemotional state and quality of life. In Chinese medicine, chemotherapy is understood as “toxic cold” that may induce a progressive hypofunctional state of immune system, thus compromising the fast recovery of immunity during chemotherapy. In this study, we performed a standardized acupuncture and moxibustion protocol to enhance immunity in cancer patients undergoing chemotherapy and to assess if the improvement of immunity status correlates with a better psychoemotional state and quality of life.

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Zavadova, Eva, Jan Spacek, Michal Vocka, Bohuslav Konopasek y Lubos Petruzelka. "Decreased cellular and humoral immunity in patients with breast cancer." Journal of Clinical Oncology 36, n.º 5_suppl (10 de febrero de 2018): 4. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.4.

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4 Background: A growing body of evidence over the past few years suggests that the presence of immune elements within the tumor or in the tumor stroma has prognostic and predictive value in breast cancer. Immunotherapy is successfully used in many types of cancer, and modulation of immune system became standard part of the cancer patients treatment Responses in breast cancer have been more recently reported. However it has yet to be determined whether predictable biomarkers of response can be identified. Therefore in recent years, research focused on a precise description of the status and function of the immune system.The purpose of the study was to monitor immune responses in patients with breast cancer, particularly the examination of cellular (CD4, CD8, B cells) as well as humoral immunity (IgG, IgG1, IgG2, IgG3, IgG4. It appears that a factor contributing to the immunosupression may be a transforming factor-beta (TGF-beta).It is highly immunosuppressive factor that inhibits the natural and specific immunity against tumors. Methods: 50 patients included in the research project were implemented routine cancer treatment. Basic parameters (histological type and grade, the degree of expression of ER and PR, HER2, and the proliferative marker) were established. Patients were evaluated by a cancer clinical immunologist to exclude immune disorders, allergic or autoimmune origin. Anti-tumor cellular immunity (CD4, CD8, CD19) was measured by flow citometry, humoral immunity (IgG, IgG1, IgG2, IgG3, IgG4) was measured and TGF beta and VEGF production was monitored by ELISA. Results: In breast cancer patients mainly depression in cellular immunity was found. Immunglobuline plasma level was decreased as well (mainly IgG4 subtype). TGF beta as well as VEGF plasma level were increased. Most patients have shown clinical symptoms of immunodeficiency (frequent infections of respiratory or urinary tract, herpetic infections).Those patient could benefit from immunomodulation. Conclusions: The state of anticancer immunity could contribute to the selection of targeted immune therapy in breast cancer patients and to help to find optimal combination of immunotherapy. This project was supported by governmental grant AZV CR 15-28188A.

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Jaunalksne, Inta, Simona Doniņa, Svetlana Čapenko, Maksims Čstjakovs y Modra Murovska. "Cellular Immunity in Human Herpes Viruses 6 and 7 Infected Gastrointestinal Cancer Patients". Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences. 63, n.º 4-5 (1 de enero de 2009): 163–67. http://dx.doi.org/10.2478/v10046-009-0052-3.

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Cellular Immunity in Human Herpes Viruses 6 and 7 Infected Gastrointestinal Cancer Patients CD4+ T lymphocytes appear to be the preferential target for replication of HHV-6 (human herpes virus) as well as HHV-7 viruses in vivo. In addition, CD8+ T cells, monocytes/macrophages, natural killer cells, epithelial, endothelial, neural cells and fibroblasts may be infected. By definition, however, even a tumour designated by pathologists to be early stage may be late stage when considered by the immune system. Certainly, even early stage tumours have evaded immune control, suggesting that they have acquired many immunosuppressive characteristics. The aim of the study was to clarify the influence of beta-herpes viruses on cellular immune response. In 95 gastrointestinal cancer patients we determined the immunocompetent cell level CD3, CD4, CD8, CD19, CD38, CD95, CD25 using laser flow cytofluorimeter and B- herpes viruses HHV-6, HHV-7 presence using a nested polymerase chain reaction method. Our data showed no statistically significant difference in immunocompetent cell level between negative, latent and active HHV-6, HHV-7 infection. Patients with immunocompromised immune status (lymphopenia) had a tendency to decreased CD4+, CD19+ absolute count. It may be suggested that virus-mediated immune response inhibition seems to be similar to cancer mediated, but differences in immune response among the same group of individuals had no influence on the average number of the immunocompetent cells in the group. Therefore, to characterise host-virus-tumour interactions, individual interpretation of each case is needed.

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Kamaeva, Inna A., Irina B. Lysenko, Aleksandr B. Sagakyants, Elena S. Bondarenko, Oksana G. Shulgina, Nadezhda V. Nikolaeva, Elena A. Kapuza et al. "Parameters of cellular immunity in patients with lymphomas after COVID-19." Journal of Clinical Oncology 39, n.º 15_suppl (20 de mayo de 2021): e19572-e19572. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e19572.

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e19572 Background: The development of lymphomas is accompanied by disorders in the structural and functional organization of the immune system leading to immune deficiency. Such patients are at greater risk of severe SARS-CoV infection. Our purpose was to assess the parameters of cellular immunity in patients with lymphomas with a history of multi-course chemotherapy, therapy with anti-CD20+ antibodies and PCR-confirmed COVID19. Methods: The study included 12 adult patients with lymphoproliferative diseases (non-Hodgkin's large B-cell lymphomas (NHL) - 7, Hodgkin's lymphomas (HL) - 5) with a history of PCR-confirmed COVID-19. All patients underwent 4 to 6 chemotherapy cycles. The relative numbers of the main populations of leukocytes, T- and B-lymphocytes, as well as subpopulations of T-lymphocytes, were assessed in the whole blood collected in K2EDTA anticoagulant using the BD FACSCanto II flow cytometer with a panel of antibodies according to the manufacturer's instructions (Becton Dickinson, USA). Results: Patients with HL showed a number of changes in the parameters of cellular immunity. The content of total lymphocytes and monocytes was reduced in comparison with patients with NHL by 34% and 56%, respectively: 14.3 (11; 17) vs. 21.7 (15.2; 32), and 6.0 (4.8; 7.1) vs. 13.5 (12.9; 13.7), respectively. An increase in granulocytes by 30% was revealed in patients with HL. No differences were found in the content of both general and main populations (CD3+, CD3+CD4+, CD3+CD8+, central and effector memory cells). However, the content of naive CD3+CD4+ and CD3+CD8+ lymphocytes in patients with HL increased by 43% and 62%, respectively. While the number of CD3+CD4-CD8- lymphocytes was 47% lower, the number of CD3+CD4+CD8+, on the contrary, exceeded the values in patients with NHL by 4.6 times. Patients with HL also showed a tendency towards a decrease in the number of NK and NKT-lymphocytes. Conclusions: The increased levels of naive lymphocytes and both populations of memory cells and a sharp increase in double-negative T-lymphocytes and B-lymphocytes in patients with HL could indicate certain characteristics of the disease course affected by COVID-19. The data require additional research and can be used to assess the condition of patients and to predict the therapy efficacy.

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Mansfield, Aaron Scott, Wendy Kay Nevala y Svetomir Markovic. "Immunologic changes in patients with metastatic melanoma on bevacizumab and chemotherapy versus chemotherapy alone." Journal of Clinical Oncology 30, n.º 15_suppl (20 de mayo de 2012): e21112-e21112. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e21112.

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e21112 Background: Metastatic malignant melanoma is difficult to treat and has a poor prognosis. Systemic therapy for metastatic melanoma has had limited success and novel drug combinations need to be tested. To that end, we have combined anti-angiogenic therapy (bevacizumab) with chemotherapy in clinical trials and have shown some clinical efficacy. Vascular endothelial growth factor (VEGF) is increasingly seen as an immunosuppressive factor that hampers dendritic cell maturation and reduces antigen presentation. We have recently shown that tumor-derived VEGF plays a role in Th-2 driven systemic chronic inflammation seen in advanced melanoma patients. Therefore, our data suggest that blocking tumor derived VEGF with the monoclonal antibody bevacizumab may impact immunity in such a way that augments anti-tumor immunity enhancing clinical efficacy. Methods: In order to understand the immune status in metastatic melanoma patients on chemotherapy (n=55) or chemotherapy plus bevacizumab (n=73), we measured levels of 42 cytokines, chemokines and growth factors in plasma by a mulit-plex bead assay. Matched pairs analysis was performed to determine if the average responses of the measured cytokines were different between the patients that received chemotherapy with bevacizumab or chemotherapy alone. The pre-treatment levels were compared with levels drawn four weeks after the first treatment. Results: There were significant differences in IL-1a, IL-1ra, IL-6, IL-8 and IP-10 between patients treated with chemotherapy alone relative to patients treated with chemotherapy plus bevacizumab. In all cases of patients treated with chemotherapy plus bevacizumab, the levels of these cytokines all decreased relative to pre-treatment samples. In patients treated with chemotherapy alone the levels of these cytokines increased relative to pre-treatment samples. Conclusions: Our data suggest that treating patients with the anti-angiogenic drug bevacizumab may affect the plasma cytokine milieu by reducing the level of many key inflammatory cytokines. Therefore, the use of bevacizumab in combination with chemotherapy may augment host immunity and elicit a more effective anti-tumor immune response.

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Hariyati, Hariyati y Ayudiah Puspita Mayasari. "Immune-checkpoint Inhibitor Treatment of Non-Small Cell Lung Cancer Patients". Jurnal Respirasi 6, n.º 1 (30 de enero de 2020): 21. http://dx.doi.org/10.20473/jr.v6-i.1.2020.21-26.

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Lung cancer is the primary cause of mortality in the world. It is able to manipulate the host immune response system through many mechanisms, such as through alteration of cytokines structure, forming regulator T-cells, obstruction of cellular immunity function, and the interference of tumor antigen presenting process. The new therapy approachment is produced by stimulating anti-cancer immune response, therefore the growth of lung cancer is able to inhibit. Immune checkpoint inhibition is considered as therapy for non-small cell lung carcinoma (NSCLC) after the unsuccesful treatment by platinum-based chemotherapy. Recent study shows that immune checkpoint inhibition monotherapy is more distinguished as first line therapy than platinum-based chemotherapy. Nonetheless, the effect of immunotherapy is only available for small population (30%) which has more than 50% PD-L1 programmed by the tumor. Therefore, some strategies are investigated to solve this issue. Nowadays, immunotherapy is expected to overcome lung cancer which is still being investigated in many studies.

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Darwin, Nopriansyah, Nur Qodir, Mulawan Umar y Theodorus. "Effects of Neo-Adjuvant Chemotherapy on CD8 + Serum Levels in Local Advanced Stage Breast Cancer Patients". Sriwijaya Journal of Surgery 3, n.º 1 (28 de junio de 2020): 45–60. http://dx.doi.org/10.37275/sjs.v3i1.27.

