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1
Jauro, Solomon, Erica C. Larson, Pauline Maiello, et al. "Evaluation of the time needed for BCG to be alive to protect against tuberculosis in intravenously BCG vaccinated SIV+ macaques." Journal of Immunology 210, no. 1_Supplement (2023): 141.20. http://dx.doi.org/10.4049/jimmunol.210.supp.141.20.
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Abstract Effective means of improving Bacille Calmette-Guérin (BCG) immunogenicity to protect against pulmonary tuberculosis (TB) is needed, especially among people living with HIV. Intravenous (IV) administration of BCG previously showed significant enhancement of immune responses and conferred ~75% protection against TB. Using our SIV/M. tuberculosis (Mtb) coinfection model (to mimic HIV/Mtb coinfection) in Mauritius cynomolgus macaques (MCM), we evaluated the length of time necessary for live BCG to elicit a protective immune responses by varying the timing of anti-BCG drug (isoniazid, rifampicin, and ethambutol: HRE) initiation. MCM were infected with SIVmac239 and randomly assigned into 4 different vaccination groups 16 weeks after SIV infection: intradermal BCG (BCG ID No HRE), BCG IV with HRE started 1 week post BCG (BCG IV 1wk HRE), BCG IV with HRE started 3 weeks post BCG (BCG IV 3wks HRE), and BCG IV without HRE treatment (BCG IV No HRE). The HRE treatment lasted for 8 weeks. Airways samples were collected by bronchoalveolar lavage (BAL), whereas lung tissue and lymph node were harvested at necropsy in a subset of BCG ID and BCG IV 3wks vaccinated MCM 20 weeks after BCG but before (Mtb) challenge. The remaining MCM were challenged with Mtb Erdman strain (~15 CFU). CD4 and CD8 T cell levels increased in BAL in all IV vaccinated MCM. CD4 T cells producing IFNg, IL-2, IL-17, and TNF peaked after BCG and were maintained until necropsy. There were increased tissue-resident T cells and cytokine production in lungs of IV vaccinated MCM compared to BCG ID. No signs of BCG dissemination were apparent in any IV vaccinated MCM. We are currently evaluating protection against infection and disease in the SIV+ MCM in each vaccination group. Supported by grant NIH (R01 AI155345)
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Lehman, Chelsea C., Hannah A. King, Supriya Pokkali, et al. "Repetitive vaccination with intravenous BCG is safe and immunogenic in naïve and SIV-infected macaques." Journal of Immunology 210, no. 1_Supplement (2023): 141.16. http://dx.doi.org/10.4049/jimmunol.210.supp.141.16.
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Abstract Tuberculosis (TB) is the leading cause of death in people with HIV (PWH) on or off antiretroviral therapy (ART); thus, new TB vaccine candidates should be evaluated in the setting of HIV. Mycobacterium bovis Bacillus Calmette-Guerin (BCG), the live attenuated bacterial TB vaccine given intradermally (ID) at birth, is contraindicated in PWH. We recently demonstrated that intravenous (IV) delivery of BCG elicits superior immunity and protection compared to ID delivery against Mycobacterium tuberculosis (Mtb) challenge in rhesus macaques. To assess IV BCG in an animal model of HIV infection, we immunized SIVmac251-infected macaques on suppresive ART (6m) and uninfected controls. Rhesus macaques received three doses of IV BCG, 8wks apart, and were monitored for the presence of BCG colony forming units (CFU) in peripheral blood and bronchoalveolar lavage (BAL) and Mtb-specific T cell responses in BAL. Repetitive IV BCG immunization was well-tolerated in SIV-infected and uninfected animals, with no difference in clinical parameters or BCG CFU in blood or BAL. T cell responses after IV BCG were similar, with both groups displaying a 10–50 fold increase in BAL T cell abundance after initial dose. Mtb-specific CD4 and CD8 responses peaked after the initial IV BCG dose and were maintained by subsequent immunizations for at least 6m. These data indicate that IV BCG is safe and immunogenic in SIV-infected, ART-suppressed macaques and that IV BCG boosting maintains T cell responses at the site of infection. NIH Intramural Program
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Morrison, Alexandra L., Charlotte Sarfas, Laura Sibley та ін. "IV BCG Vaccination and Aerosol BCG Revaccination Induce Mycobacteria-Responsive γδ T Cells Associated with Protective Efficacy against M. tb Challenge". Vaccines 11, № 10 (2023): 1604. http://dx.doi.org/10.3390/vaccines11101604.
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Intravenously (IV) delivered BCG provides superior tuberculosis (TB) protection compared with the intradermal (ID) route in non-human primates (NHPs). We examined how γδ T cell responses changed in vivo after IV BCG vaccination of NHPs, and whether these correlated with protection against aerosol M. tuberculosis challenge. In the circulation, Vδ2 T cell populations expanded after IV BCG vaccination, from a median of 1.5% (range: 0.8–2.3) of the CD3+ population at baseline, to 5.3% (range: 1.4–29.5) 4 weeks after M. tb, and were associated with TB protection. This protection was related to effector and central memory profiles; homing markers; and production of IFN-γ, TNF-α and granulysin. In comparison, Vδ2 cells did not expand after ID BCG, but underwent phenotypic and functional changes. When Vδ2 responses in bronchoalveolar lavage (BAL) samples were compared between routes, IV BCG vaccination resulted in highly functional mucosal Vδ2 cells, whereas ID BCG did not. We sought to explore whether an aerosol BCG boost following ID BCG vaccination could induce a γδ profile comparable to that induced with IV BCG. We found evidence that the aerosol BCG boost induced significant changes in the Vδ2 phenotype and function in cells isolated from the BAL. These results indicate that Vδ2 population frequency, activation and function are characteristic features of responses induced with IV BCG, and the translation of responses from the circulation to the site of infection could be a limiting factor in the response induced following ID BCG. An aerosol boost was able to localise activated Vδ2 populations at the mucosal surfaces of the lung. This vaccine strategy warrants further investigation to boost the waning human ID BCG response.
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Byrne, Kristen A., Dana C. Hill, and Crystal L. Loving. "Innate Memory Following Intravenous BCG in Neonatal Pigs." Journal of Immunology 208, no. 1_Supplement (2022): 50.17. http://dx.doi.org/10.4049/jimmunol.208.supp.50.17.
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Abstract In adults and rodents, Bacillus Calmette-Guerin (BCG) inoculation alters innate immune cells via epigenetic and metabolic modifications resulting in heightened responses to subsequent microbial exposure (innate memory). Neonatal BCG vaccination can correlate to improved disease resistance in some human populations, but studies with human infants are extremely limited. Pigs are a relevant biomedical model for human disease and offer a path to directly asses neonatal innate memory to improve disease resilience. BCG administration in a weaned (3 week old) pig model elicited monocyte memory only with intravenous (IV) but not subcutaneous administration. Therefore, to evaluate induction of innate memory in neonates, 3–5 day old piglets received intravenous (IV) BCG or mock and ex vivo monocyte memory was assessed. At 3 and 6 weeks post-BCG, monocytes from the IV-BCG group had elevated TNF but not IL-1β production in response to LPS stimulation ex vivo, indicating neonatal BCG exposure induced innate memory. Interestingly, broncho-alveolar lavage cells from IV-BCG group had minimal differences compared to mock group in response to LPS, suggesting IV-BCG alters responses in peripheral monocytes differently than tissue resident myeloid-lineage cells. Overall, IV-BCG administration induced monocyte memory in neonatal pigs, highlighting piglets as a valuable model for continued study on the utility of BCG induced innate memory to improve disease resilience. This work was funded by USDA-NIFA AFRI grant # 2019-07511 as part of the joint USDA-NIFA-NIH Dual Purpose with Dual Benefit: Research in Biomedicine and Agriculture Using Agriculturally Important Domestic Animal Species Program and USDA-ARS CRIS project 5030-32000-225-000D
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Byrne, Kristen A., and Crystal L. Loving. "Intravenous BCG Induction of Innate Memory in Young Pigs." Journal of Immunology 210, no. 1_Supplement (2023): 71.25. http://dx.doi.org/10.4049/jimmunol.210.supp.71.25.
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Abstract Exposure to vaccine strain of Mycobacterium bovis(M. bovis), Bacillus Calmette-Guerin (BCG), alters innate immune cells through epigenetic and metabolic modifications resulting in heightened responses to subsequent microbial insult (innate memory). As a biomedical model for human disease, pigs provide a critical space to study the role of innate memory in disease resistance. Young pigs were inoculated intravenous (IV) or intraperitoneal (IP) with either live or heat-inactivated BCG (IV-live, IP-live, IV-inactive, noBCG groups). At 2wks post BCG inoculation, monocyte production of IL-1β nor TNF cytokines following ex vivostimulation with LPS was not different in any BCG group compared to noBCG, i.e. no innate memory. As dose of live BCG was lower than anticipated, at 3wks post primary inoculation, all pigs were inoculated a second time with respective preparations and routes of BCG. Ex vivocytokine production in LPS stimulated monocytes was measured again at 5wks post primary inoculation (2wks post-secondary inoculation) and both IL-1β and TNF cytokines were elevated in IV-live (innate memory), but not IP-live or IV-inactive groups. Additionally, ex vivostimulation of PBMC with homologous recall antigen (purified proteins from M. bovis) resulted in a 3-fold higher IFNγ response in IP-live compared to IV-live and no IFNγ production in noBCG or IV-inactive. Together these data suggest that while BCG can induce a state of innate memory in monocytes of young pigs, induction of training cannot be inferred by T cell production of IFNγ to recall protein antigen. Additionally, data continue to highlight pigs as a valuable model as multiple BCG factors (i.e. route, dose, or viability) may need to be considered for induction of innate memory. USDA-ARS CRIS project 5030-32000-225-000D
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Larson, Erica C., Mark A. Rodgers, Amy L. Ellis, et al. "Intravenous BCG protects SIV+ macaques from tuberculosis." Journal of Immunology 206, no. 1_Supplement (2021): 59.11. http://dx.doi.org/10.4049/jimmunol.206.supp.59.11.
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Abstract Tuberculosis is the most common cause of death due to infection in people living with HIV (PLHIV). BCG, a live attenuated Mycobacterium bovis strain given intradermally to infants, is the only licensed vaccine to prevent TB. However, intradermal BCG offers little protection from pulmonary TB in adults and safety concerns limit its use in PLHIV. Recently, intravenous (IV) BCG has been shown to provide striking protection from TB in rhesus macaques. Given this dramatic success, we tested whether IV BCG could protect macaques with a pre-existing SIV infection using our established model of SIV/Mtb coinfection in Mauritian cynomolgus macaques (MCM). MCM were intrarectally infected with SIVmac239 and 5 months later were vaccinated with BCG at 8 ×107 CFU delivered IV. To prevent disseminated BCG disease in immunocompromised animals, four weeks after IV vaccination animals were treated with an 8-week regimen of isoniazid/rifampin/ethambutol (HRE). Four weeks after HRE cessation, animals were challenged with low-dose Mtb Erdman. SIV+ MCM exhibited no signs of BCG disease before or after HRE treatment. Following BCG vaccination, a rapid and sustained increase in airway T cells was observed in both SIV+ and SIV-naïve animals. Increased antibody titers to Mtb lysate were observed in plasma and airways following IV BCG. PBMC responses to Mtb-specific stimuli by IFNγ ELISpot indicated rapid and early clearance of Mtb in vaccinated animals regardless of SIV infection. All SIV-naïve (n=7) and 7 out of 10 SIV+, vaccinated animals were free of TB and without culturable bacilli in their tissues at 12 weeks post challenge. Flow cytometric analysis of PBMCs and tissues obtained at necropsy are underway to further define immune correlates of protection.
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Bucsan, Allison N., Patricia A. Darrah, James D. Dahlvang, et al. "Visualizing the early immune response to Mycobacterium tuberculosisinfection in macaques immunized with intravenous BCG." Journal of Immunology 210, no. 1_Supplement (2023): 253.07. http://dx.doi.org/10.4049/jimmunol.210.supp.253.07.
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Abstract Tuberculosis (TB) causes 1.6 million deaths annually and the standard human vaccine, intradermal (ID) Bacille-Calmette Guérin (BCG), does not prevent pulmonary TB. Previously, we showed that intravenous (IV) BCG immunization elicited robust TB-specific lung-resident T cell responses compared to ID BCG in rhesus macaques (RMs). Following Mycobacterium tuberculosis (Mtb) challenge, 6 out of 10 RMs had no detectable disease as demonstrated by bacterial burden, granuloma formation, and primary Mtb-specific immune responses. Together, these data suggest that Mtb is cleared rapidly from the lungs of IV BCG-vaccinated RMs. To investigate the vaccine-induced lung environment and anamnestic response that might mediate protection against Mtb early after challenge, we developed a high-dose Mtb infection model in RMs that allowed us to locate and live-image areas of Mtb infection in the lungs using confocal microscopy. RMs immunized for 5 months with either IV or ID BCG were challenged with Mtb Erdman mCherry and euthanized 4 or 11 days later to characterize the lung microenvironment. We observed reductions in bacterial burdens in the lungs of RMs that received IV BCG compared to ID BCG-vaccinated and unvaccinated controls by CFU plating, flow cytometry, and confocal microscopy despite using a high challenge dose. Increased T cells were quantified in the lungs of both IV and ID BCG-vaccinated RMs compared to unvaccinated controls by flow cytometry and confocal microscopy. This research provides an opportunity to mine immune correlates of protection in a preclinical model, at the site of infection, and at a post-challenge time point that has been minimally characterized. NIH Intramural Program
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Robertson, Molly A., Chelsea C. Lehman, Allison N. Buscan, et al. "Immunogenicity of intravenous irradiated or auxotrophic BCG immunization in macaques." Journal of Immunology 210, no. 1_Supplement (2023): 141.14. http://dx.doi.org/10.4049/jimmunol.210.supp.141.14.
