Journal articles on the topic 'Wang Zhiyuan'

In post-Mao China, a group of Chinese intellectuals who formed what became the New Left (新左派) sought to renew socialism in China in a context of globalization and the rise of social inequalities they associated with neo-liberalism. As they saw it, China’s market reform and opening to the world had not brought greater equality and prosperity for all Chinese citizens. As part of China Information’s research dialogue on the intellectual public sphere in China, this article provides a historical survey of the development of the contemporary Chinese New Left, exploring the range of ideas that characterized this intellectual movement. It takes as its focus four of the most prominent New Left figures and their positions in the ongoing debate about China’s future: Wang Shaoguang, Cui Zhiyuan, Wang Hui, and Gan Yang.

Abstract Small cell carcinomas of the lung, bladder, and prostate share similar transcription patterns and drug sensitivities. Due to their high cellular plasticity, these cancers often escape treatment through a trans-differentiation from adenocarcinoma to the neuroendocrine state. We previously developed a pan small cell cancer in vitro/in vivo model named PARCB that can recapitulate this transition from primary patient tissues. To understand which transcription factors may be important in this transition, we conducted bulk and single cell RNA sequencing over time. We identified a developmental trajectory that is shared among all samples and is defined by stage-specific transcription factors. We plan to interrogate the role that these transcription factors play in the PARCB transformation assay. We performed ATAC sequencing to investigate how these transcription factors regulate these transitional states. Our study will provide a basic understanding of the transcriptional changes that occur during neuroendocrine differentiation and provide new potential therapeutic targets for small cell cancers. Citation Format: Chia-Chun Chen, Kai Song, Wendy Tran, Matthew Obusan, Tyler Sugimoto, Katherine Sheu, Donghui Cheng, Grigor Varuzhanyan, Liang Wang, Lisa Ta, Zhiyuan Mao, Nathanael Bangayan, Jung-Wook Park, Thomas Graerber, Owen Witte. Elucidating transcriptional dynamics in neuroendocrine differentiation of advanced prostate 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 789.

Abstract Breast cancer has now risen to the number one cancer in the world, posing a great threat to human health. LILRB2 (leukocyte immunoglobulinlike receptor B2) is an important immunosuppressive receptor protein, which is mainly expressed in myeloid cells, such as macrophages and dendritic cells. At present, we have found clinically that patients with breast cancer bone and bone marrow metastasis have higher expression of LILRB2. In our research, we used Western blotting, real-time fluorescent quantitative Polymerase Chain Reaction (RT-PCR), flow cytometry, and other experimental methods to explore the expression and function of LILRB2 in breast cancer cells. In our research, we found that LILRB2does increase expression in breast cancer cells, therefore, we want to explore the role of LILRB2 in breast cancer cells. we find that LILRB2 will accelerate the proliferation of tumor cells and increase their migration ability. We tested the related signal pathways and found that LILRB2 can promote the enhancement of the NF-Kb signal pathway. Further, we have done related LILRB2 correlation analysis and found that LILRB2 can reduce human leukocyte antigen-A (HLA-A) Expression. Next, we tested the changes in the level of major histocompatibility complex (MHC-1) related mRNA and found that its mRNA expression increased, which was inconsistent with the decrease in its protein level we observed. Therefore, we used the proteasome inhibitor MG132 for treatment, and the results showed after adding MG132, the decrease in HLA-A expression caused by overexpression of LILRB2 was restored. Next, we knocked down the breast cancer cell line of membrane-associated ring finger (MARCH9). After we knocked down MARCH9, transfection of LILRB2 did not increase the ubiquitination of HLA-A. Therefore we show that LILRB2 can mediate the post-translational modification of HLA-A via MARCH9, which in turn mediates the degradation ofHLA-A. In conclusion, our research shows that LILRB2 maybe a candidate of clinical target for the treatment of breast cancer, preventing possible bone and bone marrow metastasis from breast cancer. Citation Format: Hui Zhao, zhiyuan jiang, zhiyu wang, yujie chang, shunyi ruan. LILRB2 mediates the immune escape of breast tumor cells by degrading HLA-A [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 5665.