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Introduction.CD8 + CTLs are important components of tumor specific cellular adaptive immunity in breast cancer. Chemotherapy can increase the response of cytotoxic lymphocytes and provide anti-tumor immunity. Therefore, chemotherapy can cause cell death and trigger tumor antigens that are processed by APC and activate CD8 + cells to destroy tumor cells. Evaluation of the immune system before treatment can predict chemotherapy response. The purpose of this study was to assess the effect of neo-adjuvant chemotherapy on serum CD8 + levels in patients with locally advanced breast cancer.Methods.Non-comparative clinical trials were conducted at Dr. Mohammad Hoesin Hospital Palembang from October 2017 to June 2018.The sample of this study was 30 breast cancer patients who met the inclusion criteria. All samples underwent FAC neo-adjuvant chemotherapy and data were analyzed with SPSS version 21. Results.The mean age of advanced breast cancer patients was 45.97 ± 10,526 years with an age range of 30-66 years. Serum CD8 + levels after chemotherapy decreased significantly compared to before chemotherapy (p = 0.000). The value of serum CD8 + before chemotherapy has a sensitivity of 42.86% and specificity of 43.48% with a cut of point of 660.7 cells / mm3.Conclusion.Neo-adjuvant chemotherapy significantly decreases serum CD8 + levels in local advanced breast cancer patients.Keyword: CD8 +, locally advanced breast cancer, immune system, neo-adjuvant chemotherapy

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Zhuang, S. R., H. F. Chiu, S. L. Chen, J. H. Tsai, M. Y. Lee, H. S. Lee, Y. C. Shen, Y. Y. Yan, G. T. Shane y C. K. Wang. "Effects of a Chinese medical herbs complex on cellular immunity and toxicity-related conditions of breast cancer patients". British Journal of Nutrition 107, n.º 5 (25 de agosto de 2011): 712–18. http://dx.doi.org/10.1017/s000711451100345x.

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Rose geranium (Pelargonium graveolens, Geraniaceae) has anti-cancer and anti-inflammatory properties, and promotes wound healing. Similarly,Ganoderma tsugae(Ganodermataceae),Codonopsis pilosula(Campanulaceae) andAngelica sinensis(Apiaceae) are traditional Chinese herbs associated with immunomodulatory functions. In the present study, a randomised, double-blind, placebo-controlled study was conducted to examine whether the Chinese medicinal herb complex, RG-CMH, which represents a mixture of rose geranium and extracts ofG. tsugae, C. pilosula and A. sinensis, can improve the immune cell count of cancer patients receiving chemotherapy and/or radiotherapy to prevent leucopenia and immune impairment that usually occurs during cancer therapy. A total of fifty-eight breast cancer patients who received chemotherapy or radiotherapy were enrolled. Immune cell levels in patient serum were determined before, and following, 6 weeks of cancer treatment for patients receiving either an RG-CMH or a placebo. Administration of RG-CMH was associated with a significant reduction in levels of leucocytes from 31·5 % for the placebo group to 13·4 % for the RG-CMH group. Similarly, levels of neutrophils significantly decreased from 35·6 % for the placebo group to 11·0 % for the RG-CMH group. RG-CMH intervention was also associated with a decrease in levels of T cells, helper T cells, cytotoxic T cells and natural killer cells compared with the placebo group. However, these differences between the two groups were not statistically significant. In conclusion, administration of RG-CMH to patients receiving chemotherapy/radiotherapy may have the capacity to delay, or ease, the reduction in levels of leucocytes and neutrophils that are experienced by patients during cancer treatment.

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Vargaftig, Jacques, Hassan Farhat, Lionel Ades, Adrien Briaux, Camille Benoist, Isabelle Turbiez, Norbert Vey, Sylvie Glaisner y Céline Callens. "Phase 2 Trial of Single Agent Gedatolisib (PF-05212384), a Dual PI3K/mTOR Inhibitor, for Adverse Prognosis and Relapse/Refractory AML: Clinical and Transcriptomic Results". Blood 132, Supplement 1 (29 de noviembre de 2018): 5233. http://dx.doi.org/10.1182/blood-2018-99-117485.

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Abstract Background: Acute Myeloid Leukemia (AML) is a heterogeneous disease carrying a dismal prognosis. This outcome is the consequence of patient factors (age, comorbidity) and intrinsic biologic abnormalities. Cytogenetic and mutational data are already used to define treatment strategy, but many cellular signaling pathways are deregulated in AML, including targetable PI3K/mTOR pathway. Activation of the PI3K/mTOR pathway promotes cell growth, survival and resistance to chemotherapy and is detected in virtually all AML samples. mTOR, a serine/threonine kinase downstream of PI3K, may be activated independently of PI3K. Gedatolisib is a small molecule in development of solid tumors. It inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of leukemic cells. We explored the clinical activity and tolerance of Gedatolisib in the particularly underserved group of relapse/refractory and adverse prognosis AML. Methods: We conducted an open, prospective, single-arm, multicentric phase 2 trial in 4 academic French hematology centers. Enrollment took place between September 2015 and August 2016. Inclusion criteria were relapse/refractory AML and therapy-related AML. Experimental drug dosage was derived from phase 1 studies in solid tumors. Treatment protocol consisted in 4 cycles, each cycle containing 4 weekly injections of Gedatolisib 150 mg delivered IV. Monitoring included weekly blood counts and bone marrow (BM) aspiration after 2 and 4 cycles. Primary objective was Overall Response Rate and secondary objectives were Progression-Free Survival (PFS) and Overall Survival (OS). An ancillary biologic study focused on RNA sequencing (RNAseq) of AML-infiltrated BM samples (>30% blasts at diagnosis) before and after drug exposure to explore its molecular impact. This trial was funded by French National Cancer Institute (INCa) and registered as NCT02438761. Results: 12 patients were included but only 10 patients were retained in the final analysis. 6 patients (pts) were males (60%) and the median age was 59.6 years (range: 33-74). All pts had relapsed AML (5 pts in 1st relapse, 5 pts in 2nd relapse) and symptomatic uncontrolled AML. 1 patient (pt) had therapy-related AML (prostate adenocarcinoma). Cytogenetic risk: 4 pts had intermediate and 6 pts had adverse risk. Only 1 pt completed the treatment including 4 cycles of Gedatolisib. 1 pt received 3 cycles, 3 pts received 2 cycles and 5 pts received 1 cycle (i.e. 4 injections). Reasons for early patient withdrawal were: objective disease progression for 5 pts (including uncontrolled hyperleukocytosis for 4 pts), global deterioration of health status for 2 pts, treatment-related adverse event for 1 pt (anal ulcer), treatment-unrelated adverse event for 1 patient (pneumonia). No objective response was detected for any of the 10 pts according to the IWG AML criteria (Cheson, 2003). Serious adverse events included mouth ulcers (2 pts) and anal ulcer (1 pt). Median follow-up was 4.4 months (mo) (range: 1.7-16.3). OS was 3.5 mo (IC95%=2 mo). PFS was 2.3 mo (IC95%=2 mo). The biologic study used 6 paired BM samples (at inclusion and after drug exposure) which could be analyzed by RNAseq: 1 pair after 4 cycles, 3 pairs after 2 cycles, 2 pairs after more than 1 cycle (6 and 7 drug injections). Transcriptomic principal component analysis showed that each pair clustered together and apart of the other samples, reflecting the heterogeneity of the cohort. The drug impacts weakly gene expression pattern as only 38 genes were significantly differentially-expressed. Among up-regulated genes, 4 were associated with NK cell immunity. Gedatolisib might affect immune cells as already described for other PI3K inhibitors. We detected 23 pathogenic variants and 58 variants of unknown pathogenicity (median=6 variants/sample [1-22]) without obvious correlation with drug resistance. Ongoing research focuses on genes and pathways previously associated with PI3K inhibitor resistance in solid tumors. Conclusion: Gedatolisib, a dual PI3K/mTOR inhibitor used as a single therapy had no clinical benefit in adverse prognosis and relapsed/refractory AML patients. Combination of Gedatolisib with chemotherapy was not explored, yet this could be a potential therapeutic development, as it was recently shown for Midostaurin and FLT3-mutated AML. Disclosures No relevant conflicts of interest to declare.

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Chertkova, A. I., E. G. Slavina, E. K. Shoua, L. G. Zhukova, M. A. Okruzhnova, V. A. Nurtdinova, A. A. Borunova, N. Т. Dzhgamadze y Z. G. Kadagidze. "THE MAIN PARAMETERS OF CELLULAR IMMUNITY IN PATIENTS WITH TRIPLE-NEGATIVE BREAST CANCER: RELATIONSHIP WITH EFFICIENCY OF CHEMOTHERAPY". Medical Immunology (Russia) 20, n.º 5 (6 de noviembre de 2018): 667–80. http://dx.doi.org/10.15789/1563-0625-2018-5-667-680.

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Chemotherapy is among the primary methods of treating advanced breast cancer. It was shown that clinical efficacy of various chemotherapeutic agents in many cases depends not only on their direct cytostatic and/or cytotoxic effect upon tumor cells, but also on their ability to modulate phenotype of the tumor cells and to influence anti-tumor immune response. Initial state of the immune system and its response to treatment is crucial. Antitumor response involves cells of innate and adaptive immunity (NK, NKT, T cells). These populations are heterogeneous and contain, e.g., cells with antitumor activity and regulatory (suppressor) cells that suppress immune response and promote tumor progression. The aim of this work was to determine the relationship between the initial state of cellular immunity of patients suffering from locally advanced breast cancer with triple negative phenotype, and clinical effect of chemotherapy (cisplatin + doxorubicin/paclitaxel), and studying effects of the therapy upon subpopulation profiles of peripheral blood lymphocytes in the patients. We registered the terms of the disease progression as well as overall survival and progression-free survival. The disease progressed in 25 of 53 cases (47.2%) whereas 28 of 53 patients (52.8%) remained progression-free. The observation period was 35.5 months. Laboratory examination of the patients included immunophenotyping of peripheral blood lymphocytes and determination of NK cell cytotoxic activity before and after chemotherapy. Percentages of effectors and regulatory lymphocyte populations were determined. The results obtained showed that, for some lymphocyte subsets, the pre-treatment differences of cell percentage deviations from control were found between the progression-free groups and patients with progression of the disease. The differences in percentages of NKT cells and lymphocytes expressing CD25 activation marker proved to be most significant. Decreased number of NKT cells and activated CD25+ lymphocytes prior to chemotherapy was associated with increased probability of disease progression. Reduced percentage of NKT cells against control was observed in 56% of patients from the progression group (PD), and only 21.4% in the group free of disease progression (DF). [OR = 4.6 (95% CI 1.4 to 15.4)]. Percentage of CD25+ lymphocytes was decreased from 68.2% in the PD group, and 28.6% for DF patients [OR = 5.4 (95% CI 1.6-18.1)]. We studied relationships between the overall survival (OS) and percentage of perforin-containing NK, NKT, and T cells, and mean perforin fluorescence density (PFD) in these lymphocyte subsets in 26 of the 53 patients before treatment. A statistically significant positive correlation was revealed between OS and perforin PFD in all the three cell populations under study. Normalization of the parameters altered before treatment, and an increase of T cell numbers was observed in the disease-free patients.

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Gan, Li-Lian, Ling-Wei Hii, Shew-Fung Wong, Chee-Onn Leong y Chun-Wai Mai. "Molecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion". Cancers 12, n.º 7 (11 de julio de 2020): 1872. http://dx.doi.org/10.3390/cancers12071872.

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Pancreatic cancer ranks high among the causes of cancer-related mortality. The prognosis of this grim condition has not improved significantly over the past 50 years, despite advancement in imaging techniques, cancer genetics and treatment modalities. Due to the relative difficulty in the early detection of pancreatic tumors, as low as 20% of patients are eligible for potentially curative surgery; moreover, chemotherapy and radiotherapy (RT) do not confer a great benefit in the overall survival of the patients. Currently, emerging developments in immunotherapy have yet to bring a significant clinical advantage among pancreatic cancer patients. In fact, pancreatic tumor-driven immune evasion possesses one of the greatest challenges leading to immunotherapeutic resistance. Most of the immune escape pathways are innate, while poor priming of hosts’ immune response and immunoediting constitute the adaptive immunosuppressive machinery. In this review, we extensively discuss the pathway perturbations undermining the anti-tumor immunity specific to pancreatic cancer. We also explore feasible up-and-coming therapeutic strategies that may restore immunity and address therapeutic resistance, bringing hope to eliminate the status quo in pancreatic cancer prognosis.