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Abstract Tuberculosis (TB), caused by the bacillus Mycobacterium tuberculosis (Mtb), is a leading cause of death worldwide, particularly in people with HIV. The current vaccine against TB, BCG, is a live-attenuated strain of M. bovis that is administered intradermally at birth in endemic countries. BCG protects children against disseminated TB but fails to protect adolescents and adults against pulmonary TB, the most transmissible form. Thus, more effective TB vaccines are urgently needed. We previously demonstrated that delivering BCG intravenously (IV) elicits a high number of Mtb-specific T cells in the airway, the site of infection, and confers robust protection against Mtb challenge 6 months later in rhesus macaques. While whole organism vaccines provide broad antigenic breadth, safety concerns may limit clinical development of a replication-competent IV BCG regimen, especially in immunocompromised individuals. To address this, we vaccinated macaques IV with either irradiation-inactivated (Ird) BCG or a live, replication-incompetent auxotroph (Aux) of BCG and compared their immunogenicity in the bronchoalveolar lavage (BAL) to wild type (WT) BCG. Early results indicate that Aux BCG elicits a similar magnitude of Mtb-specific T cell responses in the BAL compared to WT BCG; in contrast, Ird BCG is less potent in generating such responses. These studies provide data on whether whole organism vaccines need to be live, persist, or replicate to confer durable immunity against TB. Funded by the NIH Intramural Program
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Smith, Alexander A., Mark A. Rodgers, Carolyn M. Bigbee, Dirk Schnappinger, Sabine Ehrt, and JoAnne L. Flynn. "Does intravenous vaccination with self-killing BCG lead to development of an immune response that protects against Mycobacterium tuberculosis?" Journal of Immunology 210, no. 1_Supplement (2023): 141.15. http://dx.doi.org/10.4049/jimmunol.210.supp.141.15.
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Abstract The use of intradermal BCG offers limited protection against tuberculosis. Intravenous (IV) administration of BCG has shown to produce robust protection against infection in a non-human primate model of tuberculosis. However, the duration of exposure and time required to elicit an efficacious, protective response is unknown and safety of IV administration of live BCG remains a concern. Here we investigated whether a self-limiting strain of BCG (killswitchBCG; ksBCG) could induce protective responses in macaques. ksBCG uses two transcriptionally repressible lysins; the inducer doxycycline is required for repression, with the absence of inducer leading to BCG death. Our first study demonstrated the robust in vivo killing of ksBCG once doxycycline is stopped IV ksBCG elicited a robust, multicellular immune response in airways and lung up to 8 weeks, similar to standard BCG. In the current study we are assessing protection conferred against Mycobacterium tuberculosis with IV ksBCG. Mauritian cynomolgus macaques (MCM) were vaccinated intravenously with ksBCG. 5 months post vaccination, animals were challenged with M. tuberculosis and later euthanized 12 weeks post infection. Bronchoalveolar lavages were routinely taken throughout the study, and alongside tissue samples, analyzed using spectral flow cytometry. The presence of multiple cell types (CD4, CD8, and gd T cells, B cells, NK cells), cytokines (IFNg, IL-2, IL-17, TNF) and cytotoxic molecules (granzymes B and K, perforin, granulysin), as well as M. tuberculosis bacterial burden will be assessed to determine the level of protection provided by IV ksBCG. NIH R01 AI143788
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Zeppa, Joseph John, Patricia A. Darrah, Supriya Pokkali, et al. "Intravenous Bacille Calmette-Guerin provides protection across a dose spectrum in a Rhesus macaque model of tuberculosis." Journal of Immunology 202, no. 1_Supplement (2019): 139.3. http://dx.doi.org/10.4049/jimmunol.202.supp.139.3.
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Abstract Our laboratory has demonstrated that intravenous (IV) vaccination with Bacille Calmette-Guerin (BCG; 5x107CFU) provides remarkably robust protection against low-dose Mycobacterium tuberculosis (Mtb) infection in Rhesus macaques (9/10 animals protected [<50 thoracic Mtb CFU]; 100,000-fold reduction compared to intradermal [ID] BCG). IV BCG also resulted in a 100-fold increase in mycobacterium-specific T cells in the bronchoalveolar lavage (BAL) of animals compared to other routes of administration (ID or aerosol). These results led us to hypothesize that significant protection could be observed at lower IV BCG doses. We therefore vaccinated macaques with decreasing doses of BCG (5x107, 1.6x107, 5x106, 1.6x106, 5x105and 1.6 x105CFU) followed by six months of immune monitoring and a three-month low-dose Mtb challenge. As expected, a mycobacterium-specific T cell dose-dependent response was observed in both the BAL (FACS) and PBMCs (IFNgELIspot) prior to infection, as well as in the lung at time of necropsy (FACS). Remarkably, 17/25 animals had no thoracic Mtb CFU across all groups, and at least one animal from each group was protected (30–100% protection). Mycobacterium-specific CD4 T cell numbers in the BAL appear to be a correlate of protection. These results demonstrate that even at low doses IV BCG can be efficacious in preventing tuberculosis with a potential role for T cell-dependent immunity.
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Grossman, Arielle, Aline Atallah, Tiziana Cotechini, Jean-Francois Pare, Robert Siemens, and Charles H. Graham. "Abstract 2058: Effect of route of Bacillus-Calmette Guerin administration on systemic immune responses in a murine model of non-muscle invasive bladder cancer." Cancer Research 82, no. 12_Supplement (2022): 2058. http://dx.doi.org/10.1158/1538-7445.am2022-2058.
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Abstract Background: Bladder cancer is the 5th most common cancer worldwide, with the most common type being non-muscle invasive bladder cancer (NMIBC). Treatment for high grade NMIBC includes resection of the bladder tumor followed by repeated intravesical administration of Bacillus-Calmette Guérin (BCG), the live-attenuated form of Mycobacterium bovis. Unfortunately, 60-70% of patients will experience disease recurrence. Our current understanding is that BCG acts within the local bladder tumor microenvironment and draining lymph nodes, leading to the activation of a systemic immune response. Using a murine model of NMIBC, here we investigated whether different routes of BCG administration alter the systemic immune response to BCG and affect tumor size. Methods: To establish syngeneic orthotopic bladder tumors in a mouse model, female C57Bl/6 mice were catheterized and 2.5 x 105 mouse bladder cancer cells (MB49) were instilled into the bladder. Beginning on day 7, mice received either intravesical, intravenous (IV) or intraperitoneal (IP) BCG (8 mg/ml) or saline once weekly for three weeks and bladders were imaged through ultrasound. At endpoint (day 23), tumors, tumor draining lymph nodes (tdLNs), spleen, and bone marrow were harvested and stored. Immune composition of the various lymphoid organs was evaluated using polychromatic flow cytometry. Ex vivo responsiveness to lipopolysaccharide (LPS) was assessed in bone marrow cells by measuring cytokine levels in culture supernatants. Results: Mice treated with IV BCG had significantly smaller tumor volumes when compared to intravesical BCG treatment. Ex vivo LPS stimulation of bone marrow from BCG-treated mice, regardless of administration route, led to increased release of pro-inflammatory cytokines compared with saline controls. IP and IV BCG treatment skewed immune microenvironments of secondary lymphoid organs towards a cytotoxic phenotype compared with intravesical BCG treatment. Within the lymphoid compartment of tdLNs, the proportion of CD8+ T cells was significantly increased while the proportion of CD4+ T cells was significantly decreased in mice treated with IV and IP BCG compared with intravesical BCG. Conversely, the proportion of CD11b+ dendritic cells (DCs) was significantly increased in tdLNs from mice receiving intravesical BCG compared with BCG administered IV or IP. Within the spleen, the proportion of CD8+CD11b- DCs were significantly increased in the DC compartment following IP BCG treatment compared to other treatment routes. Conclusion: This provides evidence that route of BCG administration affects the immune composition of secondary lymphoid organs that may be associated with anti-tumor responses. A better understanding of the mechanism of BCG immunotherapy will lead to novel approaches to optimize anti-tumor immune responses and, consequently, improved patient outcomes. Citation Format: Arielle Grossman, Aline Atallah, Tiziana Cotechini, Jean-Francois Pare, Robert Siemens, Charles H. Graham. Effect of route of Bacillus-Calmette Guerin administration on systemic immune responses in a murine model of non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2058.
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Atallah, Aline, Arielle Grossman, Jean-Francois Pare, Robert Siemens, Tiziana Cotechini, and Charles H. Graham. "Abstract 3540: Effect of route of Bacillus Calmette Guerin administration on the immune microenvironment and growth of bladder tumors." Cancer Research 82, no. 12_Supplement (2022): 3540. http://dx.doi.org/10.1158/1538-7445.am2022-3540.
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Abstract Background: Bladder cancer is the fifth most common cancer in North America. The standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG). However, it is possible that the efficacy of this modality of BCG administration is suboptimal, as most patients do not respond fully to this immunotherapy. Furthermore, our current understanding of the immunotherapeutic effect of BCG is incomplete. Using a mouse model of NMIBC, we compared the tumor immune microenvironment (TiME) following intravesical versus intravenous administration of BCG, as well as changes in tumor volume and mice survival. Methods: Female C57Bl/6 mice (6-8 weeks old) were catheterized and instilled with 2.5x105 MB49 bladder cancer cells after poly-L-lysine treatment. Beginning on day 7, mice were treated with intravenous (IV) or intravesical BCG (8 mg/ml) or saline once weekly for three weeks. Ultrasound was performed weekly to monitor tumor growth. Similarly, a cohort of non-tumor bearing mice was treated with poly-L-lysine on day one followed by three weekly intravesical instillations of BCG. In both cohorts, mice were sacrificed on day 23 and bladders were harvested, enzymatically dispersed to generate single-cell suspensions for analysis by flow cytometry, or snap frozen for transcriptomic analysis using NanoString nCounter Platform. Results: Mice receiving IV BCG had better survival and their bladder tumors were significantly smaller compared with mice receiving intravesical BCG. This reduction in tumor size was associated with a significantly increased proportion of CD8+ T cells and a significantly reduced proportion of inflammatory monocytes in bladder tumors from mice treated with IV BCG compared with intravesical BCG. Whole tumor transcriptome analysis revealed alterations in various signalling pathways associated with route of BCG administration. Our results demonstrate similar trends in the distribution of immune populations in the TiME following intravesical saline and IV BCG treatment, as well as following IV saline and intravesical BCG treatment. We also found that the TiME after intravesical BCG treatment has more immune cells which are predominantly immature myeloid cells. Moreover, our results indicate that intravesical BCG treatment leads to a significant population of immature myeloid cells in the bladders of non-tumor bearing mice. Conclusion/Significance: These results provide evidence that the route of BCG administration is an important determinant of the TiME composition and may influence anti-tumor responses. Understanding the link between the TiME and BCG therapy may facilitate the development of new approaches to improve outcomes and reduce recurrence rates in patients with NMIBC. Citation Format: Aline Atallah, Arielle Grossman, Jean-Francois Pare, Robert Siemens, Tiziana Cotechini, Charles H. Graham. Effect of route of Bacillus Calmette Guerin administration on the immune microenvironment and growth of bladder tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3540.
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Singh, Alok K., Kara Lombardo, Monali Praharaj, et al. "Abstract 3511: Varying Treatment outcomes of small molecule STING Agonist ADU-S100 in intratumoral and intravesical treatment regimens in syngeneic murine MB49 and in the N-methyl-N-nitrosourea (MNU) rat Model of urothelial carcinoma." Cancer Research 82, no. 12_Supplement (2022): 3511. http://dx.doi.org/10.1158/1538-7445.am2022-3511.