Abstract One key hurdle for the CAR-T cell treatment of solid tumors is the limited accessibility of solid tumor antigens outside the tumor microenvironment, which prohibits the expansion of solid tumor-targeting CAR-T cells in patients. Here, we report the characterization of prostatic acid phosphatase (PAP) as a feasible CAR-T target for prostate cancer and a novel approach, named CoupledCAR, to expand solid tumor-targeting CAR-T cells lacking solid tumor antigens based on the observation of non-transduced T cells proliferating together with CD19 CAR-T cells during the treatment of acute lymphocyte leukemia. We demonstrated that CoupledCAR can significantly enhance the expansion and antitumor efficacy of PAP CAR-T cells both in vitro and in vivo. Furthermore, we showed that the expansion of solid tumor-targeting CAR-T cells does not depend on CAR/CD3ζ stimulation through direct antigen binding with CAR but enhances the memory status of CAR-T cells and causes little exhaustion. Since the CoupledCAR system does not rely on solid tumor antigens, we propose that it can be utilized in all CAR-T and T cell therapies for the treatment of solid tumors. Citation Format: Zhiyuan Cao, Chengfei Pu, Xianyang Jiang, Guiting Han, Yuzhe Peng, Wensheng Wang, Wei Ding, Xiaogang Shen, Dongqi chen, Beibei Jia, Xiaoqiang Xu, Zhipeng Huang, Xi Huang, Wenbi Liu, Ruihong Zhu, Lee Tian, Christopher Ballas, Victor.X Lu, Zhao Wu, Lei Xiao. Antigen-independent expansion enhances efficacy of CAR-T cells against solid tumor [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 2838.

Abstract Gastric adenocarcinoma (GAC), a global health burden, lacks detail understanding of the evolution-driven cellular/molecular programs that lead to GAC tumorigenesis followed by progression/metastases. The definition of the interplay(s) between immune/stromal cells and premalignant/malignant GAC cells could propel us into a new dimension of understanding and therapeutics. Here, we performed a comprehensive single-cell profiling of 68 specimens collected from 43 subjects including non-neoplastic tumor adjacent tissue, precancerous lesions, localized, and metastatic GACs. We profiled a total of 77,392 high-quality cells which revealed 62 unique cell states uncovering varying profiles. We define alterations in TMEs that underscore initiation of tumorigenesis to eventual progression. For instance, we found a striking preponderance of B lineage cells, primarily the IgA+ plasma cells, in TMEs of the precancerous lesions, whereas 3 immunosuppressive myeloid subsets with high expression of genes signature including SPP1, LAIR1, SIRPA, TIM-3, TGFB1, and MARCO dominated in advanced GACs. We observed that fractions of GZMK+ effector CD8 T cells and progenitor exhausted CD8 T cells gradually increased as GACs progressed to advanced stages with highest abundant in metastatic GACs. In addition, our analysis revealed extensive stromal remodeling along the GAC continuum, which may have contributed to enhanced angiogenesis and progressive immune suppressive signaling. Notably, we uncovered 3 unique TME interactomes that are defined by 6 cellular environtypes that provide context-dependent definition and granularity to GAC networks inhabited by 62 TME cell subsets giving GAC to a novel landscape not yet defined. The two distinct environtypes in GAC primaries are validated in three independent large-scale GAC cohorts, giving credence and definition to previously established histopathological variables, genomic/molecular subtypes and clinical outcomes. The analysis of tumor associated stromal cells discovered SDC2 as an exploitable target to pursue. SDC2 was not only abundant in the stroma, but the abundance is validated in 3 independent single-cell GAC cohorts as well as at the protein level using independent approaches. Overexpression of SDC2 formed a gradient from early GAC to metastatic and is prognostic in large-scale GAC cohorts examined. This study provides an atlas of GAC TMEs from tumorigenesis to advanced GAC that could be further developed for novel therapeutics but also serves as a community resource. Citation Format: Ruiping Wang, Shumei Song, Jiangjiang Qin, Yuan Li, Yibo Fan, Deyali Chatterjee, Ghia Tatlonghari, Zhiyuan Xu, Can Hu, Shaowei Mo, Matheus D. Sewastjanow, Ahmed Adel Fouad Abdelhakeem, Zhenning Wang, Xiangdong Cheng, Jaffer A. Ajani, Linghua Wang. A single-cell atlas of tumor microenvironment defines the continuum of gastric adenocarcinoma tumorigenesis and progression [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 5017.