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Yurkin, A. K. "Evaluation of cellular and humoral indicators immunity in the treatment of various types of sepsis in immunocompromised hemoblastosis patients". Bulletin of the Russian Military Medical Academy 21, n.º 2 (15 de diciembre de 2019): 43–47. http://dx.doi.org/10.17816/brmma25917.

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It was established that the course and development of sepsis in patients with hemoblastosis, are held against the background of complex violations of indicators of cellular and humoral immunity. However, in patients with acute myeloid leukemia, they are more pronounced, which most likely explains the higher mortality rate in this group of patients compared with patients suffering from lymphoproliferative diseases. Some features of the development of post-cytotoxic complications after chemotherapy in patients with hemoblastosis are identified. In addition, the most significant predictors of post-cytotoxic complications in patients with hemoblastosis, who are most susceptible to post-cytotoxic infectious complications and life- threatening emergency conditions, have been identified. The most probable causes of deaths in primary and secondary immunodeficiencies of the cytotoxic type in immunocompromised patients suffering from hemoblastosis with proven sepsis on the background of neutropenia after polychemotherapy are presented. Revealed some post-cytotoxic complications that significantly affect the course and outcome of the disease in patients with hemoblastosis. The nature of these complications and emergency conditions allows you to determine the volume and priority of ongoing proactive intensive therapy after polychemotherapy in the period of neutropenia or agranulocytosis, on the background of a violation of the immune status of patients. An assessment of some humoral and cellular indicators of the immune status of patients with various types of proven sepsis is given.

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Thakur, Archana, Joseph P. Uberti, Voravit Ratanatharathorn y Lawrence G. Lum. "Transfer of Immunity Using Vaccinate and Boost Strategy with Bispecific Antibody Armed T Cells (BATs) in Metastatic Breast Cancer Patients". Blood 128, n.º 22 (2 de diciembre de 2016): 3459. http://dx.doi.org/10.1182/blood.v128.22.3459.3459.

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Abstract Background. In our recent phase I immunotherapy (IT) trial in 23 women with metastatic breast cancer (MBC), 8 infusions of activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific antibody (HER2Bi) given in combination with interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF) induced specific anti-breast cancer immunity. This study investigated whether specific cellular and humoral anti-breast cancer immunity induced by infusions of HER2 bispecific antibody armed T cells (BATs) could be transferred after high dose chemotherapy (HDC) and stem cell transplant (SCT) in MBC patients. Methods. T cell were activated with OKT3 and expanded in IL-2. ATC were harvested, armed with HER2Bi, and cryopreserved in 8 doses for twice weekly infusions for 4 weeks along with IL-2 and GM-CSF. Seven to 14 days after the last infusion of BATs, the patient was leukapheresed again to obtain and expand immune T cells. Multiple infusions of immune ATC after the HDC and SCT were given to boost the transferred cellular and humoral immune responses which were monitored up to 24 months. Results. Six of 8 MBC patients enrolled were evaluable in the protocol, no dose-limiting toxicity, delays in engraftment, or life-threatening infections were observed. Five of 6 evaluable patients exhibited increased anti- breast cancer cytotoxicity and IFN-γ Elispots after vaccination with BATs and up to 18 months post SCT. Serum and culture supernatants from in vitro antibody synthesis assay showed gradual increases in anti-SK-BR-3 IgG levels after SCT. Serum cytokine profile showed increases in IL-12 and Th1 cytokines. One out of 6 evaluable patients who rapidly progressed showed poor immune response, had high serum levels of Th2 cytokines and no evidence of transfer of immunity. Flow cytometry analysis of Vβ repertoire pattern in PBMC collected post IT and post SCT indicate transfer of the major Vβ clones post SCT that produced IFN-γ upon stimulation with breast cancer cells (Fig. 1). A significant correlation (r=1.0; p<0.002) between immune ATC cytotoxicity directed at breast cancer cells and time to progression (TTP) suggests that more robust vaccinations with a Th1 shift in cytokine profiles can lead to clinical benefit (Fig. 2). Conclusions. Our pilot study suggests that cellular and humoral immunity was transferred and boosted using immune T cells after SCT. There was robust reconstitution of T and B cell functions early after SCT as evidenced by CTL and NK activity, IFN-γ EliSpots, in vivo/in vitro antibody synthesis, and Th1 cytokine responses.BATs induced endogenous anti- breast cancer cellular, humoral and innate immunity that could be detected after SCT and may have provided clinically meaningful anti-tumor immunity. Disclosures No relevant conflicts of interest to declare.

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Gryazov, A. A., M. I. Lisyany y A. B. Gryazov. "Features of immune status in patients with metastatic and glial brain tumors at the preparatory stage of radiotherapy". Український радіологічний та онкологічний журнал 28, n.º 4 (17 de diciembre de 2020): 353–63. http://dx.doi.org/10.46879/ukroj.4.2020.353-363.

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Background. Studies carried out in recent decades have shown that immune cells are essential participants in the cancer process as well as cancerrelated inflammation. Focus has been increased on understanding the way how immune cells affect a tumor at different stages of the disease: early neoplastic transformation, clinically detected tumors, metastatic spread, and at surgery and radiotherapy stages. Purpose – assessing the status of the immune system in patients with brain tumors before radiation therapy and radiosurgery and comparing the features of immunity in metastatic and glial brain tumors. Materials and methods. The study presents the immunogram findings of 61 patients. Out of those: 18 patients with primary glial tumors and 23 patients with secondary metastatic tumors to the brain. The outcomes of 20 conditionally healthy non-cancer patients are presented as a control group. The age of patients is 24–75. All patients were histologically diagnosed with the tumor. Surgery was performed 1.0–3.0 years before the examination. Assessment of the immune system in patients with brain tumors was performed taking into account the cellular, humoral and phagocytic component of innate immunity. When assessing cellular immunity, the relative and absolute count of major lymphocyte subpopulations, such as CD3+ – general T-lymphocytes, CD4+ – T-lymphocytes-helpers, CD8+ – cytotoxic lymphocytes, CD16+ – natural killer lymphocytes, CD19+-B-lymphocytes, were calculated. Determining the humoral parameters included an assessment of quantitative values of IgG, IgM and IgA. Quantitative assessment of the phagocytic component of innate immunity included phagocytic activity of neutrophils (i. e. NBT test (Nitroblue Tetrazolium test), inducing (Zymosanum) and spontaneous neutrophil myeloperoxidase activity). Results. When comparing the immune parameters of the number of T- and B-subpopulations of lymphocytes in patients with primary malignant brain tumors and secondary metastatic tumors, no statistically significant difference has been detected between these params. Glioblastomas show higher levels of СD4+- and CD8+-lymphocytes in comparison with other tumour groups as well as higher levels of IgG and IgA than in other tumors, while IgM concentration is almost at the same level in three groups of patients. There is a tendency for reducing IgG and IgM level in the blood of patients with metastatic tumors. Both groups of cancer patients under study show inhibition of myeloperoxidase activity of neutrophils in the setting of maintaining the function of NBT cell activity. Conclusions. According to the findings obtained via studying immunological indicators of brain tumors, both metastatic and primary malignant glial ones, there are partial changes in various immune system components such as cellular, humoral and phagocytic activity. However, no statistically significant difference was detected between immune status indicators, that substantiates the need for further study of this issue. At the stage of preparation for radiation therapy, no significant changes in the immune system of the patients with brain tumors, that would make such treatment impossible and be consiered as one of contraindications, are observed.

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Landa, Karenia, Eda Holl, Victoria Frazier, Eun-Sil Shelley Hwang y Smita Nair. "Understanding the peripheral cellular immunome in patients with breast cancer." Journal of Clinical Oncology 37, n.º 8_suppl (10 de marzo de 2019): 7. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.7.

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7 Background: Neoadjuvant chemotherapy (NAC) for breast cancer (BC) is being increasingly used in patients with stage I/II disease. Although previously reserved for patients with locally advanced disease, its use in patients with localized disease allows for higher rates of breast-conserving procedures and provides insight into tumor biology. A complete pathologic response (pCR) to NAC correlates with better clinical outcomes; sadly, many patients do not achieve pCR. The advent of immunotherapy has provided cancer patients with additional treatment options. To optimize immunotherapy in BC we must understand the peripheral cellular immunome (immune subsets and activation status) of patients as they undergo standard of care therapy (SOC). Methods: Our population includes patients with stages I-III BC undergoing SOC. Samples were collected pre- and post-NAC, post-surgery and at 2-month follow-up (FU). Results: Flow cytometry analysis for 11 patients was performed at each time-point to examine percentages of circulating immune cells (see Table). We grouped samples in 3 categories: human epidermal growth factor receptor 2 (HER2+) positive, HER2 negative (HER2-) and triple-negative (TN) tumors. 3 out of 11 patients had pCR (1 HER2+, 1 HER2-, 1 TN); they had highest percentage of circulating CD56+ NK cells during treatment course. Conclusions: We observed striking changes in the immunome of women with stage I-III BC undergoing NAC. Although our findings are preliminary, given our sample size, we observed distinct trends within each immune cell population in specific tumor receptor subtypes. These trends could serve to guide our therapies, allow for better patient selection and predict treatment response in patients. [Table: see text]

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Ferris, Robert L., Elizabeth M. Jaffee y Soldano Ferrone. "Tumor Antigen–Targeted, Monoclonal Antibody–Based Immunotherapy: Clinical Response, Cellular Immunity, and Immunoescape". Journal of Clinical Oncology 28, n.º 28 (1 de octubre de 2010): 4390–99. http://dx.doi.org/10.1200/jco.2009.27.6360.

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PurposeTumor antigen (TA) –targeted monoclonal antibodies (mAb), rituximab, trastuzumab, and cetuximab, are clinically effective for some advanced malignancies, especially in conjunction with chemotherapy and/or radiotherapy. However, these results are only seen in a subset (20% to 30%) of patients. We discuss the immunologic mechanism(s) underlying these clinical findings and their potential role in the variability in patients' clinical response.MethodsWe reviewed the evidence indicating that the effects of TA-targeted mAb-based immunotherapy are mediated not only by inhibition of signaling pathways, but also by cell-mediated cytotoxicity triggered by the infused TA-targeted mAb. We analyzed the immunologic variables that can influence the outcome of antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro and in animal model systems. We also analyzed the correlation reported between these variables and the clinical response to mAb-based immunotherapy.ResultsOf the variables that influence ADCC mediated by TA-targeted mAb, only polymorphisms of Fcγ receptors (FcγR) expressed by patients' lymphocytes were correlated with clinical efficacy. However, this correlation is not absolute and is not observed in all malignancies. Thus other variables may be responsible for the antitumor effects seen in mAb-treated patients. We discuss the evidence that triggering of TA-specific cellular immunity by TA-targeted mAb, in conjunction with immune escape mechanisms used by tumor cells, may contribute to the differential clinical responses to mAb-based immunotherapy.ConclusionIdentification of the mechanism(s) underlying the clinical response of patients with cancer treated with TA-targeted mAb is crucial to optimizing their application in the clinic and to selecting the patients most likely to benefit from their use.