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Abstract Introduction: Intratumoral (IT) delivery of STING agonist ADU-S100 shows strong CD8+T cells-mediated antitumor immunity. However, rapid absorption from IT sites, short terminal half-life and adverse outcomes caused withdrawal of ADU-S100 from clinical trials. We reported development of BCG-STING, a preclinical candidate for non-muscle invasive bladder cancer (NMIBC) that overexpresses a bioactive STING agonist (c-di-AMP) and shows enhanced antitumor efficacy over BCG-WT by increasing tumor infiltrating CD4+ and CD8+ T cells and inflammatory macrophages. The similar mechanism of action prompted us to compare antitumor efficacy of BCG-STING with ADU-S100 in an IT as well as intravesical (IV) dosing regimen. Methods: Syngeneic MB49 flank tumors in C57BL/6 female mice received IT treatment of BCG-WT, BCG-STING (5 x 106CFU) or ADU-S100 (100, 50 or 25 mg). Endpoint involved tumor volume measurement and flow-cytometry based tumor immune infiltrate analyses (at 100 μg). MNU carcinogen rat model of NMIBC and the standard IV administration regimen was used for BCG-WT or BCG-STING (5 x 106 CFU, 6x weekly) or ADU-S100 (25 μg, 6x weekly). Tumor involvement index (TII) and pathological tumor staging tumor involvement index were determined using histopathological analyses of MNU rat bladders. Results: IT administration of ADU-S100 in MB49 tumor remained most-effective immunotherapy as compared to BCG-WT or BCG-STING even at lowest dose (25 μg), consistent with strongest infiltration of TNF-α+MHCII+F4/80+CD11b+ macrophages and IFN-γ+CD8+ T cells as compared to BCG-STING or BCG-WT. Strikingly, we observe a significant increase in immunosuppressive IL-10+ and ARG-1+ Ly6C(hi)Ly6G(-) monocytic myeloid-derived suppressor cells (M-MDSCs) in MB49 tumors treated with ADU-S100 and BCG-WT, but not BCG-STING. In contrast to MB49 model, IV induction course of BCG-STING in MNU rat model showed the greatest antitumor effects with only 5% residual TII compared to 30% in ADU-S100 or 42% in BCG-WT. Tumor staging displayed residual T1 (50%), CIS (25%) and Ta (25%) tumors in ADU-S100 group, while BCG-WT treated group showed a lower degree of invasion to the lamina propria with CIS (50%), T1 (25%) and Ta (25%) residual tumors. BCG-STING IV therapy resulted in 60% of rat bladders showing complete tumor regression while 40% had minimal residual non-invasive tumors. Conclusions: The varying therapeutic outcomes of IT vs IV treatment regimens of ADU-S100 over BCG-STING or BCG-WT in different urothelial carcinoma models suggest the important role of varying tumor microenvironment and dosing regimens on relative antitumor efficacy. Increased percentage of immunosuppressive M-MDSCs specifically in response to ADU-S100 or BCG-WT suggests unique advantages associated with BCG-STING. Citation Format: Alok K. Singh, Kara Lombardo, Monali Praharaj, James Liu, Russel Becker, Kelly Harris, Max Kates, David McConkey, Andres Matoso, William R. Bishai, Trinity Jude Bivalacqua. Varying Treatment outcomes of small molecule STING Agonist ADU-S100 in intratumoral and intravesical treatment regimens in syngeneic murine MB49 and in the N-methyl-N-nitrosourea (MNU) rat Model of urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3511.
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Tran, Kim, and Maziar Divangahi. "BCG vaccination provides cross-protection against influenza infection through trained adaptive immunity." Journal of Immunology 206, no. 1_Supplement (2021): 110.18. http://dx.doi.org/10.4049/jimmunol.206.supp.110.18.
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Abstract The ongoing COVID-19 pandemic highlights the threat emerging viruses pose to the world. While the development of a new vaccine can take at least 1–2 years, alternative approaches are urgently needed to alleviate the burden of rapid transmission. The Bacillus Calmette-Guerin (BCG) vaccine is currently used worldwide to prevent tuberculosis but has also been shown to protect against a wide range of infections. Several studies have attributed this broad protection to trained immunity. While innate immune cells usually act in a non-specific manner, in the context of trained immunity, these cells acquire an enhanced capacity to protect against different pathogens. However, preliminary work suggests that BCG may be mediating trained immunity by enhancing the adaptive immune system as well. Before the current pandemic, Influenza A virus (IAV) was responsible for the most devastating pandemic in history and remains the cause of yearly epidemics. Thus, investigating the cross-protection of BCG against IAV could determine whether BCG vaccination could offer an alternative preventive strategy against viruses with pandemic potential. To determine the protective effects of BCG against IAV infection, C57BL/6 mice were vaccinated intravenously (-iv) or subcutaneously (-sc) with BCG then infected with H1N1. We showed that BCG-iv vaccinated mice exhibited increased survival against IAV and a decreased viral load. Interestingly, BCG-iv uniquely induces the enrichment of CX3CR1+ αβ memory T cell populations which may be contributing to protective immunity against IAV infection. Overall, the present study evaluates whether beneficial effects from a widely distributed vaccine could provide some protection against emerging pulmonary pathogens.
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Morton, Donald L., Nicola Mozzillo, Mohammed Kashani-Sabet, et al. "Long-term cure after complete resection and adjuvant immunotherapy for distant melanoma metastases." Journal of Clinical Oncology 30, no. 15_suppl (2012): 8534. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8534.
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8534 Background: In phase II trials, postoperative therapy with Canvaxin allogeneic melanoma cell vaccine plus Bacillus Calmette-Guerin (BCG) improved the survival of patients with stage IV melanoma. A multicenter, phase III placebo-controlled study was undertaken to investigate the vaccine’s efficacy. Methods: After complete resection of melanoma involving up to 5 distant sites, patients were randomized to treatment with BCG plus Canvaxin (BCG-Canvaxin) or BCG plus placebo (BCG-placebo). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS) and skin test responsiveness to the study agent. Results: Between May 1998 and April 2005, 496 patients were randomized. In April 2005, entry to the study was terminated due to low probability of demonstrating treatment differences. However, 256 patients from sites enrolled in a follow-up study were monitored until March 2010. Median OS and 5-year and 10-year rates of OS were 39.1 months, 43.3% and 33.3%, respectively, in the BCG-placebo group, versus 34.9 months, 42.5% and 36.4%, respectively, in the BCG-Canvaxin group (hazard ratio, 1.053; 95% confidence interval, 0.81 to 1.36; p=0.6964). Median DFS, 5-year DFS, and 10-year DFS were 7.6 months, 23.8% and 21.7%, respectively, for the BCG-placebo group, versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG-Canvaxin group (hazard ratio, 0.882; 95% confidence interval, 0.708 to 1.097; p=0.2595). Positive skin test results correlated with improved survival. Conclusions: BCG-Canvaxin was not superior to BCG-placebo, but the highly favorable long-term survival for combined groups indicates that complete metastasectomy should be considered as initial therapy for patients with resectable stage IV melanoma (ClinicalTrials.gov identifier: NCT00052156).
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Kaufmann, Eva, Nargis Khan, Clinton S. Robbins, Luis B. Barreiro, and Maziar Divangahi. "Systemic BCG Vaccination in “Dirty Mice” induces Protective Trained Immunity against TB." Journal of Immunology 204, no. 1_Supplement (2020): 168.6. http://dx.doi.org/10.4049/jimmunol.204.supp.168.6.
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Abstract After a century of discovery of Bacille Calmette-Guerin (BCG), our understanding of its protective mechanism(s) against TB or other pathogens is very limited. We have recently demonstrated that systemic BCG vaccination (intravenously, iv) in specific pathogen-free (SPF) mice imprints hematopoietic stem cells (HSCs) to generate macrophages with a unique protective program against pulmonary M. tuberculosis (Mtb) infection. While this proof of concept study was an important step to determine how we can harness the power of innate (trained) immunity in vaccination against TB, the translation of this novel approach to humans is still unknown. As SPF lab mice incompletely recapitulate the human immune system, additional pre-clinical models are necessary to evaluate the translational potential of systemic BCG vaccination. Thus, in the current study, we hypothesize that systemic BCG vaccination will generate protective HSC-mediated trained immunity against TB in microbe-exposed “dirty” mice whose immune landscape more closely replicates adult human traits. To test this hypothesis, we have established a bedding transfer model from pet shop mice to SPF C57BL/6 mice. Age- and sex-matched dirty or SPF mice were then iv or subcutaneously vaccinated with BCG (1×106 CFU) or PBS (control). At 4 weeks post vaccination, we generated bone marrow derived macrophages and infected them with virulent Mtb (H37Rv; MOI 1). Interestingly, the protective signature of trained immunity was completely intact in BCG-iv vaccinated dirty mice. Collectively, our results indicate that the protective imprinting of systemic BCG vaccination for generation of trained immunity is robust and independent of previous exposure of hosts to other microbes or pathogens.
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Zeppa, Joseph John, Patricia A. Darrah, Matthew Sutton, et al. "Vaccine-Elicited T cells are Important for Intravenous BCG Mediated Protection in a Rhesus macaque Model of Tuberculosis." Journal of Immunology 204, no. 1_Supplement (2020): 168.4. http://dx.doi.org/10.4049/jimmunol.204.supp.168.4.
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Abstract Our laboratories have shown that intravenous (IV) vaccination with Bacille Calmette-Guerin (BCG; 5×107 CFU) provides robust protection against low-dose Mycobacterium tuberculosis (Mtb) infection in rhesus macaques (9/10 protected [<50 thoracic Mtb CFU]; 100,000-fold reduction compared to intradermal [ID] BCG). IV BCG also resulted in a 100-fold increase in mycobacterium--specific T cells in the airways of animals compared to ID or aerosol administration. To investigate the role of T cells in this protective model, we employed two methodologies: 1. Vaccination with decreasing doses of BCG to stimulate lower-magnitude T cell responses and; 2. Antibody-mediated CD4 and CD8a T cell depletion post-vaccination but pre-infection. Animals were vaccinated for 6 months followed by a 2–3 month low-dose Mtb challenge. Surprisingly, even at low doses of BCG (0.4–2 × 105), a subset of animals was protected, with a range of outcomes across the doses. In the second study, depletion was successful in blood, airways and tissue. Interestingly, depletion of either T cell subset resulted in an intermediate total thoracic CFU phenotype. In both studies, correlates of immunity will be assessed comparing protection (CFU) to BAL and tissue resident immune responses. Our data supports that sterilizing protection is observed across the BCG IV dose spectrum and that T cells are important, but are likely not the only factors involved in this protection. Our findings are critical for identifying correlates of protection and generating a safe and effective vaccine against TB.
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Loving, Crystal L., Dana Hill, and Kristen Byrne. "Neonatal bacilllus Calmette-Guerin (BCG) administration did not limit influenza A virus replication or clinical disease in pigs." Journal of Immunology 210, no. 1_Supplement (2023): 73.09. http://dx.doi.org/10.4049/jimmunol.210.supp.73.09.
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Abstract A potential immunomodulation mechanism for improving disease resilience is innate training, which relies on epigenetic modifications of immune cells for a heightened (ie, trained) response upon repeated microbial stimulation. Prior experiences indicate bacillus Calmette-Guerin (BCG) exposure increases cytokine production upon secondary exposure to microbe-associated molecular patterns, and epidemiological data suggest improved disease resistance in humans administered neonatal BCG. Neonatal piglets received BCG or mock inoculum via intravenous (IV) route and were subsequently exposed to influenza A virus (IAV) inoculated piglets. Body temperature was recorded and nasal swabs collected through the acute phase of viral infection. At necropsy, gross lung pathology was assessed. In addition, prior to IAV challenge, peripheral blood mononuclear cells (PBMC) and monocytes were isolated from mock and BCG inoculated animals and stimulated in vitrowith LPS to evaluate in vivoinduction of a trained phenotype via cytokine production and gene expression. PBMC were stimulated with PPD antigen to assess antigen-specific T cell responses to BCG inoculation. PPD-specific IFNγ production by PBMCs was minimal; yet upon in vitroLPS exposure, monocytes isolated from IV BCG treated piglets produced more IL-1β and TNF cytokine than monocytes from mock pigs (ie, trained phenotype). However, no significant differences in clinical presentation or nasal and lung IAV titers were detected. BCG administration induced a trained phenotype in porcine peripheral monocytes, it did not translate into a significant alteration in respiratory viral infection. USDA-ARS-NIFA 2019-07511
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Kamat, Ashish M., Shahrokh Shariat, Gary D. Steinberg, et al. "Randomized comparator-controlled study evaluating efficacy and safety of pembrolizumab plus Bacillus Calmette-Guérin (BCG) in patients with high-risk nonmuscle-invasive bladder cancer (HR NMIBC): KEYNOTE-676 cohort B." Journal of Clinical Oncology 40, no. 6_suppl (2022): TPS597. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.tps597.
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TPS597 Background: Cohort A of the phase 2 KEYNOTE-057 study showed that pembrolizumab monotherapy provided effective antitumor activity and acceptable safety in patients with BCG-unresponsive HR NMIBC with carcinoma in situ (CIS). Pembrolizumab in combination with BCG at earlier stages of HR NMIBC might provide benefit superior to that of BCG monotherapy. The open-label, comparator-controlled, phase 3 KEYNOTE-676 study (NCT03711032) will be conducted to investigate the efficacy and safety of pembrolizumab + BCG versus BCG monotherapy in patients with HR NMIBC. Cohort A will enroll patients with persistent or recurrent HR NMIBC after BCG induction. Cohort B is a new, randomly assigned cohort that will help evaluate pembrolizumab + BCG in BCG treatment–naive patients who either never received BCG treatment or received BCG treatment > 2 years before enrollment. Methods: Cohort B of KEYNOTE-676 will enroll approximately 975 patients with blinded independent central review (BICR)–confirmed HR NMIBC (T1, high-grade Ta CIS) and Eastern Cooperative Oncology Group performance status score 0-2 who underwent cystoscopy/transurethral resection of bladder tumor ≤12 weeks before randomization and had not received BCG within the past 2 years. Patients will be randomly assigned 1:1:1 to receive pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) + BCG reduced maintenance (≤6 months), pembrolizumab 400 mg IV Q6W + BCG full maintenance (≤18 months), or BCG monotherapy (BCG full maintenance). Stratification factors include NMIBC stage (CIS or no CIS) and PD-L1 expression (combined positive score [CPS] ≥10 or CPS < 10), determined by central laboratory. Disease status will be assessed by use of cystoscopy, urine cytology, and biopsy (as applicable) every 12 weeks (Q12W) through year 2, then every 24 weeks through year 5; imaging with computed tomography urography will occur every 72 weeks. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of study treatment (90 days for serious AEs). The primary end point is event-free survival (EFS). Secondary end points include complete response rate by BICR, duration of response (DOR), 12-month DOR rate (CIS only), 24-month EFS rate, disease-specific survival, time to cystectomy, overall survival, and safety. The study is enrolling or planning to enroll at sites in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT03711032.