Abstract Tumor metastasis to the skeleton affects over 70% cancer patients, more than any other site of metastasis Skeletal related events (SREs) included spinal cord compression, fracture, bone radiation or surgery, and tumor-related hypercalcemia are severe complications of bone metastases, which impair patients life quality and require particular treatments The gold standard for the definitive diagnosis is still pathological examination, which needs pre-biopsy imaging review to improve the diagnosis efficacy Classic imaging review method for being CT (Computed Tomography) and 18F-FDG PET/CT Research has shown that 18F-FDG PET/CT is superior to CT in detecting bone metastasis, however, it is not validated by a prospective study Besides, as SUVmax is a metabolic parameter in oncology imaging, we can serve as a reliable semiquantitative indicator to differentiate bone lesions We conducted a prospective clinical trial at Shanghai Sixth People’s Hospital Inclusion criteria were as follows: referred for diagnostic biopsy on a suspicion of metastatic disease Exclusion criteria included contraindications for biopsy 205 patients participated in the cohort study, then were randomized into PET/CT and CT group They underwent 18F-FDG PET/CT and CT separately to confirm accurate location, then both received CT-guided bone biopsy to confirm The sensitivity, specificity and accuracy were calculated In PET/CT group, malignant bone metastases were found in 83/137 patients and biopsies proved 80 were actual metastases In CT group, 48 malignant bone metastases were spotted and 47 were truly decisive The sensitivity, specificity and accuracy of 18F-FDG PET/CT and CT are 99% vs 87%, 95% vs 93%, and 97% vs 88% A chi-square test was utilized to analyze The sensitivity of 18F-FDG PET/CT is better than CT (P=0 0065), but the specificity and accuracy had no differences, indicating 18F-FDG PET/CT could detect more bone metastatic lesions potentially than CT We also found metastasis malignant lesions had higher bone SUVmax than benign (median 9 3 vs 4 25, p <0 001) ROC curves were asked to evaluate the differential efficacy of SUVmax In all 137 patients, the SUVmax 6 3 showed an AUC of 0 874 to predict malignant metastases Our research shows that [18F]FDG PET/CT has greater sensitivity in detecting malignant bone metastases than CT, and SUVmax can be different criteria for determining the malignancy of bone lesions Citation Format: Hui Zhao, Yujie Chang, Zhiyuan Jiang, Zhiyu Wang, Shunyi Ruan. 18F-FDG PET/CT detects potentially malignant bone metastases in patients with suspected lesions: A prospective clinical trial [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 CT543.

Abstract Many aggressive epithelial cancers do not carry targetable driver mutations (Mendiratta et al. 2021, NCI-MATCH Clinical trial NCT02465060). Commonly altered signaling pathways highlight the propensity for tumors to depend on such pathways for growth and survival where genomic alterations may not be required for pathway activation. The Raf family kinases are crucial mediators of the Ras/Raf/MEK/ERK (MAPK) cascade, which has been shown to be upregulated in a subset of metastatic cancers and are mutated in many epithelial cancers. A recent study suggests non-mutated C-Raf can drive metastasis to the lungs, bone, and various other tissues (Faltermeir et al. 2016). Though the mechanism of C-Raf driven metastasis is likely through MAPK activation, C-Raf has been demonstrated to possess MAPK independent roles that may also contribute to this phenotype. In this study, we explored various C-Raf functions as drivers of metastasis in an intracardiac mouse model system. Using a series of Raf knock-out cell lines and mutants targeting functional residues in C-Raf, we demonstrated that C-Raf dimerization is necessary to drive metastasis. We further showed that the metastasis-promoting activity of C-Raf is dependent on co-expression of its family member, B-Raf, for an accelerated metastatic phenotype. However, overexpression of a kinase-dead C-Raf mutant was still able to produce metastases albeit with lower efficiency, suggesting C-Raf possesses non-kinase dependent functions that also contributed to metastasis. Together, these results point to the importance of Raf non-canonical roles in oncogenic processes that may be unappreciated in metastatic disease. Citation Format: Lisa H. Ta, Janai R. Carr-Ascher, Weixian Deng, Brandon L. Tsai, Wendy Tran, Donny Gun, Donghui Cheng, Jihui Sha, Yeonjoo Hwang, John W. Phillips, Matthew B. Obusan, Nathanael J. Bangayan, Miyako Noguchi, Zhiyuan Mao, Chia-Chun Chen, Liang Wang, Grigor Varuzhanyan, John D. Gordon, James W. Wohlschlegel, Owen N. Witte. Determining the role of non-mutated C-Raf kinase in metastatic disease [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 2438.