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Yutani, Shigeru, Nobukazu Komatsu, Satoko Matsueda, Munehiro Yoshitomi, Takahisa Shirahama, Akira Yamada, Kyogo Itoh y Tetsuro Sasada. "Juzentaihoto Failed to Augment Antigen-Specific Immunity but Prevented Deterioration of Patients’ Conditions in Advanced Pancreatic Cancer under Personalized Peptide Vaccine". Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/981717.

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Juzentaihoto (JTT) is a well-known Japanese herbal medicine, which has been reported to modulate immune responses and enhance antitumor immunity in animal models. However, it is not clear whether JTT has similar effects on humans. In particular, there is little information on the effects of JTT in antigen-specific immunity in cancer patients. Here we conducted a randomized clinical study to investigate whether combined usage of JTT could affect antigen-specific immunity and clinical findings in advanced pancreatic cancer patients undergoing personalized peptide vaccination (PPV), in which HLA-matched vaccine antigens were selected based on the preexisting host immunity. Fifty-seven patients were randomly assigned to receive PPV with (n=28) or without (n=29) JTT. Unexpectedly, JTT did not significantly affect cellular or humoral immune responses specific to the vaccine antigens, which were determined by antigen-specific interferon-γsecretion in T cells and antigen-specific IgG titers in plasma, respectively. Nevertheless, JTT prevented deterioration of patients’ conditions, such as anemia, lymphopenia, hypoalbuminemia, plasma IL-6 elevation, and reduction of performance status, which are frequently observed in advanced cancers. To our knowledge, this is the first clinical study that examined the immunological and clinical effects of JTT in cancer patients undergoing immunotherapy in humans.

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Shehata, Mahmoud A. y Nagla Abdel Karim. "Influenza Vaccination in Cancer Patients Undergoing Systemic Therapy". Clinical Medicine Insights: Oncology 8 (enero de 2014): CMO.S13774. http://dx.doi.org/10.4137/cmo.s13774.

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Background Cancer patients often experience preventable infections, including influenza A and B. These infections can be a cause of significant morbidity and mortality. The increased risk of infection may be because of either cancer itself or treatment-induced immunosuppression. 1 Influenza immunization has been shown to decrease the risk of influenza infection in patients with intact immunity. 2 In cancer patients, active immunization has been shown to confer protective immunity against several infections at similar rates to healthy individuals, which has translated into decreased duration and severity of infection and potentially improved morbidity and mortality. 3 Objectives 1. To assess the efficacy of influenza vaccination in stimulating immunological response in patients with cancer during chemotherapy compared to control groups. 2. To assess the efficacy of influenza vaccination in preventing confirmed influenza and influenza-like illness and/or stimulating immunological response in children with cancer treated with chemotherapy, compared to placebo, no intervention, or different dosage schedules. 3. To determine the adverse effects associated with influenza vaccination in patients with cancer. Search Methods We searched MEDLINE/PubMed database for articles published from 1964 to 2013 using the search terms “cancer,” “adult,” “influenza vaccination,” and “chemotherapy.” Selection Criteria We included studies based on systematic sampling with defined clinical criteria irrespective of the vaccination status of cancer patients. Studies measure the serological response or clinical response to compare between the study group and the control group. Studies assessed the inactivated influenza vaccines and live attenuated influenza vaccine (LAIV) protective serological reaction and the clinical outcomes after vaccination. Data Collection and Analysis Two independent authors assessed the methodological quality of included studies and extracted data. Main Results We included 16 studies (total number of participants = 1,076). None of the included studies reported clinical outcomes. All included studies reported on influenza immunity and adverse reaction on vaccination. We included 6 solid tumor studies and 10 hematological studies. In 12 studies, the serological response to influenza vaccine was compared in patients receiving chemotherapy (n = 425) versus those not receiving chemotherapy (n = 376). In three studies, the serological responses to influenza vaccination in patients receiving chemotherapy are compared to that in healthy adult. Measures used to assess the serological responses included a four-fold rise increase in antibody titer development of hemagglutination inhibition (HI) titer >40, and pre- and post-vaccination geometric mean titers (GMTs). Immune responses in patients receiving chemotherapy were consistently weaker (four-fold rise of 17–52%) than in those who had completed chemotherapy (50–83%) and healthy patients (67–100%). Concerning adverse effects, oncology patients received influenza vaccine, and the side effects described were mild local reactions and low-grade fever. No life-threatening or persistent adverse effects were reported. Authors’ Conclusion Patients with solid and some of hematological tumors are able to mount a serological response to influenza vaccine, but it remains unclear how much this response protects them from influenza infection or its complications. Meanwhile, influenza vaccine appears to be safe in these patients. While waiting results of randomized controlled trials to give us more details about the clinical benefits of the influenza vaccination, the clinicians should consider the currently proved benefits of influenza vaccination on management of the cancer patients undergoing systematic chemotherapy such as decrease in the duration and severity of the of the disease, and significant decrease in influenza-associated morbidity and mortality in these high-risk patients. 3

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Palacka, Patrik, Michal Mego, Terezia Mikulova, Michal Chovanec, Katarina Kalavska, Daniela Svetlovska, Jana Obertova et al. "Systemic immune-inflammation index to predict survival in Caucasian patients with metastatic urothelial carcinoma." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): e16015-e16015. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e16015.

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e16015 Background: The systemic immune-inflammation index (SII) is a prognostic factor in various malignancies that probably reflects a state of immunity. The objective of this retrospective analysis was to explore prognostic value of the SII at baseline and at week 6 during first-line platinum-based chemotherapy in Caucasian population with metastatic urothelial cancer (MUC). Methods: We evaluated 185 consecutive MUC (152 bladder, 72 upper tract) patients (139 men) treated with first-line platinum-based chemotherapy at National Cancer Institute between 2000-2015. Median Karnofsky index was 90% (30–100%), visceral metastases were present in 86 patients. SII was based on platelets (P), neutrophils (N) and lymphocytes (L) counts defined as PxN/L. Progression-free survival (PFS), overall survival (OS) and their 95% CI were estimated by Kaplan-Meier method and compared with logrank test. The study population was dichotomized by median into high SII and low SII groups. Multivariate Cox regression analysis included Karnofski index, status of visceral metastases together with baseline SII and SII at week 6, respectively. Results: At median follow-up 10 months (1-139 months), 170 patients experienced disease progression and 168 of them died.Patients with low SII at baseline had significantly better PFS and OS opposite to those with high SII (HR = 0.62, 95% CI 0.45-0.84 for PFS and HR = 0.52, 95% CI 0.38-0.71 for OS, respectively). Similarly, patients with low SII at 6 weeks had significantly better PFS and OS compared to those with high SII (HR = 0.61, 95% CI 0.45-0.83 for PFS and HR = 0.54, 95% CI 0.40–0.74 for OS, respectively). Multivariate analysis confirmed independent prognostic value of baseline SII and SII at week 6 for PFS and OS. Conclusions: Both, the SII at baseline and at week 6 during treatment with first-line chemotherapy represent independent prognostic factors for Caucasian population with MUC. Based on SII, patients could be stratified into future clinical trials. MUC patients with high SII might be candidates for an experimental first-line treatment.

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Lai, Anne Y., Jessica A. Sorrentino, Konstantin H. Dragnev, Jared M. Weiss, Taofeek K. Owonikoko, Julie A. Rytlewski, Jill Hood et al. "CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy". Journal for ImmunoTherapy of Cancer 8, n.º 2 (octubre de 2020): e000847. http://dx.doi.org/10.1136/jitc-2020-000847.

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BackgroundCombination treatment with chemotherapy and immune checkpoint inhibitors (ICIs) has demonstrated meaningful clinical benefit to patients. However, chemotherapy-induced damage to the immune system can potentially diminish the efficacy of chemotherapy/ICI combinations. Trilaciclib, a highly potent, selective and reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in development to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy, has demonstrated proof of concept in recent clinical trials. Furthermore, CDK4/6 inhibition has been shown to augment T-cell activation and antitumor immunity in preclinical settings. Therefore, addition of trilaciclib has the potential to further enhance the efficacy of chemotherapy and ICI combinations.MethodsIn murine syngeneic tumor models, a schedule of 3 weekly doses of trilaciclib was combined with chemotherapy/ICI regimens to assess the effect of transient CDK4/6 inhibition on antitumor response and intratumor T-cell proliferation and function. Peripheral T-cell status was also analyzed in patients with small cell lung cancer (SCLC) treated with chemotherapy with or without trilaciclib to gain insights into the effect of transient exposure of trilaciclib on T-cell activation.ResultsPreclinically, the addition of trilaciclib to chemotherapy/ICI regimens enhanced antitumor response and overall survival compared with chemotherapy and ICI combinations alone. This effect is associated with the modulation of the proliferation and composition of T-cell subsets in the tumor microenvironment and increased effector function. Transient exposure of trilaciclib in patients with SCLC during chemotherapy treatment both preserved and increased peripheral lymphocyte counts and enhanced T-cell activation, suggesting that trilaciclib not only preserved but also enhanced immune system function.ConclusionsTransient CDK4/6 inhibition by trilaciclib was sufficient to enhance and prolong the duration of the antitumor response by chemotherapy/ICI combinations, suggesting a role for the transient cell cycle arrest of tumor immune infiltrates in remodeling the tumor microenvironment. These results provide a rationale for combining trilaciclib with chemotherapy/ICI regimens to improve antitumor efficacy in patients with cancer.

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Zlatnik, Elena Yurievna, Inna Arnoldovna Novikova, Andrey Vladimirovich Bakhtin, Olesya N. Selyutina, Galina I. Zakora, Yuriy N. Lazutin, Sergey P. Pyltsin et al. "Immune status parameters in lung cancer patients with various levels of circulating tumor cells." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): e20018-e20018. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20018.

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e20018 Background: The purpose of the study was to evaluate parameters of cellular immunity in lung cancer patients with various levels of circulating tumor cells (CTCs) and different tumor histogenesis. Methods: Blood samples of 28 patients (24 men, 4 women, mean age 62±1.3 years) were studied. 18 (64.3%) patients had neuroendocrine tumors (small cell lung cancer, SCLC), and 10 (35.7%) patients had adenocarcinoma (AC). 11 (39.3%) patients were diagnosed with stage III disease and 17 (60.7%) – stage IV. CTCs were detected in the blood before treatment using the CellSearch System (Janssen Diagnostics, LLC) with iron microparticles coated with antibodies to EpCAM, CD45 and cytokeratins 8, 18 and 19; subsets of lymphocytes, including minor ones, were studied on FACSCantoII flow cytometer (BD). Results: CTCs were found in 25 patients (89.3%); their number ranged 1-6888. 15 (83.3%) patients with SCLC had 0-6888 CTCs, with an average of 655.7, median 38.5. All 10 patients with AC had 1-486 CTCs, with an average of 57.2, median 5.0. The number of CTCs in CTC-positive patients with SCLC was, despite high individual variability, significantly higher than in patients with AC (786.9±474 vs. 57.2±47.9, respectively; p < 0.05). Such differences were accompanied by higher levels of Th-lymphocytes with activation/apoptosis markers (CD3+CD4+CD95+): 84.2±2.7 vs. 72.2±3.7%, and cytotoxic CD16bright/56dim NKcells: 91.4±1.8 vs. 83.4±3.7%. Patients with CTC+ AC had higher levels of IFNγ-producing NK-cells, compared to SCLC patients (15.3±3.8 vs. 7.2±1.6%), as well as levels of Th with the early activation marker (CD4+CD38+) (27.8±3.5 vs. 17.4±2.3%). Presence of CTCs in SCLC patients was associated with lower levels of activated lymphocytes of various subsets: T-cells (CD4+CD38+, CD8+CD38+, CD3+CD8+HLA-DR+) and NК-cells (Granzyme B+ and CD335+). Conclusions: Levels of CTCs were significantly higher in patients with SCLC than in those with AC; immune status parameters had a number of differences in CTC+ tumors with various histogenesis. The presence of CTCs in SCLC was accompanied by reduced blood levels of activated T- and NK-cells. The reported study was partially supported by RFBR, research project No. 16-34-00244mol_a

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Kit, Oleg Ivanovich, Aleksandr V. Snezhko, Elena Yu Zlatnik, Inna A. Novikova, Nabil Al-haj, Elena S. Bondarenko y Liubov Yu Vladimirova. "Factors of local immunity in patients with rectal cancer after prolonged radiotherapy." Journal of Clinical Oncology 37, n.º 15_suppl (20 de mayo de 2019): e15164-e15164. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15164.