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Ravaud, A., H. Eghbali, M. Trojani, G. Hoerni-Simon, P. Soubeyran, and B. Hoerni. "Adjuvant bacillus Calmette-Guérin therapy in non-Hodgkin's malignant lymphomas: long-term results of a randomized trial in a single institution." Journal of Clinical Oncology 8, no. 4 (1990): 608–14. http://dx.doi.org/10.1200/jco.1990.8.4.608.
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Between 1973 and 1977, 48 patients less than 65 years old with non-Hodgkin's malignant lymphoma (NHML) of poor prognosis (+/- high grade malignancy, +/- clinical stages III or IV, +/- first or repeated relapse) were included in a prospective clinical trial. After complete remission (CR), obtained with chemotherapy and radiotherapy, patients were randomized to receive bacillus Calmette-Guérin (BCG) or no further therapy. BCG was administered in weekly scarifications up to 3 years. Forty-three patients are assessable. Twenty-four patients have relapsed: nine out of 21 in the BCG group, and 15 out of 22 in the control group. There is a significant difference in favor of the BCG group in disease-free survival (P = .03). Twenty-one patients have died, 18 from NHML: seven in the BCG group, and 11 in the control group. There is a significant difference in favor of the BCG group for overall survival at 10 years (P = .05). A multivariate analysis points out BCG as a significant prognostic factor. Adjuvant BCG may improve particularly disease-free survival and overall survival for patients with clinical stages I and II or intermediate- and high-grade malignancy. These results suggest that in patients less than 65 years old with NHML of poor prognosis, BCG may significantly increase disease-free survival and overall survival.
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Morton, D. L., N. Mozzillo, J. F. Thompson, et al. "An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites." Journal of Clinical Oncology 25, no. 18_suppl (2007): 8508. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.8508.
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8508 Background: Active specific immunotherapy with BCG and an allogeneic, melanoma cell vaccine can induce antibody and T-lymphocyte immune responses to numerous antigens expressed by melanoma cells. This study compared overall and disease-free survival in patients receiving BCG plus placebo versus BCG plus MCV. Methods: Between June 1998 and November 2005, 1,656 patients without evidence of residual disease after resection of stage III (n = 1,160) or stage IV (n = 496) melanoma were randomly assigned to the two treatment arms (1:1). BCG was given as an immunologic adjuvant for the first two injections of both MCV and placebo, which thereafter were administered by intradermal injection every two weeks for the next three injections, every month for the remainder of the first year, every two months for the second year and every three months for years three, four and five. Results: Based on the recommendation of the independent Data and Safety Monitoring Board (DSMB), both studies were terminated after the interim analysis. The recommendation was based on a low probability of demonstrating significant improvement in survival of the BCG plus MCV arm if the study had continued to completion of follow-up and final analysis. Conclusions: This is the largest multicenter clinical trial of postoperative adjuvant immunotherapy after resection of melanoma metastatic to regional lymph nodes or distant sites. It is a landmark study not only because it represents the first randomized multicenter trial to use surgical resection as initial therapy for stage IV melanoma patients with up to five metastatic sites, but also because its results demonstrate excellent survival for the entire study population with 42.3% of stage IV and 63.4% of stage III patients projected to be alive at five years. Updated data for survival and immunologic endpoints which show a significant correlation between immune responses and survival will be provided at the meeting. [Table: see text]
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Abate, Getahun, Krystal A. Meza, Chase G. Colbert, Octavio Ramos-Espinosa, Nancy J. Phillips, and Christopher S. Eickhoff. "Immunity Against Mycobacterium avium Induced by DAR-901 and BCG." Vaccines 13, no. 6 (2025): 619. https://doi.org/10.3390/vaccines13060619.
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Background: The prevalence of pulmonary nontuberculous mycobacteria (NTM) is increasing in Europe and North America. Most pulmonary NTM cases are caused by Mycobacterium avium complex (MAC). The treatment of pulmonary MAC is suboptimal with failure rates ranging from 30% to 40% and there is a need to develop new vaccines. Methods: We tested the ability of two whole-cell vaccines, DAR-901 (heat-killed M. obuense) and BCG (live-attenuated M. bovis), to induce MAC cross-reactive immunity by first immunizing BALB/c mice and then performing IFN-γ ELISPOT assays after overnight stimulation of splenocytes with live MAC. To study the ability of these vaccines to protect against MAC infection, BALB/c mice were vaccinated with DAR-901 (intradermal) or BCG (subcutaneous or intranasal) and challenged with aerosolized MAC 4 weeks later. A group of mice vaccinated with BCG were also treated with clarithromycin via gavage. Lung colony-forming units (CFU) in immunized mice and unvaccinated controls were quantified 4 weeks after infection. Histopathology was used to quantify lung inflammation and flow cytometry was used to study lung immunity in BCG-vaccinated and unvaccinated mice following MAC infection. To increase the safety profile of mucosal BCG vaccination, we studied BCG with a “kill switch” (tetR BCG) in scnn1b-transgenic mice (i.e., mice prone to cystic fibrosis-type lung diseases). Results: Our results showed that (i) DAR-901 induced cross-reactive immunity to MAC to a similar level as BCG, (ii) DAR-901 and BCG protected against aerosol MAC challenge, (iii) mucosal BCG vaccination, compared to systemic BCG and DAR-901 vaccinations, provided the best protection against MAC challenge, (iv) BCG vaccination did not interfere with anti-MAC activities of clarithromycin, (v) BCG-vaccinated mice had increased inflammation and increased frequencies of activated CD4 and CD8 T cells following MAC infection, and (vi) doxycycline treatment of tetR BCG-vaccinated mice decreased lung BCG CFU without affecting MAC immunity. Conclusions: Both DAR-901 and BCG vaccinations induce MAC cross-reactive immunity and protect against aerosolized MAC challenges. Mucosal BCG vaccination provides the best protection and TetR BCG could enhance the safety of mucosal BCG vaccination.
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Octavini, Nanda Andreas, Weni Yunisa Adriani, Nopi Yana, and Rolando Mandela. "ANALISIS BOSTON CONSULTING GROUP (BCG) PADA PORTOFOLIO PRODUK UNILEVER." Journal Of Economic And Business Retail 2, no. 1 (2023): 8. http://dx.doi.org/10.69769/jebr.v2i1.86.
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Tujuan dalam penelitian ini adalah untuk menganalisis matriks Boston Consulting Group (BCG) pada portofolio produk Unilever dan merumuskan strategi pemasaran yang tepat berdasarkan analisis matriks Boston Consulting Group (BCG). Teknik pengumpulan data yang digunakan dalam penelitian ini yaitu studi pustaka dan wawancara. Metode analisis yang digunakan adalah matriks Boston Consulting Group (BCG). Berdasarkan hasil pemetaan pada matriks Boston Consulting Group (BCG) dapat dijelaskan bahwa kesepuluh produk Unilever menempati kuadran (posisi) yang berbeda-beda yaitu : pada kuadran I atau Question Mark ada empat produk yang dipetakan ke dalam kuadran ini yaitu Savory, Spread, Tea and Soy Beverages, House Hold Care. Produk tersebut memiliki tingkat pertumbuhan yang tinggi namun pangsa pasar yang rendah. Hal ini perlu ditingkatkan agar semua produk dapat bergeser ke posisi Star . Pada kuadran IV atau Dog ada enam produk yang berada dalam kuadran ini yaitu Skin Cleansing, Skin Care, Oral Care, Deodorant, dan Hair Care. Pada kuadran ini pertumbuhan produk sangat kecil dan pangsa pasar juga rendah. Oleh karena itu, perusahaan harus melakukan sesuatu agar produk tersebut tetap dapat bersaing dan berkembang dan bisa bergerak ke posisi Question Mark.
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Larsson, LO, M. Magnusson, BE Skoogh, and A. Lind. "Sensitivity to sensitins and tuberculin in Swedish children. IV. The influence of BCG-vaccination." European Respiratory Journal 5, no. 5 (1992): 584–86. http://dx.doi.org/10.1183/09031936.93.05050584.
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BCG-vaccinated schoolchildren, 8-9 yrs of age, were simultaneously tested on separate arms with tuberculin and a sensitin. Using the 6 mm cut-off they reacted in 49% to two tuberculin units purified protein derivative (PPD RT23), in 67% to 0.1 micrograms Mycobacterium avium sensitin RS10, and in 58% to 0.1 micrograms M. scrofulaceum sensitin RS95. The corresponding figures for non-BCG-vaccinated schoolchildren of the same age tested at the same time were 3, 25 and 32%, respectively. The results indicate a stimulating influence of BCG-vaccination on tuberculin and sensitin reactivity. Since the sensitin reactions were the larger ones, these reactions were not only due to the vaccination. The BCG-vaccinated schoolchildren seem to have acquired infections by atypical mycobacteria despite vaccination.
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Condori Bustillos, Rocio, María Rebeca De la Fuente Olmos, María Elena Villacastín Ruiz, and Marta Alvarez Garcia. "Sepsis con afectación peritoneal por BCG: A propósito de un caso." Revista Medica 28, no. 1 (2023): 70–73. http://dx.doi.org/10.58296/rm.v28i1.77.
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La instilacion intravesical de BCG es utilizado en el tratamiento del carcinoma vesical in situ, generalmente es bien tolerada y con raras complicaciones, sobre estas se ha descrito mecanismos por diseminación hematógena (con pruebas microbiológicas e histopatológicas positivas) o por hipersensibilidad tipo IV (Pruebas microbiológicas negativas, granulomas y buena respuesta a corticoides) o mixto. Presentamos el caso de un paciente con Carcinoma vesical en tratamiento con instilaciones intravesicales de BCG, con factores de riesgo de lesión de la barrera urotelial, comienza con fiebre hasta llegar a una sepsis, con cultivos: negativos y en pruebas de imagen: engrosamiento peritoneal con adenopatías necróticas de nueva aparición, negativas para malignidad tras la biopsia dado el antecedente neoplásico del paciente, patrón miliar en TC tórax, evolucionando con buena respuesta a antituberculosos. Dada la relación temporal los hallazgos clínico, radiológicos e histopatológicos se llega al diagnóstico de Sepsis por hipersensibilidad a BCG con afectación peritoneal.
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Roupret, Morgan, Yann Neuzillet, Aurelie Bertaut, et al. "ALBAN: An open label, randomized, phase III trial, evaluating efficacy of atezolizumab in addition to one year BCG (bacillus Calmette-Guerin) bladder instillation in BCG-naive patients with high-risk nonmuscle invasive bladder cancer (AFU-GETUG 37)." Journal of Clinical Oncology 37, no. 15_suppl (2019): TPS4589. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps4589.
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TPS4589 Background: The majority of patients with bladder cancer are diagnosed with non-muscle invasive bladder cancer (NMIBC). Trans-urethral resection of bladder tumor (TURBT) followed by Bacillus Calmette-Guerin (BCG) therapy is the standard of care for most patients with high-risk NMIBC, although clinical outcomes remain poor. Data from preclinical and clinical studies suggest that programmed death-ligand 1 PD-L1 inhibition may enhance antitumor activity of BCG therapy. Atezolizumab, an anti–PD-L1 monoclonal antibody, is approved in the United States and the European Union as monotherapy when patients are ineligible for cisplatin or after prior platinum therapy. This approval was based on the results from phase II and III IMvigor210/211 trials. We have designed ALBAN, a phase III trial to evaluate the efficacy and safety of atezolizumab given in combination with BCG versus BCG alone in patients with high-risk NMIBC. Methods: In 30 centers in France, ALBAN (NCT03799835) is enrolling patients with histologically documented NMIBC who have not received prior BCG therapy. Eligible patients have to have high-risk features (T1 staging, high grade, or in situ carcinoma), ECOG PS 0-2, and a tissue sample for PD-L1 testing (by Ventana SP142 immunohistochemistry assay). Patients are randomized 1:1 to: (Arm A) BCG alone (six weekly instillations of BCG, followed by three weekly maintenance instillations at 3, 6, 12 months), or (Arm B) atezolizumab (1200 mg; IV; q3w for up to 1 year) combined with BCG given as in arm A. Treatment with atezolizumab and BCG are continued in the absence of unacceptable toxicity, for 1 year. The primary endpoint is recurrence-free survival in the intent-to-treat population. Secondary efficacy endpoints include overall survival, PFS, complete response, disease worsening, and quality of life. Safety, biomarkers, and other exploratory endpoints will also be evaluated. Enrollment began in December 2018 with a target of 614 pts. Clinical trial information: NCT03799835.
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Hahn, Noah M., Gary D. Steinberg, Kelly Lynn Stratton, et al. "Atezolizumab (atezo) with or without Bacille Calmette-Guérin (BCG) in patients (pts) with high-risk nonmuscle-invasive bladder cancer (NMIBC): Results from a phase Ib/II study." Journal of Clinical Oncology 40, no. 6_suppl (2022): 493. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.493.