Abstract Emerging studies revealed that tumor derived 2’3’-cGAMP could act as an immune transmitter and directly trigger anti-tumor immunity. Damage associated molecular patterns, e.g. damaged genomic DNA, released from injured cancer cells can be converted into 2’, 3’-cGAMP by cGAS. Subsequently, cGAMP triggers STING pathway activation to produce type I interferons (IFNs) and other related innate immunity in the tumor microenvironment. Ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), a membrane-bound nucleotide hydrolase, has been discovered as the predominant enzyme hydrolyzing 2’3’-cGAMP (Li, et al). Hence, ENPP1 blockade in the tumor milieu is a potential strategy against tumors by improving innate immunity response. In this report, we present a potent ENPP1 inhibitor ZX-8177. ZX-8177 showed an IC50 of 9.5 nM in a biochemical assay and an IC50 of 11 nM in MDA-MB-231 cell-based enzymatic assay. In a functional assay for evaluating efficacy of ZX-8177, the production of IFN-β1 by THP-1 cells was measured after the cells were cultured in the conditioned medium collected from MDA-MB-231 cells treated with or without ZX-8177. The interferon production assay showed an EC50 of 15 pM, suggesting that ZX-8177 effectively facilitated IFN-β1 production via cGAMP-STING axis. In CT-26 syngeneic mouse model, ZX-8177 treatment at 2 mg/kg, BID for 14 days can achieve around 37-60% tumor growth inhibition (TGI). No body weight loss was observed during treatment. Flow cytometry analysis indicated that ZX-8177 treatment resulted in a 2-3-fold increase in tumor-infiltrating NK (CD314+CD335+) cells, cytotoxic CD8 T cells (GranzB+CD8+), and M1-macrophages (CD206-MHCII+); and a decrease in M2-macrophages (CD206+MHCII-) (p< 0.05). Combination of Mitomycin C (0.5 mg/kg, i.p., BIW) and ZX-8177 (2 mg/kg, i.p., BID) in CT-26 model yielded synergistic anti-tumor efficacy (increased >30% TGI). The level of cGAMP in tumor tissue harvested from the combination treatment group was around 2-fold higher than that in the vehicle group. Furthermore, synergistic tumor inhibition of ZX-8177 and anti-PD-L1 antibody was also observed in MC38 mouse model. TGI of anti-PD-L1 antibody vs. combo treatment is 53% vs. 75%, p < 0.05. ZX-8177 has a favorable DMPK and safety pharmacology profile to support it as a clinical candidate for further development. Citation Format: Ying-ying Li, Zhiyuan Peng, Shuaijun Sun, Kun Guo, Deming Kong, Xiaomin Li, Yuning Xie, Siyu Shui, Yin Wang, Jinfu Yang, Xiaolin Alan Hao, Xiaoli (Shelley) Qin. ENPP1 inhibitor ZX-8177 enhances anti-tumor activity of conventional therapies by modulating tumor microenvironment [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 5486.

Abstract The discovery of predictive biomarkers of response is critical for forecasting patient benefit from novel immune-modulatory therapeutics. However, their discovery is hindered by the complexity of the drug modes of action and the lack of adequate biological models. We designed an approach to define biomarkers of response by subjecting dissociated tissue from human tumors to T cell-targeting biologics or their combinations, followed by single-cell transcriptomic profiling and TCR clonotype characterization. Responding cells are identified as those showing treatment-specific shifts in gene expression profiles. Specifically for T cells, TCR clonotypes can be used to match responding T cells in treatment conditions to their sister clones in the baseline state. Comparing the baseline gene expression profiles between T cell clonotypes that responded to the treatment and those that did not allows the discovery of gene expression signatures that can predict response. We processed over 20 tumor samples obtained from cancer patients and treated them ex vivo with two novel biologics currently under clinical development - HFB301001, a potentially best-in-class 2nd generation OX40 agonist, and HFB200301, a potentially first-in-class TNFR2 agonist. We applied our biomarker discovery strategy to the pooled scRNA-seq and scTCR-seq data from these samples to define predictive signatures of response to these drugs. To further validate this strategy, we also generated single-cell data in our ex vivo system to characterize response to anti-PD-1 treatment. In the anti-PD-1 predictive response signature, we identified genes involved in inflammatory response and genes in the pathway of other co-inhibitory checkpoints. Application of the anti-PD-1 predictive response signature to bulk transcriptomic data from clinical studies with checkpoint inhibitors successfully stratified patients into two groups with significantly different risk of progression. The predictive response signatures for the two novel agonistic antibodies shared genes involved in inflammatory pathway with the anti-PD-1 signature, but also contained other distinct gene sets. Application of these predictive response signatures to bulk transcriptomic data from TCGA was able to stratify patients across cancer indications by predicted likelihood of response to individual treatments or combinations. The predictive biomarkers of response for the novel OX40 and TNFR2 agonist antibodies will be validated in our Phase I clinical trials. Ex vivo single-cell profiling coupled with TCR clonotype characterization enabled the discovery of predictive response signatures that informed patient selection strategies for the early clinical development of novel therapeutics. Citation Format: Dean Lee, Monika Manne, Roshan Kumar, Rebecca Silver, Alexandra Staskus, Julianna Crivello, Zhiyuan Wang, Dohyun Lee, Ross Fulton, Zhizhan Gu, Christos Hatzis, Francisco Adrian, Andreas Raue, Liang Schweizer. Discovery of predictive biomarkers of response to T cell-targeting biologics using ex vivo single-cell profiling coupled with TCR clonotype characterization [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 618.