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e15164 Background: Immunological study of the blood and tumor tissues was performed in patients with rectal cancer receiving neoadjuvant chemoradiotherapy. Methods: 30 patients with rectal cancer (13 women and 17 men aged 37-68 years with stage II-III adenocarcinomas G1-G3) were divided into groups according to results of DNA cytometry and their response to neoadjuvant treatment. When tumor proliferative activity was stable for 4 weeks of treatment, patients received surgery on time (group 1), while patients with verified inhibition of tumor proliferation (the index decrease by 1.5 times and more) continued treatment for 6-8 weeks and then were operated on (group 2). The immune status of patients (T, B, NK, DN, Tregs) was assessed during treatment. Homogenates of tumor tissue samples obtained during surgery were studied for the levels of lymphocytes (flow cytometry) and cytokines TNF-α, IL-1ß, IL-1RA, IL-6, IL-8, IFN-α, IFN-γ (ELISA); tumor proliferation index was assessed by DNA cytometry. Results were analyzed by Statistica 10.0 program. Results: The dynamics of parameters of the cellular immunity was different in patients of two groups. In group 1, percentage of T lymphocytes in blood decreased (from 66.7±3.3 to 50.4±1.6%), as well as their main subsets (CD4+ and CD8+ cells: from 33.6±2.7 to 27.0±1.7% and from 26.7±2.4 to 20.7±1.7% respectively). Patients of group 2 developed an increase in levels of NK cells from 10.1±1.2 to 15.3±2.2%, and levels of CD3+, CD4+ and CD8+ cells were significantly higher than in group 1: 35.0±1.8% for CD4+ and 28.3±2.9% for CD8+ (p < 0.05). The groups also differed in indices of local immunity: DN cells levels in group 2 were lower than in group 1 (5.8±1.0 vs. 18.4±5.4%) and CD4+ were higher (36.6±3.3 vs. 26.2±3.1%; p < 0.05). Patients of group 2 showed lower levels of IL-1ß, IL-6, IL-10, while IFNγ was elevated by 5.4 times, indicating a more favorable local cytokine status of the patients, compared to group 1. Conclusions: In rectal cancer patients with effect confirmed by DNA cytometry, prolongation of chemoradiotherapy to 6-8 weeks provides the formation of a more favorable immunological microenvironment of the tumor, and in such cases it is considered appropriate.

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Sitkovskaya, Anastasia O., Oleg I. Kit, Elena Yu Zlatnik, Inna A. Novikova, Aleksandr B. Sagakyants, Elena P. Ulianova, Oksana G. Shulgina et al. "Presence of circulating tumor cells is more significant than tumor stage in characterizing cellular local immunity in colorectal cancer." Journal of Clinical Oncology 38, n.º 15_suppl (20 de mayo de 2020): e16073-e16073. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16073.

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e16073 Background: The purpose of the study was a correlation analysis of parameters of local immunity and markers of the epithelial-mesenchymal transition (EMT) with the number of circulating tumor cells (CTCs) in patients with stage II-IV colorectal cancer (CRC). Methods: The study included 60 patients newly diagnosed with stage II-IV CRC. CTCs were detected with the Cell Search System (Janssen Diagnostics, LLC) prior to surgery. CTC≤3 were considered negative, CTC > 3 – positive. After surgery, IHC analysis of tumor infiltration with immune system cells was performed with monoclonal antibodies for human CD3, CD4, CD8, CD20 and CD56; expression of EMT-associated proteins (E-cadherin, N-cadherin) was measured. All patients were informed of the goal of the study and provided informed consent. Results: CTC-negative patients with later cancer stages showed the loss of connection between the local levels of CD4+ and CD8+, and in stage IV - between CD3+ and CD4+. Starting from stage III, a negative correlation was observed between the expressions of E- and N-cadherin, not associated with the studied indices of local cellular immunity. The presence of CTCs in all 3 investigated stages of CRC, apparently, causes the loss of many connections between the indicators of the 3 units of local cellular immunity. While negative correlations were revealed between T-, B- and NK-cells in CTC-negative status, in CTC+ their number decreased to 1. An important positive correlation was between local levels of CD3+ and CD8+, indicating the predominance of cytotoxic T cells in the tumor and detected at all stages in CTC-negative patients, losing significance in the presence of CTCs regardless of the stage. In stage II, the only correlation (inverse one) was observed between the parameters of local (CD4+) immunity and the expression of cadherins (E-cadherin), which probably reflected the presence of immunosuppressive and growth-stimulating Tregs fraction among these cells. Conclusions: In general, the presence of CTCs was more significant for the number and nature of interconnections of cellular parameters of the local immunity than the tumor stage.

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Boopathi, Ettickan y Chellappagounder Thangavel. "Dark Side of Cancer Therapy: Cancer Treatment-Induced Cardiopulmonary Inflammation, Fibrosis, and Immune Modulation". International Journal of Molecular Sciences 22, n.º 18 (19 de septiembre de 2021): 10126. http://dx.doi.org/10.3390/ijms221810126.

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Advancements in cancer therapy increased the cancer free survival rates and reduced the malignant related deaths. Therapeutic options for patients with thoracic cancers include surgical intervention and the application of chemotherapy with ionizing radiation. Despite these advances, cancer therapy-related cardiopulmonary dysfunction (CTRCPD) is one of the most undesirable side effects of cancer therapy and leads to limitations to cancer treatment. Chemoradiation therapy or immunotherapy promote acute and chronic cardiopulmonary damage by inducing reactive oxygen species, DNA damage, inflammation, fibrosis, deregulation of cellular immunity, cardiopulmonary failure, and non-malignant related deaths among cancer-free patients who received cancer therapy. CTRCPD is a complex entity with multiple factors involved in this pathogenesis. Although the mechanisms of cancer therapy-induced toxicities are multifactorial, damage to the cardiac and pulmonary tissue as well as subsequent fibrosis and organ failure seem to be the underlying events. The available biomarkers and treatment options are not sufficient and efficient to detect cancer therapy-induced early asymptomatic cell fate cardiopulmonary toxicity. Therefore, application of cutting-edge multi-omics technology, such us whole-exome sequencing, DNA methylation, whole-genome sequencing, metabolomics, protein mass spectrometry and single cell transcriptomics, and 10 X spatial genomics, are warranted to identify early and late toxicity, inflammation-induced carcinogenesis response biomarkers, and cancer relapse response biomarkers. In this review, we summarize the current state of knowledge on cancer therapy-induced cardiopulmonary complications and our current understanding of the pathological and molecular consequences of cancer therapy-induced cardiopulmonary fibrosis, inflammation, immune suppression, and tumor recurrence, and possible treatment options for cancer therapy-induced cardiopulmonary toxicity.

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Moore Dalal, Kimberly, Cristina R. Antonescu, Ronald P. DeMatteo y Robert G. Maki. "EBV-Associated Smooth Muscle Neoplasms: Solid Tumors Arising in the Presence of Immunosuppression and Autoimmune Diseases". Sarcoma 2008 (2008): 1–6. http://dx.doi.org/10.1155/2008/859407.

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Background. Epstein-Barr virus (EBV)-related smooth muscle neoplasms (SMNs) have been associated with immune dysregulation, most notably in patients who have undergone solid organ transplantation or in patients with HIV/AIDS.Objective. to report our experience with EBV-related neoplasms as well as describing the first EBV-related SMN in the setting of administration of glucocorticoids and the tumor necrosis factor inhibitor etanercept.Design. We have case reports, of minimum 3-year follow-up, 2002–2005.Setting. It was held in an academic and tertiary referral cancer center.Patients. Patients are with dysregulated immunity after solid organ transplantation, HIV/AIDS, or with psoriasis after treatment with etanercept.Interventions. There were discontinuation of etanercept, right hepatic trisegmentectomy, and chemotherapy.Measurements. We use survival as a measurement here.Results. Patients who were able to withstand reduction in immunosuppression survived. Surgical resection or chemotherapy was successful in delaying progression of disease.Limitations. There was a relatively short follow-up for these slow-growing neoplasms.Conclusion. EBV-related SMNs have variable aggressiveness. While chemotherapy may slow disease progression, resection and improving the host immune status provide the best opportunity for primary tumor control.

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van Gorkom, Gwendolyn N. Y., Eline L. Lookermans, Catharina H. M. J. Van Elssen y Gerard M. J. Bos. "The Effect of Vitamin C (Ascorbic Acid) in the Treatment of Patients with Cancer: A Systematic Review". Nutrients 11, n.º 5 (28 de abril de 2019): 977. http://dx.doi.org/10.3390/nu11050977.

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Many cancer patients on intensive chemotherapy lack vitamin C. Vitamin C stimulates the production and activation of immune cells, so perhaps supplementation could be used to improve the immunity in those patients. This review assesses the effectiveness and safety of vitamin C administration in cancer. The PubMed and EMBASE databases were searched and all study designs except for phase I studies, and case reports were included in this review. A total of 19 trials were included. In only 4 trials randomization was used to determine if patients received vitamin C or a placebo. The result of this review does not prove that there is a clinically relevant positive effect of vitamin C supplementation in cancer patients in general on the overall survival, clinical status, quality of life (QOL) and performance status (PS), since the quality of the studies published is low. Interventions and patient groups are very diverse, hence an effect in some patient groups is possible. There seems to be a better effect with intravenous than oral administration. Nevertheless, treatment with vitamin C is safe with minimal side effects. Thereby, we think it is safe to examine the effects of vitamin C on specific groups of patients in a randomized controlled setting.

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Castelli, Roberto, Riccardo Schiavon, Carlo Preti y Laurenzia Ferraris. "HIV-Related Lymphoproliferative Diseases in the Era of Combination Antiretroviral Therapy". Cardiovascular & Hematological Disorders-Drug Targets 20, n.º 3 (26 de noviembre de 2020): 175–80. http://dx.doi.org/10.2174/1871529x20666200415121009.