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493 Background: Standard treatment (tx) for high-risk NMIBC is transurethral resection of bladder tumor (TURBT) followed by BCG induction and maintenance. However, ≈50% of pts experience recurrence and/or progression after tx and may be ineligible for or refuse cystectomy. The PD-L1/PD-1 pathway may be involved with immune escape in NMIBC following BCG exposure. Here, we report results of atezo (antiPD-L1) ± BCG in BCG-unresponsive, high-risk NMIBC. Methods: This multicenter study (NCT02792192) enrolled pts with BCG-unresponsive NMIBC with carcinoma in situ who had repeat TURBT. Cohort 1A and 1B pts received atezo 1200 mg IV q3w for ≤96 wk. Cohort 1B pts also received standard BCG induction (qw × 6 doses) and maintenance (qw × 3 doses at 3 mo), with optional maintenance courses at 6, 12, 18, 24, and 30 mo. For cohort 1B only, de-escalation was allowed for ≤3 BCG dose levels (full dose 50 mg, 66% and 33% of full dose). Co-primary outcomes were safety and complete response (CR) rate at 6 mo (6-mo bladder biopsy required). Duration of CR and 3-mo CR rate (key secondary outcomes) and 12-mo CR rate (exploratory) were also shown. Results: Cohorts 1A and 1B enrolled 12 pts each. Median age was 74 y; most pts had ECOG PS 0 (n = 7 [58%] in each cohort). At data cutoff (Sep 29, 2020), median atezo tx duration was 22.7 wk in cohort 1A and 31.6 wk in 1B. Following dose de-escalation in cohort 1B, the recommended BCG dose was 50 mg. BCG dose modification/interruption occurred in 4 pts (33%) due to an AE. The most common reason for tx discontinuation was disease recurrence or progression in both cohorts. Three pts (25%) in cohort 1A had atezo-related Gr 3 AEs (most common: maculopapular rash, n = 2); no atezo- or BCG-related Gr ≥3 AEs were seen in cohort 1B. Three dose-limiting toxicities occurred (1 [8%] in cohort 1A and 2 [17%] in cohort 1B), all reported as AEs of special interest. No Gr 4/5 AEs were reported. CRs, which appeared durable, were seen in both cohorts (Table). Conclusions: In this first report of atezo + BCG in NMIBC, atezo as mono- and combination therapy was well tolerated, with no new safety signals or tx-related deaths. Preliminary data suggested clinically meaningful activity, especially with atezo + BCG, requiring confirmation in a larger setting. Clinical trial information: NCT02792192. [Table: see text]
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Hallworth, Pam, Anthony Eccleston, Brad Mason, et al. "Quantifying patient preferences for bacillus Calmette-Guérin (BCG) and PD-(L)1 inhibitors in high-risk non-muscle invasive bladder cancer (NMIBC): A discrete choice experiment." Journal of Clinical Oncology 43, no. 16_suppl (2025): 4579. https://doi.org/10.1200/jco.2025.43.16_suppl.4579.
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4579 Background: Intravesical Bacillus Calmette-Guerin (BCG) induction + maintenance (I+M) is the standard of care for high-risk NMIBC. Disease recurrence and progression is common. The studies investigating programmed cell death-1/programmed death-ligand 1 (PD-[L]1) inhibitors + BCG aim to enhance treatment outcomes and reduce burden in BCG naïve high-risk NMIBC. There is limited evidence on patient preferences for these combination regimens. Methods: A discrete choice experiment quantified preferences for attribute levels related to BCG and PD-(L)1 inhibitors. Attributes and levels were informed by a literature review, patient interviews, regulatory scientific advice, clinical experts and a patient advocate. Patients completed hypothetical choice tasks describing administration mode and frequency for PD-(L)1 inhibitors and BCG (induction [I]; I+M), median event-free survival (EFS) and adverse events (AEs: bladder AEs; chronic endocrine conditions; serious immune AEs). Hierarchical Bayesian modelling estimated preference weights (PWs) for attribute levels. PWs identified level combinations with the lowest choice probability. Relative importance (RI) was calculated by systematically varying attribute levels and capturing the gain in choice probability. Results: 150 patients (77 BCG-naïve; 73 BCG-experienced) in the United States completed the survey. Clinician-confirmed diagnosis (17%) and/or self-reported ongoing or planned BCG I+M (99%) was obtained. The sample was 51% male, had a median age of 63 years (49-74) and diverse by race (Caucasian 46%; African American/Black 27%; Other 27%) and ethnicity (Hispanic/Latino/Spanish 21%). EFS was the most important attributes to patients (RI 17.2), followed by bladder AEs (RI 16.4) and serious immune AEs (RI 14.0). Administration attributes were important (RI 9-9.9), but less important than other attributes. PWs show that short duration ( < 1 minute) subcutaneous (SC) injections was the most preferred PD-(L)1 route and shorter BCG schedule was preferred. Conclusions: Findings highlight the value of prolonging EFS, effective clinical management of BCG AEs and reducing administration burden in future BCG + PD(L)1 regimens. Attribute Level Mean PW 95% CI (±) RI*(%) EFS (months) 362722 3.46-1.03-2.43 0.280.110.22 17.2 Bladder AEs (%) 03575 2.98-0.10-2.88 0.290.120.26 16.4 Serious immune AEs (%) 01020 1.40-0.09-1.31 0.220.090.18 14.0 Chronic endocrine conditions (%) 0510 0.99-0.08-0.91 0.150.080.16 12.6 PD-(L)1 frequency (weeks) 643 0.45-0.10-0.35 0.100.100.06 9.9 PD-(L)1 administration route and time SC <1 minuteSC 7-10 minutesIV 30-60 minutes 0.150.06-0.21 0.090.100.08 9.5 BCG schedule II+M 0.25-0.25 0.140.14 9.0 *Sums to 88.7. The remaining 11.3 corresponds to an attribute used for analysis only. CI: confidence interval; IV: intravenous infusion.
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Ramos, Romela Irene, Misa A. Shaw, Leland Foshag, et al. "Genetic Variants in Immune Related Genes as Predictors of Responsiveness to BCG Immunotherapy in Metastatic Melanoma Patients." Cancers 13, no. 1 (2020): 91. http://dx.doi.org/10.3390/cancers13010091.
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Adjuvant immunotherapy in melanoma patients improves clinical outcomes. However, success is unpredictable due to inherited heterogeneity of immune responses. Inherent immune genes associated with single nucleotide polymorphisms (SNPs) may influence anti-tumor immune responses. We assessed the predictive ability of 26 immune-gene SNPs genomic panels for a clinical response to adjuvant BCG (Bacillus Calmette-Guérin) immunotherapy, using melanoma patient cohorts derived from three phase III multicenter clinical trials: AJCC (American Joint Committee on Cancer) stage IV patients given adjuvant BCG (pilot cohort; n = 92), AJCC stage III patients given adjuvant BCG (verification cohort; n = 269), and AJCC stage III patients that are sentinel lymph node (SLN) positive receiving no immunotherapy (control cohort; n = 80). The SNP panel analysis demonstrated that the responder patient group had an improved disease-free survival (DFS) (hazard ratio [HR] 1.84, 95% CI 1.09–3.13, p = 0.021) in the pilot cohort. In the verification cohort, an improved overall survival (OS) (HR 1.67, 95% CI 1.07–2.67, p = 0.025) was observed. No significant differences of SNPs were observed in DFS or OS in the control patient cohort. This study demonstrates that SNP immune genes can be utilized as a predictive tool for identifying melanoma patients that are inherently responsive to BCG and potentially other immunotherapies in the future.
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Joseph-Munné, Joan, Milena Maya-Hoyos, Narcís Saubi, et al. "Recombinant Mycobacterium bovis BCG-Based HIV Vaccine: Failures and Promising Approaches for a Successful Vaccine Strategy." Vaccines 13, no. 6 (2025): 606. https://doi.org/10.3390/vaccines13060606.
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During 2022, AIDS claimed a life every minute and about 9.2 million HIV-infected people were not on treatment. In addition, a person living with HIV is estimated to be 20–30 times more susceptible to developing active tuberculosis. Every year, 130,000 infants are newly infected, with vertical transmission being the main cause of pediatric HIV infection. Thus, the development of an effective, safe, and accessible vaccine for neonates and/or adults is an urgent need to prevent or control HIV infection or progression to AIDS. An effective HIV vaccine should induce long-lasting mucosal immunity, broadly neutralizing antibodies, innate immunity, and robust stimulation of CD4+ and CD8+ T-cell responses. Recombinant BCG is a promising live-attenuated bacterial vaccine vector because of its capacity to stimulate T-cell immunity. As a slow-growing microorganism, it provides prolonged low-level antigenic exposure upon infecting macrophages and APCs, potentially stimulating both effector and memory T-cell responses. BCG is considered safe and is currently administered to 80% of infants in countries where it is part of the national immunization program. Additionally, BCG offers several benefits as a live vaccine vehicle since it is cost-effective, easy to mass-produce, and heat stable. It is also well-suited for newborns, as maternal antibodies do not interfere with its efficacy. Furthermore, BCG has a strong safety profile, having been administered to over three billion people as a TB vaccine. In this review, we provide an extensive summary of the literature relating to immunogenicity studies in animal models performed since 2011. Moreover, we provide a comprehensive analysis of the key factors influencing the design of recombinant BCG as a live vaccine vehicle: (i) expression vectors; (ii) selection of HIV immunogen; (iii) promoters to regulate gene expression; (iv) BCG strain and BCG codon optimization; (v) genetic plasmid stability; (vi) influence of preexisting immunity, route, and dose immunization; and (vii) safety profile.
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José Caetano de Lima, Igor, Moacir Cavalcante de Albuquerque Neto, Thomé Décio Pinheiro Barros Júnior, Fabio de Oliveira Vilar, José Weslley Silva Bezerra, and Danilo de Lima Cavalcanti. "Intravesical adjuvant therapy with gemcitabine for patients with high-risk non-muscle invasive bladder cancer: Experience from a public hospital in Brazil." Recet 11, no. 1 (2024): e00167. http://dx.doi.org/10.55825/recet.sbu.0167.
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Introdução: A terapia intravesical adjuvante é o tratamento de escolha para o câncer de bexiga não músculo-invasivo (CBNM) de alto risco, o que reduz a recorrência e a progressão da doença. O Bacilo Calmette-Guerin (BCG) é o principal fármaco utilizado, mas apresenta escassez mundial. Aqui, relatamos o uso de gencitabina intravesical (GEN-IV) em nosso hospital.
 Metodologia: Este estudo incluiu pacientes com diagnóstico histológico de NMIBC urotelial de alto risco. Os pacientes foram submetidos a uma segunda ressecção transuretral de tumor de bexiga (RTUB) até 6 semanas após o diagnóstico. A terapia com GEM-IV foi indicada se a progressão T2 não fosse alcançada. O acompanhamento foi recomendado com cistoscopia e ultrassonografia do trato urinário 1 mês após o último ciclo de GEN-IV e depois a cada 6 meses ou até recorrência e/ou progressão.
 Resultados: Este estudo incluiu 28 pacientes no período de julho de 2017 a junho de 2019. Destes, 8 foram excluídos. A média de idade foi de 66,9 anos. O número médio de lesões detectadas no RTUB inicial foi de 3,75 e o tamanho médio estimado das lesões foi de 4 cm. Com seguimento de 4,43 anos, 40% não apresentou recidiva. A recorrência ocorreu em 12 pacientes e o tempo médio para esse evento foi de 15,58. Dentre estes com recidiva, 33,3% tiveram progressão da doença.
 Conclusão: A terapia GEM-IV demonstrou baixa toxicidade e taxas aceitáveis de recorrência e progressão com seguimento de >4 anos. Alternativas devem ser desenvolvidas para suprir a falta de BCG.
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Sonpavde, Guru, Charles Joel Rosser, Chong-xian Pan, et al. "Phase I trial of ALT-801, a first-in-class T-cell receptor (TCR)-interleukin (IL)-2 fusion molecule, plus gemcitabine (G) for Bacillus Calmette Guerin (BCG)-resistant non-muscle-invasive bladder cancer (NMIBC)." Journal of Clinical Oncology 34, no. 2_suppl (2016): 451. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.451.
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451 Background: Novel agents are necessary to treat BCG-resistant NMIBC to avoid radical cystectomy (RC). This phase I clinical trial evaluated the safety and activity of ALT-801, a recombinant humanized TCR-IL-2 fusion protein in BCG-resistant NMIBC. Methods: This is a Phase I trial using the 3+3 design to evaluate intravenous (IV) ALT-801 plus IV G 1000 mg/m2 in BCG-resistant high-risk NMIBC patients (pts) defined as high grade Ta, T1 or carcinoma in situ, size > 4 cm or multi-focal tumors. BCG-intolerant pts, those who refused or were unfit to undergo RC were also eligible. Initially, patients received ALT-801 monotherapy; an amendment added G. Pts received induction of 2 cycles, with a 13-day rest between cycles. Each cycle consisted of 4 doses of ALT-801 on Day 3, Day 5, Day 8, and Day 15 and 2 doses of G, one each on Day 1 and Day 8. Pts who have a biopsy-proven complete response (CR) after induction received one maintenance cycle and underwent response assessment. The initial dose of ALT-801 was 0.08 mg/kg with 2 step-down doses allowed if dose limiting toxicities (DLTs)- 0.06 mg/kg and 0.04 mg/kg. Results: 2 pts in cohort one received ALT-801 alone at 0.08 mg/kg per dose, a 3rd pt received G and ALT-801 at 0.08 mg/kg per dose. Grade ≥ 3 hepatotoxicity in the 3rd patient led to a step-down to 0.06 mg/kg dose. One pt in the 0.06 mg/kg dose experienced a DLT (Grade ≥ 3 hepatotoxicity) and the cohort was expanded to 6 pts with no further DLTs. Other attributed adverse events were: anorexia, pruritus, rash, edema, fatigue, chills. For the 0.06 mg/kg ALT-801 + G regimen, 6 pts received up to 2 cycles of induction and 4 pts received the maintenance cycle. All pts have completed therapy without further DLTs. CR was observed in 3 pts, which was durable in 2 pts lasting ≥ 18 months. Preliminarily immune studies have shown transient IFN-γ and IL-6 but not TNF-α and IL-10 induction after ALT-801 dosing. Conclusions: ALT-801 plus gemcitabine was feasible in BCG-resistant NMIBC and demonstrated immune responses and potential durable clinical activity. Further evaluation in expansion cohorts in a phase Ib/II trial is planned. Clinical trial information: NCT01625260.