Abstract Background: Although the discovery and development of first-generation of immune checkpoint inhibitors (towards PD1 and CTLA-4) was a major milestone for cancer therapy, current clinical response rates are still considered very limited. Combination treatments are predicted to improve on these current immunotherapies including the targeting of the adenosine pathway (CD39, CD73 or A2AR), which has shown a lot of promise in preclinical and early clinical studies. CD73 is an ecto-5′-nucleotidase which transforms adenosine monophosphate (AMP) to adenosine. Adenosine is a soluble immunosuppressive metabolite that can suppress natural killer cells and cytotoxic CD8+ T cells. Blockade of CD73-mediated conversion of AMP to adenosine may therefore recover anti-tumor immunity through preventing the enrichment of adenosine in the tumor microenvironment. Method: In this campaign, two humanized and Fc-silenced IgG antibodies were generated named 7002-01 and 7002-04. The target binding epitopes of these candidates were revealed by binning experiments through bio-layer interferometry. Cell binding experiments were tested on human and cynomolgus CD73 overexpression CHO cell lines by flow cytometry. Cellular CD73 enzyme inhibition experiments were tested using A375, MDA-MB-231, H2030 and BT549 tumor cell lines via the CellTiter-Glo method. Soluble CD73 enzymatic tests were carried out on patient sera or recombinant CD73 protein using a similar method. T cell proliferation assays were performed using PBMC. In vivo efficacy studies were tested in B-NDG B2M-KO mice that were injected subcutaneously with A375 tumor cells and human PBMC. Results: Two candidates, 7002-01 and 7002-04, were selected based on their functional activity, that recognize different non-overlapping binding epitopes on CD73. Both candidates selectively bind to and can inhibit the activities of both membrane-bound and soluble human CD73 to high levels and seem to maintain inhibition at high dose-ranges without a hook effect. Both candidates can potently rescue adenosine-mediated T cell regulation. Additionally, 7002-01 and 7002-04 have combination synergy or additive effects for CD73 inhibition on soluble CD73, tumor cell lines that express CD73, and PBMC. 7002-01 and 7002-04 have single-agent anti-tumor efficacy and combination synergy with anti-PD1 antibodies in mice. 7002-01 has a typical antibody-like PK profile when rhesus monkeys were administered with a single intravenous dose at 25 or 50 mg/kg. No drug-related toxicities have been observed in GLP toxicity studies with dosages at 50, 250, and 500 mg/kg (QW, 4 weeks). Conclusion: Highly differentiating anti-CD73 antibodies were discovered that show maximal inhibition of both membranous and soluble CD73 without hook effects at high concentrations. 7002-01 was chosen as the lead molecule for its better overall activity profile and should be entering clinical trials by early 2022. Citation Format: Zhenqing Zhang, Yunli Jia, Xiaoniu Miao, Weifeng Huang, Chao Wang, Zhijun Yuan, Wenchao Jiang, Zhiyuan Li, Liandi Chen, Andy Tsun. Development of functionally differentiating anti-CD73 antibodies for cancer therapy [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 6115.