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HIV-positive patients have a 60- to 200-fold increased incidence of Non-Hodgkin Lymphomas (NHL) because of their impaired cellular immunity. Some NHL are considered Acquired Immunodeficiency Syndrome (AIDS) defining conditions. Diffuse large B-cell Lymphoma (DLBC) and Burkitt Lymphoma (BL) are the most commonly observed, whereas Primary Effusion Lymphoma (PEL), Central Nervous System Lymphomas (PCNSL), Plasmablastic Lymphoma (PBL) and classic Hodgkin Lymphoma (HL) are far less frequent. Multicentric Castleman disease (MCD) is an aggressive lymphoproliferative disorder highly prevalent in HIV-positive patients and strongly associated with HHV-8 virus infection. In the pre-Combination Antiretroviral Therapy (CART) era, patients with HIV-associated lymphoma had poor outcomes with median survival of 5 to 6 months. By improving the immunological status, CART extended the therapeutic options for HIV positive patients with lymphomas, allowing them to tolerate standard chemotherapies regimen with similar outcomes to those of the general population. The combination of CART and chemotherapy/ immuno-chemotherapy treatment has resulted in a remarkable prolongation of survival among HIVinfected patients with lymphomas. In this short communication, we briefly review the problems linked with the treatment of lymphoproliferative diseases in HIV patients. Combination Antiretroviral Therapy (CART) not only reduces HIV replication and restores the immunological status improving immune function of the HIV-related lymphomas patients but allows patients to deal with standard doses of chemotherapies. The association of CART and chemotherapy allowed to obtain better results in terms of overall survival and complete responses. In the setting of HIVassociated lymphomas, many issues remain open and their treatment is complicated by the patient’s immunocompromised status and the need to treat HIV concurrently.

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Sridhar, Srikala S. "Evolving Treatment of Advanced Urothelial Cancer". Journal of Oncology Practice 13, n.º 5 (mayo de 2017): 309–15. http://dx.doi.org/10.1200/jop.2017.022137.

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Urothelial cancer of the bladder is a smoking-related cancer and the fifth most common cancer in the United States. At presentation, up to 25% of patients will have muscle-invasive disease and, despite cystectomy or bladder-sparing trimodality approaches, will develop metastatic disease. Cisplatin-based combination chemotherapy regimens remain the standard of care in first-line metastatic disease. Although response rates to these regimens are high, they are rarely durable, and median overall survival is only 12 to 15 months. Treatment options following progression on cisplatin-based regimens or for patients unfit for cisplatin due to poor performance status, impaired renal function, or comorbidities have been quite limited. However, there is now a new class of drugs known as immune checkpoint inhibitors, which target the programmed cell death 1/programmed cell death-ligand 1 axis and promote antitumor immunity, that are showing both efficacy and tolerability. These drugs have now been approved for use in both cisplatin-treated and most recently cisplatin-unfit patients. Clinical trials are currently ongoing to determine how best to use these drugs and whether they should be used alone or in combination with other treatments. This review will discuss the current standard of care in the management of urothelial cancer and highlight recent trials of immunotherapy in this disease.

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Meng, Lingkai, Ling Ding, Yue Yu, Wang Li y Tao Huang. "JAK3 and TYK2 Serve as Prognostic Biomarkers and Are Associated with Immune Infiltration in Stomach Adenocarcinoma". BioMed Research International 2020 (19 de septiembre de 2020): 1–15. http://dx.doi.org/10.1155/2020/7973568.

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Background. Stomach adenocarcinoma (STAD) is one of the most common malignant tumors. The Janus kinases (JAKs) play a significant part in cellular biological process, inflammation, and immunity. The roles of JAKs in STAD are still not systematically described. Methods. A series of bioinformatics tools were used to clarify the role of JAKs in STAD. Results. JAK3/TYK2 levels were significantly increased in STAD during subgroup analyses based on gender, tumor grade, cancer stages, and nodal metastasis status. STAD patients with high levels of JAK3/TYK2 had poor overall survival, postprogression survival, and first progression. Immune infiltration revealed a significant correlation between JAK3/TYK2 expression and the abundance of immune cells as well as immune biomarker expression in STAD. JAK3/TYK2 was associated with the adaptive immune response, chemokine signaling pathway, and JAK-STAT signaling pathway. Conclusions. JAK3 and TYK2 serve as prognostic biomarkers and are associated with immune infiltration in STAD.

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Lin, Xuan, Longyun Ye, Xu Wang, Zhenyu Liao, Jia Dong, Ying Yang, Rulin Zhang et al. "Follicular Helper T Cells Remodel the Immune Microenvironment of Pancreatic Cancer via Secreting CXCL13 and IL-21". Cancers 13, n.º 15 (22 de julio de 2021): 3678. http://dx.doi.org/10.3390/cancers13153678.

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Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.

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Vishnu, Kaniyarakkal, Edakuneri Najna, Pottammal Ambili y Dinesh Kavitha. "#6: Varicella Outbreak Investigation in a Cancer Hospital". Journal of the Pediatric Infectious Diseases Society 10, Supplement_1 (1 de marzo de 2021): S23. http://dx.doi.org/10.1093/jpids/piaa170.074.

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Abstract Background Primary varicella infection is usually self-limited in immunocompetent hosts, whereas it can be quite severe in immunocompromised hosts. Atypical presentations of varicella in immunocompromised hosts can be diagnostically challenging, without laboratory testing. Varicella is an occupational hazard for susceptible healthcare providers (HCP). It assumes importance in infection prevention and control, due to the possibility of spread to other susceptible coworkers and patients. Methods This outbreak investigation report is from a 300-bed cancer care hospital in South India. A 62-year-old male patient with lymphoplasmacytic non-Hodgkin’s lymphoma was admitted on October 1 with features of bronchopneumonia and extensive skin lesions, 2 months after his last chemotherapy cycle. The patient was received in the emergency department (ED) and later shifted to the intensive care unit (ICU) due to worsening clinical condition. The clinical picture was more in favor of Stevens–Johnson syndrome, but oral acyclovir therapy was given considering a differential diagnosis of varicella. His condition deteriorated further requiring ventilator support and on the 19th day of admission, the patient succumbed to his illness and passed away. From October 14 to 19, eight HCP presented with vesicular eruptions and fever, clinically diagnosed as having varicella. This aroused the suspicion of an outbreak. An emergency outbreak control group meeting was convened to assess and address the situation. Results All outbreak cases were confirmed as varicella, clinically. Contacts, including patients assigned to HCP involved in the outbreak were traced, and their varicella immune status was assessed. Nonimmune contacts were given oral acyclovir prophylaxis as per CDC recommendations. Other HCP in the hospital were offered first dose of varicella vaccine based on their varicella immune status. With these infection prevention and control measures in place, no additional cases were identified. Being a hospital in low- to middle-income country, it was not routine practice to vaccinate susceptible HCP, after screening of varicella immune status at the time of recruitment. In the wake of the outbreak, assessment of immunity against varicella, and vaccination of susceptible HCP, is being followed up meticulously. Conclusion Varicella can present with atypical symptoms, especially in the immunocompromised host. Suspected cases should be isolated until sensitive PCR studies are done. Varicella immune status of HCP should be assessed at recruitment and vaccination should be offered to susceptible individuals. Implementation and infection prevention and control measures can help prevent and mitigate varicella outbreaks within healthcare facilities.

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Forde, Patrick M., Jamie E. Chaft, Enriqueta Felip, Stephen Broderick, Nicolas Girard, Mark M. Awad, Keith Kerr et al. "Checkmate 816: A phase 3, randomized, open-label trial of nivolumab plus ipilimumab vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): TPS8577. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps8577.

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TPS8577 Background: At initial diagnosis, 20% of patients (pts) with NSCLC present with early-stage disease. The 5-year overall survival (OS) rate after surgery for stage IB–IIIA NSCLC is 25%–60%. Addition of adjuvant chemotherapy to surgery only provides a 5% absolute OS benefit at 5 years. Neoadjuvant treatment with immune checkpoint inhibitors may extend OS in early-stage NSCLC by enhancing systemic immunity and eradicating micrometastatic disease. In contrast to the adjuvant setting, the neoadjuvant setting is associated with a higher tumor burden, the presence of abundant tumor antigens, and the consequent potential for tumor-associated neoantigen presentation to the immune system. In an ongoing feasibility trial in pts with stage IB–IIIA NSCLC, nivolumab (nivo; a fully human PD-1 immune checkpoint inhibitor antibody) given alone as neoadjuvant treatment induced a major pathological response (MPR; < 10% residual viable tumor cells) rate of 39% (7/18), did not delay or interfere with surgery, and was not associated with new safety signals. In a phase 1 study in pts with stage IIIB/IV NSCLC, first-line nivo + ipilimumab (ipi; a CTLA-4 immune checkpoint inhibitor antibody) showed a greater radiologic objective response rate than nivo alone (39% vs 23%). These data provided the rationale for Checkmate 816 (NCT02998528), a phase 3 study evaluating nivo + ipi vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC. Methods: Approximately 326 pts aged ≥18 years with resectable stage IB/II/IIIA NSCLC, ECOG performance status 0–1, pulmonary function capable of tolerating lung resection, and available lung tumor tissue will be enrolled in North America, South America, Europe, and Asia. Pts are ineligible if they have autoimmune disease or had received prior treatment with immune checkpoint inhibitors. Pts will be randomized to receive nivo + ipi or platinum-doublet chemotherapy. The primary endpoint is MPR rate. Secondary endpoints include event-free survival, OS, and complete pathological response. Start date is January 2017. The estimated primary completion date is July 2019. Clinical trial information: NCT02998528.

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Mellemgaard, Anders, Lotte engel-Norregaard, Mads Hald Andersen, Mai-Britt Zocca y inge Marie Svane. "Combination immunotherapy with IDO vaccine and PD-1 inhibitors in advanced NSCLC." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): TPS2610. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps2610.

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TPS2610 Background: Multible checkpoints regulate host immune response, and development has focused on three of these: IDO, CTLA-4 and PD-1. Presently, several checkpoint inhibitors have been approved for advanced NSCLC including nivolumab, pembrolizumab, and atezolizumab all targeting PD-1 and PD-L1. Depending on level of PD-L1 tumor expression, response rates vary, and a substantial proportion of patients do not respond to treatment with immune checkpoint inhibitors. The combination of checkpoint inhibitors have been shown in malignant melanoma and other tumor types to clearly increase the effect. IO102 is a synthetic peptide under development as an immune-modulatory agent targeting cells expressing indoleamine 2,3-dioxygenase (IDO). IDO potently inhibits T-cell immunity in patients with cancer. Treatment with IO102 in NSCLC patients after first line palliative chemotherapy lead to long PFS in a number of patients in a small single arm study. Methods: IO102-001 is a randomized, double-blinded Phase 2 trial to evaluate the safety and efficacy of IO102 in combination with anti-PD-1 mAb in locally advanced and/or metastatic NSCLC stage III-IV patients eligible for anti-PD-1 mAb 2nd line treatment after first line of chemotherapy. Patients are randomized (2:1) to either a PD-1 inhibitor + IO201 vaccine or a PD-1 inhibitor (SOC). The PD-1 inhibitor will be administered according to label while IO102 will be given as s.c. injection every 2 weeks for the first 12 weeks, and subsequently every 4 weeks for 12 months or until progression, death or withdrawal from trial, whichever comes first. Treatment is continued to progression, unacceptable toxicity or withdrawal of consent. Main inclusion criteria is patients diagnosed with locally advanced and/or metastatic NSCLC Stage III-IV, measurable disease according to RECIST (1.1), patients eligible for anti PD-1 mAb treatment after 1st line of chemotherapy , ECOG performance status 0 or 1 and available tumor tissue for further analysis. A total of 90 patients will be included in the trial, and the trial will be active in countries in Europe and the US from Q2 2017.

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40

Sun, Dao-Ping, Wen-Ming Chen, Li Wang, Zhen Wang, Jin-Hua Liang, Hua-Yuan Zhu, Lei Fan, Yu-Jie Wu, Wei Xu y Jian-Yong Li. "Clinical characteristics and immunological abnormalities of Castleman disease complicated with autoimmune diseases". Journal of Cancer Research and Clinical Oncology 147, n.º 7 (5 de febrero de 2021): 2107–15. http://dx.doi.org/10.1007/s00432-020-03494-2.