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Chystiakov, R. S., F. I. Kostyev, V. V. Lysenko, O. V. Bondar, V. O. Varbanets, and E. M. Nareiko. "Effectiveness of hyperthermic intravesical chemotherapy in the combined treatment of patients with high-risk non-muscle-invasive bladder cancer." Urologiya 28, no. 1-4 (2024): 5–12. https://doi.org/10.26641/2307-5279.28.1-4.2024.322074.
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The aim of the study was to increase the effectiveness of treatment of patients with high-risk non-muscle-invasive bladder cancer (HR NMIBC) by using hyperthermic intravesical chemotherapy in the adjuvant mode after transurethral resection of the bladder (HIVEC-therapy group; n=53) and to compare the treatment results with patients in which adjuvant therapy was carried out with BCG vaccine (BCG therapy group; n=54). The frequency of recurrence and progression during the 36-month follow-up period differed significantly between the two groups – 22.6 and 42.6% and 7.5 and 20.4%, respectively. The difference between RFS indicators was significantly higher in the HIVEC-therapy group in periods of 12 months. (HR 0.32; p=0.02) and 36 months. (HR 0.48; p=0.04) after the end of the course of induction therapy. The median time to recurrence in patients receiving HIVEC therapy was longer than in patients receiving BCG therapy: 31.5 months. and 26.0 months. respectively (Log Rank test; p=0.034). The expression level of the proliferative activity marker Ki-67 decreased by 6.5 times in recurrent tumors under the influence of HIVEC therapy and by 2.1 times under the influence of BCG therapy (p<0.001). According to the EORTC QLQ-30 and FACT-BL questionnaires, the best level of quality of life in patients with HR NMIBC was when adjuvant chemohyperthermia was performed. When evaluating the level of toxicity of treatment according to the CTCAE scale of adverse events, a significantly higher number of cases of fever, bladder spasms, and non-infectious cystitis were found in the BCG therapy group when comparing the frequency of grade I–II adverse events. The number of grade III-IV adverse events, such as fever and urinary tract infection, was also higher in the BCG group. The implemented method of treatment of patients with high-risk non-muscle-invasive bladder cancer using the method of hyperthermic intravesical chemotherapy demonstrates treatment results comparable to the results of intravesical immunotherapy, while providing patients with a better quality of life during treatment.
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OTSUKA, MORIO. "Re-emerging infectious disease, pulmonary tuberculosis. IV. Treatment. 3. Significance of BCG vaccination." Nihon Naika Gakkai Zasshi 89, no. 5 (2000): 916–20. http://dx.doi.org/10.2169/naika.89.916.
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Black, Peter C., Catherine Tangen, Parminder Singh, et al. "Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816)." Journal of Clinical Oncology 38, no. 15_suppl (2020): 5022. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.5022.
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5022 Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or elect bladder preservation. Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 in NMIBC after BCG therapy, this trial was designed to evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This single arm phase II registration trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year aimed to enroll 135 (70 CIS and 65 non-CIS) eligible patients with histologically proven BCG-unresponsive high risk NMIBC who were unfit for or declined RC. Here we report on the subset with CIS (with or without concomitant Ta/T1) among patients who received at least one protocol treatment. The primary endpoint was pathological complete response (CR) rate at 6 months as defined by mandatory biopsy with a null hypothesis of 30% and alternative of 50% with a 1-sided alpha = 0.05 and 96% power. The 3 month CR rate, defined by cytology, cystoscopy and for-cause biopsy, is reported here as a secondary endpoint, in addition to safety. Results: Seventy-five eligible CIS patients were enrolled. Two received no treatment and are not evaluable. Of 73, median patient age was 73.4 years and median number of prior BCG doses was 12. Concomitant Ta/T1 tumor was found in 30 (41.1%) patients, including T1 disease in 16 (21.9%). A CR was observed in 30 (41.1%; 95% CI 29.7%, 53.2%) patients at 3 months and 19 (26.0%; 95% CI 16.5%, 37.6%) at 6 months. Any possibly or probably treatment-related adverse event (AE) was observed in 61 (83.6%) patients. The most frequent AEs were fatigue 36 (49.3%), pruritis 8 (11.0%), hypothyroidism 8 (11.0%), and nausea 8 (11.0%). Grade 3-5 AEs occurred in 9 (12.3%) patients and there was one treatment-related death (myasthenia gravis with respiratory failure and sepsis). Conclusion: The observed response to atezolizumab at 3 and 6 months in patients with BCG-unresponsive CIS was similar to that reported in recent similar trials and meets the benchmark for initial CR defined by the FDA guidance. This trial provided no new safety concerns. The duration of response will determine if this is a suitable treatment option for patients with BCG-unresponsive high risk CIS. Clinical trial information: 02844816 .
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Black, Peter C., Tangen Catherine, Seth P. Lerner, et al. "S1605: Phase II trial of atezolizumab in BCG-unresponsive nonmuscle invasive bladder cancer." Journal of Clinical Oncology 36, no. 6_suppl (2018): TPS527. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.tps527.
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TPS527 Background: Radical cystectomy is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC). Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 expression in NMIBC after BCG therapy, this trial will evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This is a single arm phase II trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year in 135 patients with BCG-unresponsive high risk NMIBC. The study will enroll 70 patients with CIS (with or without concomitant Ta/T1) and 65 with Ta/T1 only. Patients with CIS at baseline will undergo mandatory repeat biopsy at 6 months, and all other patients only for suspected recurrence. Patients with persistent CIS, high grade Ta/T1 recurrence or progression to muscle invasive or metastatic disease will be taken off treatment. The co-primary endpoints are: (1) complete response (CR) at 6 months in the CIS subgroup, and (2) event-free survival (EFS) at 18 months in the overall population. A hierarchical approach will be used to test the two co-primary endpoints. Secondary endpoints include duration of CR as well as progression-free, cystectomy-free, bladder cancer-specific, and overall survival in all patients. Response will be correlated to expression of PD-L1 and CD8 by IHC, and to molecular subtypes and immune signatures by RNA-sequencing. If ≥28 (40%) CIS patients respond, the agent will be considered promising. This design has a significance level of 4.6%, and a power of 96%. If the lower bound of the 90% confidence interval of the 18-month EFS excludes 20%, the investigators will conclude the regimen significantly improves EFS relative to historical data (type I error rate 0.05 and statistical power 0.93). Successful completion of this trial could lead to a new treatment paradigm for patients with BCG-unresponsive high risk NMIBC. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, and CA180863. Clinical trial registry: NCT02844816 Clinical trial information: NCT02844816.
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Singh, Parminder, Tangen Catherine, Seth P. Lerner, et al. "S1605: Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer." Journal of Clinical Oncology 35, no. 15_suppl (2017): TPS4591. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps4591.
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TPS4591 Background: Radical cystectomy is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC). Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 expression in NMIBC after BCG therapy, this trial will evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This is a single arm phase II trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year in 135 patients with BCG-unresponsive high risk NMIBC. The study will enroll 70 patients with CIS (with or without concomitant Ta/T1) and 65 with Ta/T1 only. Patients with CIS at baseline will undergo mandatory repeat biopsy at 6 months, and all other patients only for suspected recurrence. Patients with persistent CIS, high grade Ta/T1 recurrence or progression to muscle invasive or metastatic disease will be taken off treatment. The co-primary endpoints are: (1) complete response (CR) at 6 months in the CIS subgroup, and (2) event-free survival (EFS) at 18 months in the overall population. A hierarchical approach will be used to test the two co-primary endpoints. Secondary endpoints include duration of CR as well as progression-free, cystectomy-free, bladder cancer-specific and overall survival in all patients. Response will be correlated to expression of PD-L1 and CD8 by IHC, and to molecular subtypes and immune signatures by RNA-sequencing. Results: If ≥28 (40%) CIS patients respond, the agent will be considered promising. This design has a significance level of 4.6%, and a power of 96%. If the lower bound of the 90% confidence interval of the 18-month EFS excludes 20%, the investigators will conclude the regimen significantly improves EFS relative to historical data (type I error rate 0.05 and statistical power 0.93). Conclusion:Successful completion of this trial could lead to a new treatment paradigm for patients with BCG-unresponsive high risk NMIBC. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, and CA180863. Clinical trial information: NCT02844816.
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Li, Roger, Gary Steinberg, Paras Shah, et al. "Abstract CT036: CORE1: Phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG)." Cancer Research 82, no. 12_Supplement (2022): CT036. http://dx.doi.org/10.1158/1538-7445.am2022-ct036.
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Abstract Introduction: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ~20%.This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods:35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety of the combination. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction, viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: Thus far, 10 patients are evaluable at the 3 m timepoint for efficacy. Assessment of these 10 pts demonstrates 100% CR at 3 mos. Six of the 10 pts have also reached the 6 m hallmark in a CR as well as 2 at the 12 mos timepoint. Treatment related AE have been limited to transient grade 1-2 local-regional genitourinary adverse events with no grade 3 or 4 treatment related AE reported date. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. An update on the study will be provided at the time of presentation. Citation Format: Roger Li, Gary Steinberg, Paras Shah, Ed Uchio, Donald Lamm, Trinity Bivalacqua, Vignesh Packiam, Ashish Kamat, Michael Chisamore, John McAdory, Paola Grandi, Jee-Hyun Kim, James Burke. CORE1: Phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT036.
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Azim, Sidra, Sanna Fatima, Benjamin Chang, and Vijaya Ram. "ODP079 BCG-Osis, a Rare Cause of 1,25 Hydroxy Vitamin D Mediated Hypercalcemia." Journal of the Endocrine Society 6, Supplement_1 (2022): A158. http://dx.doi.org/10.1210/jendso/bvac150.323.
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Abstract Background Non-parathyroid hormone (PTH) mediated hypercalcemia is mostly related to malignancy and less commonly caused by granulomatous diseases. We report a rare case of severe hypercalcemia caused by systemic granulomatous disease after intravesical Bacillus Calmette-Guerin (BCG) treatment for bladder cancer (BCGosis). Clinical Case 74-year-old male with history of bladder cancer treated with intravesical BCG a year ago, was hospitalized with confusion, weakness, recurrent falls and polyuria for a few days. He had night sweats and 50 lb weight loss over 6 months. Lab evaluation showed hypercalcemia with calcium 10.9 mg/dL, albumin 3.6 g/dL, corrected calcium 11.2 mg/dL, PTH 12 pg/ml, and 25 OH vitamin D 44ng/ml. He had normal thyroid hormone levels, serum electrophoresis and PTHrP &lt;2 pmol/L. CT chest/abdomen/pelvis without contrast revealed sub-cm pulmonary nodules and non-obstructive renal calculi and bone scan showed no evidence of osseous metastases. He was treated with intravenous (IV) hydration and pamidronate 60 mg infusion, and his corrected calcium improved to 9.7 mg/dL. He was admitted again 3 weeks later with hypercalcemia, calcium 11.9 mg/DL, albumin 3.2 g/dL, corrected calcium 12.5 mg/dL, 25 OH vitamin D 24 ng/ml, PTH 14.6 pg/ml, and PTHrP &lt;2 pmol/L. He received IV hydration and zoledronic acid 4 mg infusion. 3 weeks later he was hospitalized for the third time for recurrent hypercalcemia and worsening renal failure, calcium 13.2, albumin 2.6 g/dL, corrected calcium 14.2 mg/dL, PTH 19.2 pg/ml. 1,25 OH vitamin D checked this time was elevated at 113 pg/mL. He received another infusion of zoledronic acid 4 mg infusion and 10 days later required denosumab 120 mg for resistant hypercalcemia. PET CT scan showed multiple hypermetabolic foci in right neck, right anterior 4th rib, scrotum, and around left kidney and aorta. He underwent biopsy of the right rib lesion which demonstrated + AFB on smear and histiocytic inflammation, which led to diagnosis of BCGosis, with subsequent cultures positive for Mycobacterium bovis. He was started on multi drug regimen with rifampin, isoniazid and ethambutol. Follow up labs at 4 weeks showed normalization of calcium 8.9 mg/dL, albumin 3.2 g/dL, corrected calcium 9.78 mg/dL, PTH 54 pg/ml and low 1,25 OH vitamin D 17 pg/mL. Calcium and 1,25 OH vitamin D levels were stable at 4 months follow up. Conclusion Intravesical BCG treatment can be associated with systemic reactions in 1- 5% of patients. Granulomas associated with disseminated BCG infection can lead to hypercalcemia due to increased 1-alpha-hydroxylase activity in macrophages, causing elevated 1,25 OH vitamin D levels. Therefore, evaluation of 1,25 OH vitamin D levels is critical to determine the etiology of hypercalcemia. Treatment of underlying BCGosis with anti-tuberculosis treatment is key in management of hypercalcemia along with supportive treatments that may include IV hydration, bisphosphonates and/or glucocorticoids. Presentation: No date and time listed
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Hidayah, Listiani, Nur Muflihah, Andhika Mayasari, and Fatma Ayu Nuning Farida Afiatna. "Perencanaan Strategi Pemasaran Untuk Meningkatkan Penjualan Produk Batik Khas Jombang di Era New Normal." Jurnal Ilmiah Universitas Batanghari Jambi 22, no. 3 (2022): 1857. http://dx.doi.org/10.33087/jiubj.v22i3.2707.