Abstract Background: There is an increasing demand for effective combinatory agents to improve upon PD-1/PD-L1-based therapeutics. One combinatory target axis is the adenosine metabolism pathway that consists of three major players, including CD39, CD73 and A2AR. Inhibition of any of these targets have shown enhanced preclinical efficacy in combination with PD-1/PD-L1 inhibitors. CD39 is an ectonucleotidase which degrades extracellular ATP to adenosine monophosphate (AMP). This is considered a rate-limiting step for the further degradation to adenosine by CD73. Adenosine is an immunosuppressive metabolite that can suppress NK and T cells. Blockade of CD39-mediated degradation of ATP to AMP may therefore recover anti-tumor immunity through preventing the enrichment of adenosine in the tumor microenvironment. Method: Two anti-CD39 VHH molecules were generated, named Ye-37 and Ye-46, which bind to two different epitopes on CD39. Binding experiments were carried out by bio-layer interferometry. Cell binding experiments were tested on CD39-overexpression cell lines by flow cytometry. Cellular CD39 enzymatic inhibition experiments were tested using an MOLP-8 cell line and PBMC via a luminescence-based assay. Soluble CD39 enzymatic tests were carried out on recombinant CD39 protein using a similar method. T cell proliferation assays were performed and observed on CD4+ or CD8+ T cell populations. In vivo efficacy studies were tested in B-NDG B2M-KO mice that were injected subcutaneously with A375-CD39+ tumor cells and human PBMC. An anti-PD1 x CD39 bispecific antibody was then generated by fusing the anti-CD39 biparatopic antibody to the C-terminus of an anti-PD1 IgG and tested using similar methods. Results: Two candidates, Ye-37 and Ye-46, were selected for their functional activity that recognize non-overlapping epitopes on CD39. The combination of Ye-37 and Ye-46 shows high potency in cell-based and soluble CD39 assays in blocking CD39 activity. Two biparatopic molecules were generated by fusing the biparatopic unit to the N- or C-termini of Fc (46-37-Fc and Fc-37-46) and showed similar activity to the combination. In vivo, we showed single-agent control of tumor growth and potentiation of tumor-growth inhibition when combined with anti-CD73 antibodies. An anti-PD1 x CD39 bispecific was generated and showed potent inhibition of PD-1/PD-L1 interactions by cell-based assays. Potent anti-tumor efficacy was shown, which was as effective as the combination of anti-PD1 plus anti-CD39 antibodies. Conclusion: Potent anti-CD39 and anti-PD1 x CD39 therapeutic candidates have been generated with promising activity as a combinatory or single agent, respectively. As such, we plan to file for clinical trial authorization of these programs by 2022. Citation Format: Zhenqing Zhang, Yunli Jia, Xiaoniu Miao, Weifeng Huang, Chao Wang, Zhijun Yuan, Wenchao Jiang, Liandi Chen, Zhiyuan Li, Andy Tsun. A highly potent anti-CD39 biparatopic antibody and bispecific for cancer therapy [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 5528.

Abstract T cell receptor (TCR)-engineered T cells are a promising approach to cell therapy for cancer. TCRs targeting public tumor associated antigens (TAAs) offer the widest potential coverage of patients within and across tumor types. TAA-specific TCRs, however, are rare in the blood and when detected are frequently of low affinity due to negative selection of high-affinity self-antigen reactive T cells in the thymus. Here, we present a TCR discovery platform based on in vitro generation of T cells from human pluripotent stem cells (PSCs) using the previously described artificial thymic organoid (ATO) system. We hypothesized that ATO-derived T cells offer several advantages for TCR discovery including a novel TCR repertoire and the absence of negative selection against TAAs during T cell development. Sequencing of the TCR repertoire of polyclonal CD8+ T cells generated from a HLA-A*02:01+ PSC line confirmed low junctional diversity at both the TCR beta and alpha loci, consistent with our previous finding of low TdT expression during T cell development from PSCs and an enrichment for germline-like TCRs. We then interrogated this novel TCR repertoire for reactivity against two well-described HLA-A2-restricted epitopes of NY-ESO-1 and WT1, reactivities to which are rare in the blood. Following co-culture with artificial APCs, a surprisingly high frequency of antigen-specific T cells was detected by MHC-tetramer staining. From these, high frequency TCR clonotypes were functionally validated by reconstitution in Jurkat TCR-reporter cells. Interestingly, from a single experimental run multiple antigen-specific TCRs were validated (5 out of 10 tested clonotypes for NY-ESO-1, and 2 out of 5 for WT1). This finding was reproducible across independent experimental runs, yielding further validated TCRs against these targets. To benchmark relative TCR affinities, we compared a panel of 5 ATO-derived NY-ESO-1 TCRs with 4 blood-derived TCRs with the same specificity, as well as the affinity-enhanced 1G4 TCR. ATO-derived TCRs showed not only superior performance to their blood derived counterparts in peptide dilution assays, but TCRs were identified with equivalent or superior cytotoxicity to 1G4, including against cell lines with endogenous NY-ESO-1 expression. Comparative in vivo anti-tumor efficacy studies are in process. A similarly high level of specificity and cytotoxicity was observed for ATO-derived WT1-specific TCRs. Finally, we demonstrate proof-of-concept identification of TCRs specific to a prostate-specific antigen for which high quality TCRs have remained elusive. In conclusion, the PSC ATO TCR-discovery platform efficiently identifies high-affinity TAA-specific TCRs, including against previously intractable targets. Considering the potential for MHC modularity of this in vitro system, this approach may theoretically enable rapid discovery of therapeutic TCRs based on any designated peptide/MHC-I combination. Citation Format: Chloe S. Wang, Suwen Li, Zhiyuan Mao, Olivia Zhou, Carlos Botero, William Satyadi, Patrick Chang, Sang Pil Yoo, Ho-Chung Chen, Shawn Lopez, Jami McLaughlin, Amélie Montel-Hagen, Owen N. Witte, Gay M. Crooks, Christopher S. Seet. PSC-derived T cells as a novel source of tumor antigen-specific T cell receptors [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 3604.