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Abstract Purpose To explore the clinical features and immunological mechanisms of Castleman disease (CD) complicated with autoimmune diseases (AID). Methods We explored the prevalence and clinical manifestations of CD complicated with AID by reviewing clinical, pathological, and laboratory data of 40 CD patients retrospectively, and then explored abnormal immune mechanisms in the co-existence of the two entities by monitoring lymphocyte subsets in peripheral blood. Results Paraneoplastic pemphigus, autoimmune hemolytic anemia, Sjogren’s syndrome, myasthenia gravis, and psoriasis were found to be coexisted with CD in 9/40 (22.5%) patients with different sequence of onset. No bias in the clinical and histological type of CD was observed for the occurrence of AID. CD patients with AID were more likely to have skin and/or mucous membrane damage and pulmonary complications, and presented elevated erythrocyte sedimentation rate, hypergammaglobulinemia, and positive autoantibodies than those without AID (p < 0.05). Deregulated cellular and innate immune responses as indicated by decreased CD3+ T cells and increased natural killer cells were observed in peripheral blood of CD patients with AID (p < 0.05). UCD patients with AID were successfully treated with surgery and immunosuppressive therapy. MCD complicated by AID relieved with immunosuppressors, cytotoxic chemotherapy, and rituximab. Conclusion Systemic inflammation/immunological abnormalities and organ dysfunction were associated with the occurrence of AID in CD. Impairment of cellular and innate immunity may be a candidate etiology for the coexistence of the two entities.

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Liang, Raymond, George K. K. Lau y Y. L. Kwong. "Chemotherapy and Bone Marrow Transplantation for Cancer Patients Who Are Also Chronic Hepatitis B Carriers: A Review of the Problem". Journal of Clinical Oncology 17, n.º 1 (enero de 1999): 394. http://dx.doi.org/10.1200/jco.1999.17.1.394.

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In places where hepatitis B virus (HBV) infection is endemic, itis often necessary to give chemotherapy to or perform bone marrowtransplantation for cancer patients who are also chronic HBV carriers.When standard chemotherapy was given to lymphoma patients, elevation ofliver transaminases was observed in nearly half of those who werechronic HBV carriers. Ten percent of them became jaundiced, and theoverall liver-related mortality was about 5%. There is currently noreliable way to predict the severity of HBV reactivation afterchemotherapy. The risk is probably higher when the chemotherapy used issignificantly immunosuppressive and the viral load in the liver ishigh. Different strategies have been used in an attempt to reduce therisk of HBV reactivation after chemotherapy, but they have not beenvery successful. Further studies will be required to determine theimpact of newly available antiviral agents that are active against HBV. Recipients who are carriers of HBV or who receive hepatitis B surfaceantigen (HBsAg)-positive marrow are at increased risk of hepatitisB-related morbidity and mortality after bone marrow transplantation(BMT). There is evidence to suggest that prophylactic use of an activeantiviral agent, such as famciclovir, may result in a significantdecrease in the incidence and severity of HBV reactivation after BMT.Sustained serologic clearance of chronic HBV infection has also beenreported in many HBsAg-positive marrow recipients receiving hepatitis Bsurface antibody-positive marrow from their allogeneic donors. Thereseems to be a transfer of both humoral and cellular immunity againstHBV from donors to recipients. Further prospective studies are required to define the best approach tomanage HBsAg-positive cancer patients receiving chemotherapy or BMT. Itis recommended that all cancer patients be checked for their hepatitisB status before receiving chemotherapy or a bone marrow transplant,especially if they reside in or come from endemic areas of HBVinfection.

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Prokopi, N., M. Heeren, I. Milenova, K. van Pul, T. Muijlwijk, M. Arends, S. van der Velde et al. "P09.02 Mapping and tackling tumor and chemotherapy-induced immune suppression in breast cancer sentinel lymph nodes". Journal for ImmunoTherapy of Cancer 8, Suppl 2 (octubre de 2020): A52—A53. http://dx.doi.org/10.1136/jitc-2020-itoc7.102.

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BackgroundBreast cancer (BrC) is the most prevalent cancer in women worldwide. Unfortunately, still limited treatment options are available for the most aggressive subtypes (i.e. hormone receptor [HR] negative). The response to neoadjuvant chemotherapy (NACT) in patients with HR-negative BrC can in part be influenced by an effective anti-tumor immune response. The sentinel lymph node (SLN) is the first site where BrC-specific T cell priming will occur but unfortunately it is also a major target of BrC-induced immune suppression. Lymph-node resident dendritic cells (LNR-DC) were found to be suppressed in metastatic SLN.1 In addition, this tumor-mediated immune suppression of LNR-DC is related to high-risk triple-negative BrC and may be a negative predictor for prognosis1. Preliminary data showed that NACT further reduced the activation status of LNR-DC. The goal of this study is to identify immune-enhancing agents that can counteract the tumor-mediated immune suppression of LNR-DC and promote tumor-specific T cell responses in order to improve therapy outcome in BrC patients upon NACT.Materials and MethodsPhenotypic analyses were performed on immune-cell subsets in human BrC SLN using multi-color flow cytometry. In addition, ex-vivo cultures with human BrC SLN-derived cells and in vivo mouse experiments were performed to study the therapeutic efficacy of Toll-like receptor (TLR)-ligands (R848 and CpG) and a STING-ligand (STING-L; 2’3’-c-di-AM(PS)2(Rp,Rp)).ResultsHigher rates of LNR-DCs, but with an apparently reduced activation state, were found in SLN of NACT-treated patients compared to patients treated with surgery only. A comparative ex-vivo study with SLN cultures on the effects of R848, CpG-B and STING-L showed R848 to be superior in terms of LNR-DC activation. In a Krt14 (K14)-cre;Cdh1F/F;Trp53F/F (KEP) BrC mouse model, the effects of intratumoral administration of TLR- and STING-L were determined in combination with doxorubicin. STING-L outperformed R848 and CpG-B in terms of controlling primary tumor growth. Of note, in human ex-vivo cultures CpG-B proved effective in LNR-DC activation when combined with a STAT3 inhibitor, leading to the boosting of mammaglobin-specific T cell responses, Th1 skewing, and a drop in CpG-induced Treg levels.ConclusionsIn summary, intratumoral delivery of TLR- and STING-ligands in combination with NACT might be an interesting therapeutic approach in patients with high-risk HR-negative BrC, leading to SLN potentiation and enhanced antitumor T cell immunity. Future clinical studies should demonstrate the therapeutic benefit of this approach.Referencevan Pul, et al. 2019, Journal for ImmunoTherapy of Cancer.Disclosure InformationN. Prokopi: None. M. Heeren: None. I. Milenova: None. K. van Pul: None. T. Muijlwijk: None. M. Arends: None. S. van der Velde: None. K. Vrijland: None. A. van Weverwijk: None. K. de Visser: None. R. van de Ven: None. T. de Gruijl: None.

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Zerdes, Wallerius, Sifakis, Wallmann, Betts, Bartish, Tsesmetzis et al. "STAT3 Activity Promotes Programmed-Death Ligand 1 Expression and Suppresses Immune Responses in Breast Cancer". Cancers 11, n.º 10 (1 de octubre de 2019): 1479. http://dx.doi.org/10.3390/cancers11101479.

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Signal transducer and activator of transcription 3 (STAT3) is an oncogene and multifaceted transcription factor involved in multiple cellular functions. Its role in modifying anti-tumor immunity has been recently recognized. In this study, the biologic effects of STAT3 on immune checkpoint expression and anti-tumor responses were investigated in breast cancer (BC). A transcriptional signature of phosphorylated STAT3 was positively correlated with PD-L1 expression in two independent cohorts of early BC. Pharmacologic inhibition and gene silencing of STAT3 led to decreased Programmed Death Ligand 1 (PD-L1) expression levels in vitro, and resulted as well in reduction of tumor growth and decreased metastatic dissemination in a mammary carcinoma mouse model. The hampering of tumor progression was correlated to an anti-tumoral macrophage phenotype and accumulation of natural-killer cells, but also in reduced accrual of cytotoxic lymphocytes. In human BC, pro-tumoral macrophages correlated to PD-L1 expression, proliferation status and higher grade of malignancy, indicating a subset of patients with immunosuppressive properties. In conclusion, this study provides evidence for STAT3-mediated regulation of PD-L1 and modulation of immune microenvironment in BC.

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Xu, Huilin, Zhucheng Yin, Anbing He y Dedong Cao. "The Impact of Javanica Oil Emulsion Injection on Chemotherapy Efficacy and Cellular Immune Indicators in Patients with Advanced NSCLC: A Systematic Review and Meta-Analysis". Evidence-Based Complementary and Alternative Medicine 2019 (22 de octubre de 2019): 1–12. http://dx.doi.org/10.1155/2019/7560269.

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Background. This meta-analysis aimed to evaluate the efficacy and safety of Javanica oil emulsion injection (JOI) combined with chemotherapy versus chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Methods. Electronic databases including EMBASE, PUBMED, the Cochrane library, and Chinese Biological Medical disc (CBM) were searched until May 2018. The clinical trials reporting efficacy and immune function of JOI combined with chemotherapy versus chemotherapy in advanced NSCLC were included according to the inclusion and exclusion criteria. Stata 11 and RevMan 5.3 were used for meta-analysis. Results. Twenty-four studies involving 2089 cases were included. The results of the meta-analysis showed that there were significant differences in objective response rate (risk ratio (RR) = 1.17; 95% confidence interval (CI): 1.05–1.29; P<0.05), improvement in Karnofsky Performance Status (standard mean difference (SMD) = 1.59; 95% CI: 1.41–1.77; P<0.01), incidence of adverse events (RR = 0.78; 95% CI: 0.7–0.87; P<0.05), percentage changes of CD3+ cells (SMD = 2.0; 95% CI: 1.49–2.50; P<0.01), CD4+ cells (SMD = 1.55; 95% CI, 1.2–1.9; P<0.01), natural killer cells (SMD = 1.98; 95% CI: 1.15–2.82; P<0.01), but not CD8+ (SMD = −1.44; 95% CI: −4.53–1.65; P=0.36), and value of CD4+/CD8+ (SMD = 0.32; 95% CI: 0.28–0.36; P<0.01) between the JOI combination group and control group. Funnel plot and Begg’s and Egger’s analysis indicated that there was no significant publication bias (P>0.05). Conclusions. JOI may be effective to improve the efficacy of chemotherapy in advanced NSCLC patients, accompanied with better levels of immune cells.

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Crosby, Erika J., Amy C. Hobeika, Donna Niedzwiecki, Christel Rushing, David Hsu, Peter Berglund, Jonathan Smith et al. "Long-term survival of patients with stage III colon cancer treated with VRP-CEA(6D), an alphavirus vector that increases the CD8+ effector memory T cell to Treg ratio". Journal for ImmunoTherapy of Cancer 8, n.º 2 (noviembre de 2020): e001662. http://dx.doi.org/10.1136/jitc-2020-001662.