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UKM Batik Tulis New Colet Jombang produces three types of batik, namely hand-written batik, stamped batik, and semi-written batik. The problem occurs when batik sales decline due to the Covid-19, so it requires planning a marketing strategy to increase sales in the new normal era. The study aims to determine the internal and exsternal factor in UKM Batik Tulis New Colet Jombang, planning a marketing strategy using SWOT, BCG, and QSPM methods. Internal factors consist of strengths and weaknesses, while external factors consist of opportunities and threats. The results of the SWOT matrix can be seen that difference between internal factors is 1,95 and eksternal factors is -0,19. This shows that position of SMEs in quadrant IV and requires a W-T (Weaknesses-Threats) strategy. The BCG matrix in the dogs position, meaning that sales level is low at 3,25% and has a market share of 0,97 times of the competitor. Furthermore, alternative strategy QSPM method that gets highest TAS score of 4,4 is alternative 1, which means that the SMEs must innovate products with creative motivies.
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Arora, Sunisha, K. Upasana, Dhwanee Thakkar, Anjali Yadav, Neha Rastogi, and Satya P. Yadav. "Fatal Severe Cytokine Release Syndrome Post-haploidentical Stem Cell Transplant With Post-transplant Cyclophosphamide in an Infant With Severe Combined Immunodeficiency and Disseminated Bacille Calmette-Guérin Infection." Journal of Pediatric Hematology/Oncology 45, no. 6 (2023): e773-e774. http://dx.doi.org/10.1097/mph.0000000000002700.
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Introduction: Severe Combined Immunodeficiency (SCID) is a primary immunodeficiency disorder characterized by absent or dysfunctional T lymphocytes, leading to defective cellular and humoral immunity requiring urgent hematopoietic stem cell transplantation (HSCT). We report a case of SCID with disseminated Bacille Calmette-Guérin (BCG) infection who developed cytokine release syndrome (CRS) and possible Immune reconstitution inflammatory syndrome (IRIS) after Haploidentical HSCT with post-transplant cyclophosphamide. Methods: Data were retrospectively retrieved from electronic medical records. Result: A 5-month-old male infant was referred with fever, cough, and generalized maculopapular rash for 15 days, and had pallor without hepatosplenomegaly or lymphadenopathy. He had a history of previous male sibling death at 6 months of age due to pneumonia. Investigations: hemoglobin: 4.7 g/dL, TLC-6.37×103/uL, absolute lymphocytes: 0.98×103/uL, platelets: 319×103/uL, bilateral patchy opacities in both lung fields, and low immunoglobulin levels. Lymphocyte subset analysis revealed T−, B+, NK− SCID. Genetic analysis showed a hemizygous mutation in IL2RG (c.314A>G). The child received intravenous (IV) antibiotics, antifungal, antitubercular drugs, irradiated blood products, and IV immunoglobulins. Urgent haploidentical HSCT from the mother was planned. Conditioning was Fludarabine-40 mg/m2/d for 4 days, cyclophosphamide: 14.5 mg/kg/d for 2 days. He received peripheral blood hematopoietic stem cells with CD34− 15×106 cells/kg and CD3− 805×106 cells/kg. Within 2 hours of stem cell infusion, he developed respiratory distress, fever, shock, and flaring of rash. Methylprednisolone was started in view of CRS. On day+2, he had sudden desaturation and bradycardia needing mechanical ventilation and inotropes. His inflammatory markers were elevated (Ferritin: 3640 ng/mL, IL-6:5000 pg/mL, CRP:255 mg/L). In view of high-grade CRS, he received an injection of tocilizumab 8 mg/kg on day +2 and day +4. He received post-transplant cyclophosphamide 5 mg/kg on day +3. The endotracheal secretion GeneXpert was positive for Mycobacterium supporting the diagnosis of disseminated tuberculosis. Our patient had disseminated BCG infection which could also be contributory in the initiation of IRIS as the mother was immunized with the BCG vaccine in childhood so she must be having cytotoxic T cells specific for BCG, which were transferred to the infant with peripheral blood stem cell product. He succumbed to severe acute respiratory distress syndrome and multiorgan dysfunction on day +5 post-transplant. Conclusions: In haploidentical HSCT of SCID, post-transplant course can be complicated by CRS and IRIS as these patients are inefficient in mounting any response to infused donor lymphocytes resulting in their unregulated growth.
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Olson, Devra, Yen Lin Chia, Enaharo Iboi, et al. "Abstract LB246: Enfortumab vedotin, a nectin-4-directed antibody-drug conjugate, demonstrates compelling antitumor activity in non-muscle invasive bladder cancer models which predicts minimal systemic exposure when administered by intravesical instillation in patients." Cancer Research 83, no. 8_Supplement (2023): LB246. http://dx.doi.org/10.1158/1538-7445.am2023-lb246.
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Abstract Enfortumab vedotin (EV) is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder cancers. Preclinically, EV has demonstrated tumor cell killing by direct cytotoxicity and bystander effect and can induce the hallmarks of immunogenic cell death. EV improves survival in adults with previously treated locally advanced or metastatic urothelial carcinoma (la/mUC) and is approved in the US, Europe, Japan, and others. Most newly diagnosed bladder cancer cases are non-muscle invasive (NMIBC). Standard treatment of high-risk NMIBC involves transurethral resection followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although response to BCG is high, recurrence is common, and treatment options for patients with BCG-unresponsive tumors are limited, underscoring the significant unmet need. Previously, we demonstrated compelling preclinical antitumor activity of EV in NMIBC models with a favorable safety profile and minimal systemic exposure. EV-mediated antitumor activity was confirmed in a mouse model of NMIBC by both bioluminescence imaging and IHC for hNectin-4-expressing cancer cells. Following intravesical administration of EV, tumor growth inhibition ranged 46-96% across the dose range tested. Colocalization of EV to Nectin-4-positive tumor tissues was confirmed by IHC in the engrafted tumor cells. Systemic EV exposure in tumor-bearing mice was low, consistent with previous nonclinical studies, supporting that the antitumor activity is driven by local exposure within the bladder. In a repeat-dose GLP toxicology study in rats, no systemic toxicities were observed at intravesical doses up to 6-fold higher than the maximum tolerated IV dose. This lack of systemic toxicities that can occur with IV administration in rats was likely due to minimal systemic exposure of both EV and unconjugated MMAE. Currently, the safety, tolerability, and antitumor activity of intravesical EV are being evaluated in a Phase 1 study in adults with high-risk, BCG-unresponsive NMIBC (EV-104, NCT05014139). The initial dose level for EV-104 was selected to be active and predicted to have minimal systemic absorption based on preclinical and known clinical IV data. Here, we present confirmatory clinical data demonstrating that EV and unconjugated MMAE are undetectable in the bloodstream at the starting dose. These findings confirm the translatability of our nonclinical models and provide evidence that intravesical administration of EV in NMIBC is a promising approach that limits systemic exposure. These data support the potential for a favorable safety and activity profile and warrant continued investigation of intravesical EV in patients with NMIBC. Citation Format: Devra Olson, Yen Lin Chia, Enaharo Iboi, Lauren Farr, Maddy Burcher, Anthony Lee, Kelly Hensley, Sean Allred, Abbie Wong, Masashi Shimazaki, Masamichi Mori, Sharsti Sandall, Christopher Carosino. Enfortumab vedotin, a nectin-4-directed antibody-drug conjugate, demonstrates compelling antitumor activity in non-muscle invasive bladder cancer models which predicts minimal systemic exposure when administered by intravesical instillation in patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB246.
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Bellmunt, Joaquim, Alejo Rodríguez-Vida, Imanol Martinez, et al. "A phase II prospective, open-label, multi-center, single-arm study of sasanlimab plus sacituzumab govitecan in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) pts: SSANTROP (APRO07-2022)." Journal of Clinical Oncology 43, no. 16_suppl (2025): 4596. https://doi.org/10.1200/jco.2025.43.16_suppl.4596.
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4596 Background: Radical cystectomy (RC)is the standard treatment forBCG unresponsive high-risk (HR) NMIBC patients (pts). Pembrolizumab (Pem) was approved by the FDA based on Keynote-057 (41% complete response rate (CRR)) and offers a non-surgical option for pts who decline or are ineligible for RC. Nadofaregene firadenovec and Nogapendekin alfa inbakicept have been recently approved in this setting. Sacituzumab govitecan (SG) demonstrated encouraging efficacy and safety in metastatic urothelial cancer (mUC) in the TROPHY-U-01 trial. Combining ADCs with immunotherapy showed promising results in mUC. We hypothesized if the combination of sasanlimab (Sa), a subcutaneous (SC) anti-PD1 agent, and SG would improve the CRR of Pem in BCG-unresponsive NMIBC pts who refuse or are ineligible for RC. Methods: SSANTROP is a phase II study conducted across 18 sites in Spain to assess the CRR at 3 months (mo) of the combination of Sa (5 cy of Sa 300 mg SC on day 1 every 28 days) plus SG (7 cy of SG 10 mg/kg IV on days 1 and every 21 days) in BCG unresponsive HR NMIBC. Pts achieving CR at 3 mo received maintenance therapy: Sa 300 mg SC every 28-day for up to 2 years. Primary endpoint was CRR at 3 mo with plan for percentage of response assessment maintained at 12 and 15 mo. Key eligibility criteria: ECOG PS 0-1, histologically confirmed BCG-unresponsive HR NMIBC, refusal or ineligibility for RC, urothelial carcinoma histology, and no prior anti-PD1/L1 or anti-CTLA-4 therapy. The sample size of 116 pts was calculated to demonstrate a 53% CRR for the combination, based on a Pem historical control of 41% (one-sided alpha 0.05, power 82%). Design was modified to finally include 40 pts based on a change in the treatment landscape of UC. Results: As of January 21, 2025, 59 pts were screened, and 41 initiated treatment and were included in the safety analysis. Among them, 32 (78%) male, median age of 70.6 years (SD 7.8). Types of BCG-unresponsive disease included: persistent/recurrent CIS alone or with recurrent HG Ta/T1 within 12 mo post-BCG (22 pts, 53.7%), recurrent HG Ta/T1 within 6 mo post-BCG (16 pts, 39%), and T1 HG disease at first evaluation post-induction BCG (3 pts, 7.3%). The most common adverse events (AEs) were diarrhea (58.5%), asthenia/fatigue (58.5%), alopecia (41.5%), neutropenia (36.6%), anemia (24.4%) and stomatitis (22%). Most common grade ≥ 3 AEs included neutropenia (9 pts, 22%), febrile neutropenia (5 pts, 12.2%). G-CSF prophylaxis was implemented as of 09/2024. As of 12/2024 and based on 25 evaluable pts, CRR at 3 mo was 68% (17/25). Conclusions: This trial is the first to evaluate the combination of Sa and SG in BCG-unresponsive HR-NMIBC. With preliminary 3 mo CRR of 68%, the safety analysis identified no unexpected concerns, with severe AEs mainly involving neutropenia and febrile neutropenia. No treatment related toxic deaths occurred. Clinical trial information: 2022-002998-28 .
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Hoshimoto, S., T. Shingai, H. Wang, R. M. Elashhoff, D. L. Morton, and D. S. Hoon. "Validation of a multimarker blood assay for postoperative assessment of stage IV melanoma patients in a prospective international phase III trial." Journal of Clinical Oncology 27, no. 15_suppl (2009): 9045. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.9045.