The paper is the first of a series, which aims to present a consistent interpretation of the suprageneric taxa of fossil beetles in the current century and their generic and species composition. Order Coleoptera is considered in composition of the superorder Coleopteroidea Handlirsch, 1903 (= Coleopterida sensu Boudreaux, 1979, nec Pearse, 1936) together with orders Skleroptera and Strepsiptera, and also with the family Umenocoleidae of unclear position. This paper includes the archostematan superfamilies Coleopseoidea and Cupedoidea of the infraorder Cupediformia, i.e., Coleopseidae (one genus and one species), Tshekardocoleidae (12 genera, 15 species), Labradorocoleidae (one genus, one species), Permocupedidae (together with Taldycupedinae, stat. nov., 24 genera and 54 species) and Cupedidae (three subfamilies, 49 genera, 253 species). The preliminary information on structure of the larva of Tshekardocoleidae from Tshekarda is done. There are also described the new taxa: genus Afrotaldycupes Kirejtshuk, gen. nov. with the type species: genus Taldycupes africanus Ponomarenko in Ponomarenko & Mostovski, 2005 [Afrotaldycupes africanus comb. nov.] and Afrotaldycupes lidgettoniensis (Ponomarenko in Ponomarenko & Mostovski, 2005), comb. nov. [Taldycupes]; genus Allophalerus Kirejtshuk, gen. nov. with the type species: Tetraphalerus aphaleratus Ponomarenko, 1969 [Allophalerus aphaleratus comb. nov.], and also with Allophalerus antiquus (Ponomarenko, 1964), comb. nov. [Tetraphalerus], Allophalerus bontsaganensis (Ponomarenko, 1997), comb. nov. [Tetraphalerus], Allophalerus incertus (Ponomarenko, 1969), comb. nov. [Tetraphalerus], Allophalerus latus (Tan, Ren et Shih, 2007), comb. nov. [Tetraphalerus], Allophalerus maximus (Ponomarenko, 1968), comb. nov. [Tetraphalerus], Allophalerus okhotensis (Ponomarenko, 1993), comb. nov. [Tetraphalerus], Allophalerus tenuipes (Ponomarenko, 1964), comb. nov. [Tetraphalerus], Allophalerus verrucosus (Ponomarenko, 1966), comb. nov. [Tetraphalerus]; genus Bukhkalius Kirejtshuk et Jarzembowski, gen. nov. with the type species: Tetraphalerus lindae Jarzembowski, Wang et Zheng, 2017 [Bukhkalius lindae comb. nov.]; genus Burmocoleus Kirejtshuk, gen. nov. with the type species: Burmocoleus prisnyi sp. nov. and Burmocoleus zhiyuani (Liu, Tan, Ślipiński, Jarzembowski, Wang, Ren et Pang, 2017), comb. nov. [Brochocoleus]; genus Cionocups Kirejtshuk, gen. nov. with the type species: Cionocups manukyani sp. nov.; genus Echinocups Kirejtshuk et Jarzembowski, gen. nov. with the type species: Notocupes neli Tihelka, Huang et Cai, 2020 [Echinocups neli comb. nov.], and also Echinocups ohmkuhnlei (Jarzembowski, Wang et Zheng, 2020), comb. nov. [Notocupes] and Echinocups denticollis (Jiang, Li, Song, Shi, Liu, Chen et Kong, 2020), comb. nov. [Notocupes]; genus Jarzembowskops Kirejtshuk, gen. nov. with the type species: Brochocoleus caseyi Jarzembowski, Wang et Zheng, 2016 [Jarzembowskops caseyi comb. nov.]; genus Lobanovia Kirejtshuk, gen. nov. with the type species: Simmondsia permiana Ponomarenko, 2013 [Lobanovia permiana comb. nov.]; genus Pintolla Kirejtshuk, gen. nov. with the type species: Kaltanicupes ponomarenkoi Pinto, 1987 [Pintolla ponomarenkoi comb. nov.]; genus Polyakius Kirejtshuk, gen. nov. with the type species: Polyakius