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BackgroundThere remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer.MethodsOS was monitored for patients with stage IV cancer treated in a phase I study of virus-like replicon particle (VRP)-carcinoembryonic antigen (CEA), an alphaviral replicon particle encoding a modified CEA. An expansion cohort of patients (n=12) with resected stage III colorectal cancer who had completed their standard postoperative adjuvant chemotherapy was administered VRP-CEA every 3 weeks for a total of 4 immunizations. OS and relapse-free survival (RFS) were determined, as well as preimmunization and postimmunization cellular and humoral immunity.ResultsAmong the patients with stage IV cancer, median follow-up was 10.9 years and 5-year survival was 17%, (95% CI 6% to 33%). Among the patients with stage III cancer, the 5-year RFS was 75%, (95%CI 40% to 91%); no deaths were observed. At a median follow-up of 5.8 years (range: 3.9–7.0 years) all patients were still alive. All patients demonstrated CEA-specific humoral immunity. Patients with stage III cancer had an increase in CD8 +TEM (in 10/12) and decrease in FOXP3 +Tregs (in 10/12) following vaccination. Further, CEA-specific, IFNγ-producing CD8+granzyme B+TCM cells were increased.ConclusionsVRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. Long-term survivors were identified in both cohorts, suggesting the OS may be prolonged.

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Janjigian, Yelena Y., Eric Van Cutsem, Kei Muro, Zev A. Wainberg, Salah-Eddin Al-Batran, Woo Jin Hyung, Daniela Molena et al. "MATTERHORN: Efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer—A randomized, double-blind, placebo-controlled, phase 3 study." Journal of Clinical Oncology 39, n.º 15_suppl (20 de mayo de 2021): TPS4151. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps4151.

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TPS4151 Background: Gastric and gastroesophageal junction cancers (GC, GEJC) are the fifth most common cancer types and the third leading cause of cancer-related deaths globally (Globocan 2020). Standard of care for resectable GC/GEJC includes neoadjuvant-adjuvant FLOT chemotherapy (5-fluorouracil + leucovorin + oxaliplatin + docetaxel) combined with surgery and lymph node dissection for some regions of the world. While treatment advances have improved survival, the 5-year recurrence rate remains high and 5-year overall survival (OS) is poor for patients with resectable disease. Evidence suggests cytotoxic chemotherapy can promote antitumor immunity, thus the combination of immune checkpoint inhibitors, such as durvalumab (an anti–PD-L1 antibody), with cytotoxic chemotherapy may result in increased efficacy (Yu et al. Cancer Lett. 2019; Li et al. Mol Cancer. 2021). MATTERHORN (NCT04592913) is a phase 3, multicenter study evaluating the efficacy and safety of neoadjuvant-adjuvant durvalumab or placebo with FLOT followed by adjuvant durvalumab or placebo in patients with resectable GC/GEJC. Methods: Approximately 900 adult patients will be randomized 1:1 to Arm A or Arm B for 2 neoadjuvant and 2 adjuvant cycles (single cycle defined as durvalumab or placebo every 4 weeks [Q4W] + FLOT [Q2W × 2]); followed by durvalumab or placebo Q4W for 10 cycles. Eligible patients must have histologically confirmed, resectable, stage II or higher GC or GEJC not treated with anticancer therapy, ECOG performance status 0 or 1, and adequate organ function. Complete surgical resection of the primary tumor must be achievable. A tumor tissue sample will be taken at screening or <3 months prior to enrollment. Key exclusion criteria are any prior immune-mediated therapy, peritoneal dissemination or distant metastasis, (adeno)squamous cell carcinoma, or gastrointestinal stromal tumor. The primary endpoint is event-free survival (EFS) assessed by blinded independent central radiology review (BICR) and/or local pathology testing. Secondary endpoints include OS and pathological complete response rate (pCR). Safety and tolerability will be evaluated by adverse events, vital signs, laboratory parameters, and electrocardiogram. Enrollment is ongoing. Funding: AstraZeneca. Clinical trial information: NCT04592913.

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Colombo, Nicoletta, Maria Pilar Barretina-Ginesta, Philip James Beale, Kenichi Harano, Emma Hudson, Frederik Marmé, Christian Marth et al. "AtTEnd/ENGOT-en7: A multicenter phase III double-blind randomized controlled trial of atezolizumab in combination with paclitaxel and carboplatin in women with advanced/recurrent endometrial cancer." Journal of Clinical Oncology 37, n.º 15_suppl (20 de mayo de 2019): TPS5608. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps5608.

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TPS5608 Background: Prognosis of advanced/recurrent endometrial cancer (EC) is poor with median survival of 12-15 months for patients with measurable disease. Treatment options are limited, with primary management being chemotherapy with carboplatin and paclitaxel. EC is known to be one of the tumor types with highest mutational load. Ultra- and hyper-mutated EC, which harbor POLE and mismatch repair gene defects respectively, have shown peri-tumoral T cell infiltration and high expression of PD-1 and PD-L1 proteins, suggesting that immune regulation may enhance specific T cell responses and result in improved anti-tumour immunity. Preliminary data in EC patients have shown tumour control activity of the PD-L1 targeting agent atezolizumab. Methods: 550 patients with newly diagnosed, advanced stage III/IV or recurrent EC will be accrued during a period of 24 months with a 1:2 randomization ratio into two arms: i. control group receiving standard chemotherapy plus placebo IV every 21 days up to 6/8 cycles followed by placebo until progression; ii. experimental group receiving standard chemotherapy plus 1200 mg atezolizumab IV every 21 days up to 6/8 cycles followed by atezolizumab until progression. Standard chemotherapy will consist of 175 mg/m2 paclitaxel plus AUC5/6 carboplatin. Stratification factors are: histology, disease stage, microsatellite status, country of experimental site. The study is planned to demonstrate a survival increase and is equally powered for PFS. Secondary endpoints include ORR, duration of response, PFS2, quality of life, adverse events and compliance. The study is sponsored by MaNGO group and will involve sites from ENGOT and GCIG networks across Europe, Japan, Australia and New Zealand. Currently, the trial is open in Italy and in Switzerland where a total of 6 patients have been enrolled. Clinical trial information: NCT03603184.

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Wakelee, Heather A., Nasser K. Altorki, Eric Vallieres, Caicun Zhou, Yunxia Zuo, Michael Howland, Fan Xia, Alan Sandler y Enriqueta Felip. "A phase III trial to compare atezolizumab (atezo) vs best supportive care (BSC) following adjuvant chemotherapy in patients (pts) with completely resected NSCLC: IMpower010." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): TPS8576. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps8576.

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TPS8576 Background: The anti–PD-L1 mAb atezo blocks the interaction between PD-L1 and its receptors PD-1 and B7.1 and restores anti-tumor immunity. In the OAK trial, pts with 2L/3L advanced NSCLC had improved mOS in the atezo arm (13.8 mo) vs the docetaxel (doc) arm (9.6 mo), with a survival benefit observed regardless of PD-L1 expression levels on tumor cells (TC) or tumor-infiltrating immune cells (IC). However, more effective treatment options are needed for pts with early-stage NSCLC. A global Phase III, randomized, open-label trial, IMpower010 (NCT02486718), is being conducted to evaluate the efficacy and safety of atezo vs BSC following adjuvant cisplatin (cis)–based chemotherapy (chemo) in pts with resected stage IB (tumors ≥ 4 cm)-IIIA NSCLC. Methods: Pts eligible for study must have complete tumor resection 4 to 12 weeks prior to enrollment for pathologic stage IB (tumors ≥ 4 cm)-IIIA NSCLC, be adequately recovered from surgery, be able to receive cis-based adjuvant chemo and have an ECOG PS 0-1. Pts with other malignancies, autoimmune disease, hormonal cancer or radiation therapy within 5 years and prior chemo or immunotherapy are excluded from study. Approximately 1127 pts will be enrolled regardless of PD-L1 status. Pts will receive up to four 21-d cycles of cis-based chemo (cis [75 mg/m2 IV, d 1] + vinorelbine [30 mg/m2 IV, d 1, 8], doc [75 mg/m2 IV, d 1] or gemcitabine [1250 mg/m2 IV, d 1, 8], or pemetrexed [500 mg/m2 IV, d 1; only non-squamous NSCLC]). No adjuvant radiation therapy is permitted. After adjuvant chemo, eligible pts will be randomized 1:1 to receive 16 cycles of atezo 1200 mg q3w or BSC. Stratification factors include sex, histology (squamous vs non-squamous), disease stage (IB vs II vs IIA) and PD-L1 status by IHC (TC2/3 [≥ 5% expressing PD-L1] and any IC vs TC0/1 [ < 5%] and IC2/3 vs TC0/1 and IC0/1 [ < 5%]). The primary endpoint is disease-free survival; secondary endpoints include OS and safety. Exploratory biomarkers, including PD-L1 expression, immune- and tumor-related biomarkers before, during and after treatment with atezo and at radiographic disease recurrence, or confirmation of new primary NSCLC, will be evaluated. Clinical trial information: NCT02486718.

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Gonda, Kenji, Masahiko Shibata, Takashi Yazawa, Rei Yashima, Takashi Kimura, Akira Kenjo, Izumi Nakamura et al. "Correlation of production of IL-17 with immune suppression relating myeloid-derived suppressor cells (MDSC) and nutritional damages in patients with digestive system cancer." Journal of Clinical Oncology 31, n.º 4_suppl (1 de febrero de 2013): 437. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.437.

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437 Background: Although a causal relationship between inflammation and innate immunity of cancer is more widely accepted today, many of the precise cellular mechanisms mediating this relationship remain unclear. Th17 cells, which produce the proinflammatory cytokine IL-17, have been recognized as one of the key factors in regulation of inflammatory bowel disease and rheumatoid arthritis. Methods: This study demonstrated that, in patients with digestive system cancers including 7 patients with esophageal, 14 with gastric, 20 with colorectal, 5 with hepatocellular, 7 with cholangiocellular, and 7 with pancreatic carcinomas, IL-17 production was correlated with MDSC level and with markers for nutritional impairment, immune suppression and chronic inflammation. Results: IL-17 production was significantly higher in patients with all types of digestive cancer than in normal volunteers. In addition, IL-17 production levels were significantly correlated with neutrophil counts and the neutrophil/lymphocyte ratio, and significantly inversely correlated with cell mediated immune response indicators (lymphocyte PHA-blastogenesis and IL-12 production) and patients’ nutritional status (prealbumin levels). Circulating MDSC levels were significantly correlated with IL-17 production. Conclusions: These results suggest that, in human gastrointestinal cancers, chronic inflammation involving IL-17 may be an important mechanism for disease progression through enhancement of immune suppression or cachexia. Controlling activation of Th17 cells may prove to be a valuable strategy for treatment of patients with gastrointestinal cancer.

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Velleuer, Eunike y Carsten Carlberg. "Impact of Epigenetics on Complications of Fanconi Anemia: The Role of Vitamin D-Modulated Immunity". Nutrients 12, n.º 5 (9 de mayo de 2020): 1355. http://dx.doi.org/10.3390/nu12051355.

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Fanconi anemia (FA) is a rare disorder with the clinical characteristics of (i) specific malformations at birth, (ii) progressive bone marrow failure already during early childhood and (iii) dramatically increased risk of developing cancer in early age, such as acute myeloid leukemia and squamous cell carcinoma. Patients with FA show DNA fragility due to a defect in the DNA repair machinery based on predominately recessive mutations in 23 genes. Interestingly, patients originating from the same family and sharing an identical mutation, frequently show significant differences in their clinical presentation. This implies that epigenetics plays an important role in the manifestation of the disease. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 controls cellular growth, differentiation and apoptosis via the modulation of the immune system. The nuclear hormone activates the transcription factor vitamin D receptor that affects, via fine-tuning of the epigenome, the transcription of >1000 human genes. In this review, we discuss that changes in the epigenome, in particular in immune cells, may be central for the clinical manifestation of FA. These epigenetic changes can be modulated by vitamin D suggesting that the individual FA patient’s vitamin D status and responsiveness are of critical importance for disease progression.

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