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9045 Background: Currently there are no validated prognostic molecular biomarkers for assessment of outcome after complete resection of stage IV melanoma patients. To validate blood molecular biomarkers for prognostic value and monitoring of these patients, we evaluated the clinical utility of a multimarker quantitative reverse-transcription PCR (qRT-PCR) for detecting circulating tumor cells (CTC) of patients blood enrolled in a multicenter international (29 sites) phase III trial of postoperative adjuvant therapy. After complete metastasectomy, AJCC stage IV patients underwent immunotherapy with bacille Calmette-Guerin (BCG) plus placebo or BCG plus melanoma vaccine. Methods: Bleeds were taken before and during treatment in both randomized treatment arms. Pre- and during treatment bleeds from patients were assessed by an optimized qRT-PCR assay for MART1, MAGEA3, and PAX3 genes mRNA. Median clinical follow-up time was 21.8 and 24.2 mos. for disease-free survival (DFS) and overall survival (OS), respectively. Results: MART1, MAGEA3, and PAX3 were detected in 64 (26%), 56 (23%), 73 (29%) of 244 post-operative pretreatment patients, respectively. Multivariate Cox analysis showed that biomarker-negative patients had significantly higher DFS than biomarker- positive patients (risk ratio 1.56, 95% CI, 1.14 - 2.15; P=0.0062). In serial-bleeds (pretreatment, mos 1 and 3) analysis of 214 patients, biomarker-negative patients had significantly higher OS than patients with 1–2 positive- or 3 positive-biomarkers (risk ratio 2.37, 95% CI 1.14 - 4.94, P=0.021; and risk ratio 2.90, 95% CI 1.28 - 6.53, P=0.01, respectively). Multivariate analysis confirmed that 1–2 positive- and 3 positive-biomarkers were significant independent prognostic factors for poor OS (risk ratio 2.44, 95% CI 1.16 - 5.12, P=0.019; and risk ratio 3.08, 95% CI 1.36 to 6.98, P=0.007, respectively). Conclusions: This prospective multicenter blood biomarker validation study demonstrates that multimarker qRT-PCR analysis of CTC has significant clinical utility as a prognostic factor of disease outcome at pretreatment, and as a treatment monitoring prognostic factor in stage IV melanoma patients. No significant financial relationships to disclose.
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Simonson, Andrew W., Allison N. Bucsan, Joseph J. Zeppa, et al. "The role of lymphocyte subsets in preventing tuberculosis following intravenous vaccination with BCG." Journal of Immunology 208, no. 1_Supplement (2022): 181.11. http://dx.doi.org/10.4049/jimmunol.208.supp.181.11.
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Abstract Background We previously demonstrated in non-human primates (NHP) that intravenous (IV) administration of BCG induces substantial T cell responses and often sterilizing immunity against Mycobacterium tuberculosis (Mtb) infection. Here, we investigated the role of T cell populations in this unmatched response in the context of necessary immune mechanisms for protection against tuberculosis (TB). Methods Beginning 20 weeks after vaccination and through the end of the study, rhesus macaques were infused with antibodies to deplete CD4, CD8α, or CD8β expressing T cells, or with control IgG/saline. NHPs inoculated with ~15 CFU Mtb Erdman via bronchoscope were monitored for 8 weeks. Granulomas, areas of disease, lung tissue and thoracic lymph nodes (LNs) were harvested at necropsy using FDG PET CT as a map to identify inflamed lesions. Immune responses were analyzed by spectral flow cytometry and homogenates were plated for colony forming unit (CFU) quantification. Results Successful depletion of expected cell types was seen in blood, airways, LNs and lung tissue. Depletion of CD4 T cells ablated IV BCG mediated protection in all NHPs. CD8α and CD8β depleted NHPs retained varying levels of protection, leading to mixed outcomes by bacterial burden. Preliminary results indicate the loss of protection following CD8α (both innate and adaptive cells) and CD8β (mainly adaptive cells) depletion is similar, suggesting a key role for conventional CD8 T cells in vaccination. Conclusions Our results provide critical insight regarding roles played by CD4 and CD8 T cell populations in terms of defining desired responses for vaccination against progressive TB. Functionality of these cells in immunized NHPs will clarify the purposes of T cell subsets. Supported by grants from Bill and Melinda Gates Foundation and NIH NIAID (75N93019C00071)
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Shore, Neal D., Shilpa Gupta, Girish S. Kulkarni, et al. "Phase 2 KEYNOTE-057 cohort C: Pembrolizumab (pembro) with vibostolimab or favezelimab for patients (pts) with high-risk (HR) bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC)." Journal of Clinical Oncology 41, no. 6_suppl (2023): TPS591. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.tps591.
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TPS591 Background: The PD-1 inhibitor pembro showed antitumor activity in cohort A of the phase 2 KEYNOTE-057 study (NCT02625961), with 41% of pts with HR BCG-unresponsive carcinoma in situ (CIS) of the bladder ± papillary tumors achieving a CR at 3 months with a median DOR of 16.2 months. Based on these results, pembro was approved in the United States for treatment of pts with BCG-unresponsive HR NMIBC with CIS ± papillary tumors who are ineligible for or have elected not to undergo radical cystectomy (RC). However, novel combinations that improve the efficacy of pembro are needed. Immune checkpoints TIGIT and LAG-3 have been shown to contribute to treatment resistance in many cancers, and their inhibition may enhance the activity of pembro. Cohort C of KEYNOTE-057 will evaluate the efficacy and safety of coformulations of pembro and TIGIT inhibitor vibostolimab or LAG-3 inhibitor favezelimab in pts with HR BCG-unresponsive NMIBC with CIS ± papillary tumors. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC that is unresponsive to BCG (defined as persistent or recurrent CIS alone or with Ta/T1 ≤12 months of completion of adequate BCG therapy) who are ineligible for or elect not to undergo RC, have CIS ± papillary tumors at baseline (CIS alone, Ta + CIS or T1 + CIS), and have an ECOG score of 0-2. Approximately 60 pts will be randomly assigned 1:1 to Arm 1 (coformulation of pembro 200 mg and vibostolimab 200 mg) or Arm 2 (coformulation of pembro 200 mg and favezelimab 800 mg) IV Q3W (≤35 administrations) until central pathology-confirmed ≥T1 at any time point or persistent or recurrent CIS or high-grade ≥Ta at the 24-week efficacy review or thereafter. Pts with central pathology–confirmed low-grade pTa at any time point may continue treatment following resection of visible tumors. In the absence of disease persistence/recurrence or progression, treatment will continue until unacceptable toxicity, decision to withdraw, or administrative reasons. Tumor evaluations will be performed Q12W until year 2, then Q24W thereafter for up to 5 years. The primary efficacy end point is 12-month CR rate of HR NMIBC as determined by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review. Secondary efficacy end points include DOR of HR NMIBC in responders; overall CR rate and CR rate at 3 and 6 months; PFS to worsening of grade, stage, or death; PFS to muscle-invasive or metastatic disease or death; and OS. The safety objective will characterize the safety and tolerability in all pts who received ≥1 dose of study treatment. Efficacy will be evaluated in all pts who received ≥1 dose of study treatment and have a baseline evaluation consisting of pre-enrollment cystoscopy, TURBT/biopsy, urine cytology, and baseline CT urography imaging. Clinical trial information: NCT02625961 .
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Li, Roger, Gary Steinberg, Donald Lamm, et al. "955 CORE1: phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non muscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guerin (BCG)." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (2021): A1005. http://dx.doi.org/10.1136/jitc-2021-sitc2021.955.
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BackgroundCG0070, an oncolytic vaccine available as an intravesical therapy, is a serotype 5 adenovirus engineered to express GM-CSF and replicate in tumor cells with mutated or deficient RB (which results in increased of the transcription factor E2F). The CG0070 mechanism of action includes direct cell lysis in conjunction with immunogenic cell death which is enhanced in the presence of GM-CSF. In an initial phase 1 study as well as a subsequent phase 2 study, an overall CR rate of ~62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. Intravenous Pembrolizumab was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12m CR rate of ~20%. This phase 2 study (NCT04387461) will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC.Methods35 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVE) CG0070 at a dose of 1x10e12 vp in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at 3, 6, 9, 12, and 18m. Patients with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 CG0070. Pembrolizumab will be administered up to 24m. Assessment of response will include q 3m cystoscopy with biopsy, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12m.ResultsThe primary endpoint is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety of the combination. Correlate assessments will include changes in the TME, systemic immune induction, viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response. At this time the first 5 patients demonstrates 100% 3 m CR. Treatment related AE have been limited to transient grade 1-2 urinary frequency (3 patients) and grade 1 bladder spasm, hematuria, painful urination, thyroiditis, and flu-like symptoms (one patient/each). No grade 3, 4, 5 AE or SAE were observed.ConclusionsThe study is currently enrolling. Preliminary safety and efficacy data on 8 patients will be available by November 2021Trial RegistrationNCT04387461Ethics ApprovalIRB: CG2003C
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Tambunan, Willy, Yudi Sukmono, and Luvita Okti Anggreani. "Analisis Strategi Pemasaran untuk Meningkatkan Volume Penjualan dan Daya Saing." Jurnal Optimalisasi 7, no. 1 (2021): 48. http://dx.doi.org/10.35308/jopt.v7i1.3419.
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UKM Roti H-34 is one of the Small and Medium Enterprises (UKM) in Samarinda City which is engaged in the culinary field that produces unyil bread. The superior product has decreased in sales. Based on this, this study aims to determine the best alternative marketing strategy solutions to increase sales volume and competitiveness based on internal and external factors that affect the company. Marketing strategy analysis is carried out in several stages, the first is using the IFE and EFE matrices. The results obtained on the IFE matrix is 3.779, while the EFE matrix is 2.905. The second stage is the matching stage using the BCG matrix, benchmarking, IE matrix and SWOT matrix. In the BCG matrix, the results show that the market growth rate of -37% of the market share of each competing company is 0.22, 0.23, and 0.25, which indicates that the company is in the dog quadrant. In the IE matrix, it is found that UKM Roti H-34 is in cell IV, a strategy that can be used, namely growth and build. Then formulated a strategy using the SWOT matrix and obtained nine alternative strategies. The final stage is the decision stage to use QSPM for the selection of strategies that can be implemented by UKM Roti H-34. The alternative strategy that is most appropriate to be applied is to use the internet media to carry out online promotions in order to increase sales and the number of consumers with a TAS of 5.447.
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Hena, Zafar, Priya Kannu, and Prakash Jaiswal Bir. "Impact of Malnutrition on TB Development in BCG-Vaccinated Children Aged 2 Months to 12 Years." International Journal of Current Pharmaceutical Review and Research 16, no. 05 (2024): 228–32. https://doi.org/10.5281/zenodo.12785727.
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AbstractAim: The aim of the present study was to assess the influence of malnutrition in development of tuberculosis inBCG vaccinated children in age group of 2 months to 12 years.Methods: The Present study was a prospective study carried out at Nalanda Medical College and Hospital, Patna,Bihar, India. Study population was children in the age group of 2 months to 12 years with symptoms suggestiveof tuberculosis. In our study, we studied 100 patients.Results: Majority of the patients belong to 1 to 5 years (40%) followed by 6 to 10 years (26%). Patients less than1 year were 17%. In our study, positive history was shown by 22% population and 78% showed negative historyfor tuberculosis. The predominant symptoms of presentation are Fever 66 (66%) and cough 59 (59%). 37 (37%)had initial presentation as seizures. 36% had weight loss or poor weight gain, significant lymphadenopathy wasobserved in 25 (25%) cases and 14 (14%) had wheezing. 21 (21%) had Grade I, 16 (16%) had Grade II PEM, 14(14%) had Grade III PEM and 5 (5%) had Grade IV PEM according to IAP Classification of Malnutrition. 44(44%) cases had normal nutritional status. Disseminated and Milliary TB was more in children with Grade IIIand Grade IV malnutrition. 5 cases of TBM had normal nutrition whereas 3 cases each had grade I and grade IIImalnutrition. 1 case of abdominal tuberculosis had normal nutrition and 1 case had grade I malnutrition.Conclusion: Protective benefit of BCG vaccine against the dissemination of tuberculosis is children in possibleonly if they have normal nutrition
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Kulkarni, Girish S., Kyle A. Richards, Peter C. Black, et al. "A phase II clinical study of intravesical photo dynamic therapy in patients with BCG-unresponsive NMIBC (interim analysis)." Journal of Clinical Oncology 41, no. 6_suppl (2023): 528. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.528.
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528 Background: Novel therapies are required for BCG-unresponsive, high risk non-muscle invasive bladder cancer. We report the interim results of a Phase II Clinical Study of Intravesical Photo Dynamic Therapy (PDT) in patients with BCG-Unresponsive Carcinoma In-Situ (CIS) with or without papillary disease. Methods: Out of a planned 125 patients, 42 patients have been enrolled and treated with two Study Treatments (Day 0 and Day 180) consisting of an intravesical instillation of the photosensitizer TLD-1433 (0.70 mg/cm2) followed by activation with a 520 nm intravesical laser under general anesthesia (Study Device TLC-3200) to a total of 90 J/cm2 of laser light. The primary outcome assessed was efficacy, evaluated by Complete Response (CR), at any point in time. The secondary outcome was duration of CR at 12 months, post initial CR. A tertiary objective is safety, evaluated by the incidence and severity of Adverse Events, Grade 4 or higher that do not resolve within 450 days post treatment. Patients with a negative cystoscopy and positive cytology have been defined as indeterminate response (IR), as these patients remain under investigation for lower and upper tract urothelial carcinoma. Results: Interim analyses included the first 42 patients, along with 3 patients treated in a preceding Phase Ib NMIBC clinical study assessing the safety of TLD-1433 PDT who weretreated at the same parameters, for a total of 45 patients. Data for the primary and secondary outcomes are listed in the table.The interim clinical data demonstrates a 90 day CR of 50% and a duration of response at 360 and 450 days of 35% and 21%, respectively.There have been eight Serious Adverse Events (SAE) identified (2 Grade II (tachycardia, hematuria), 3 Grade III (acute kidney injury, cellulitis), 2 Grade IV (urosepsis, depression/anxiety) and 1 Grade V). None of the SAEs were deemed to be directly related to the PDT. Conclusions: The interim data support that treatment with Photo Dynamic Therapy provides a viable treatment option for patients with BCG unresponsive CIS (+/- papillary disease) with an acceptable ongoing safety profile. Clinical trial information: NCT03945162 . [Table: see text]