alberti Kirejtshuk, sp. nov. and Polyakius pubescens Kirejtshuk, sp. nov.; Clessidromma zengi Kirejtshuk, sp. nov.; Cupes golovatchi Kirejtshuk, sp. nov.; Cupes legalovi Kirejtshuk, sp. nov.; Cupes lutzi Kirejtshuk, sp. nov.; Cupes nabozhenkoi Kirejtshuk, sp. nov.; Cupes wedmannae Kirejtshuk, sp. nov.; Mallecupes prokini Kirejtshuk, sp. nov. and Omma janetae Kirejtshuk, sp. nov. The new synonymy is established for the generic names Clessidromma Jarzembowski, Wang et Zheng, 2017 and Lepidomma Jarzembowski, Wang et Zheng, 2019, syn. nov. The rank of Cainomerga A. Kirejtshuk, Nel et P. Kirejtshuk, 2016 is elevated from subgeneric to generic. Also other new combinations are proposed: Cainomerga brevicornis (A. Kirejtshuk, Nel et P. Kirejtshuk, 2016), comb. nov. [Mesocupes], Cainomerga fraterna (A. Kirejtshuk, Nel et P. Kirejtshuk, 2016), comb. nov. [Mesocupes], Cainomerga immaculata (Piton, 1940: 194), comb. nov. [Zonabris, Mesocupes], Cainomerga palaeocenica (A. Kirejtshuk, Nel et P. Kirejtshuk, 2016), comb. nov. [Mesocupes], and Cainomerga ponti (A. Kirejtshuk, Nel et P. Kirejtshuk, 2016), comb. nov. [Mesocupes], Clessidromma tianae (Jarzembowski, Wang et Zheng, 2019), comb. nov. [Lepidomma], Diluticupes applanatus (Tan et Ren, 2009), comb. nov. [Brochocoleus], Diluticupes crowsonae (Jarzembowski, Yan, Wang et Zhang. 2013), comb. nov. [Brochocoleus], Diluticupes magnus (Tan et Ren, 2009), comb. nov. [Brochocoleus], Diluticupes minor (Ponomarenko, 2000), comb. nov. [Brochocoleus], Diluticupes validus (Tan et Ren, 2009), comb. nov. [Brochocoleus], Diluticupes yangshuwanziensis (Jarzembowski, Yan, Wang et Zhang. 2013), comb. nov. [Brochocoleus], Monticupes curtinervis (Tan, Ren et Shih, 2007), comb. nov. [Tetraphalerus], Monticupes decorosus (Tan, Wang, Ren et Yang, 2012), comb. nov. [Tetraphalerus], Odontomma sulcatum (Tan, Ren et Shih, 2007), comb. nov. [Brochocoleus], Omma ancistrodontum (Tan, Wang, Ren et Yang, 2012), comb. nov. [Pareuryomma], Omma grande (Ponomarenko, 1964), comb. nov. [Tetraphalerus], Omma longicolle (Ponomarenko, 1997), comb. nov. [Tetraphalerus], Pareuryomma angustum (Tan, Ren et Shich, 2007), comb. nov. [Brochocoleus], Pareuryomma magnum (Tan et Ren, 2009), comb. nov. [Brochocoleus], Zygadenia aliena (Tan et Ren, 2006), comb. nov. [Ovatocupes], Zygadenia baojiatunensis (Hong 1992), comb. nov. [Chengdecupes], Zygadenia brachycephala (Ponomarenko, 1994), comb. nov. [Notocupes], Zygadenia caduca (Ponomarenko, 1969), comb. nov. [Notocupes], Zygadenia caudata (Ponomarenko, 1966), comb. nov. [Notocupes], Zygadenia cellulosa (Ponomarenko, 1969), comb. nov. [Notocupes], Zygadenia crassa (Ponomarenko, 1969), comb. nov., [Notocupes], Zygadenia cyclodontus (Tan, Ren, Shih et Ge, 2006), comb. nov. [Amblomma, Notocupes], Zygadenia dischdes (Zhang, 1986), comb. nov. [Notocupes], Notocupes dundulaensis (Ponomarenko, 1994), comb. nov. [Notocupes], Zygadenia elegans (Ponomarenko, 1994), comb. nov. [Notocupes], Zygadenia epicharis (Tan, Ren et Liu, 2005), comb. nov. [Amblomma, Notocupes], Zygadenia eumeura (Tan, Ren et Liu, 2005), comb. nov. [Amblomma, Notocupes], Zygadenia excellens (Ponomarenko, 1966), comb. nov. [Notocupes], Zygadenia exigua (Ponomarenko, 1994), comb. nov. [Notocupes], Zygadenia foersteri (Ponomarenko, 1971), comb. nov. [Procarabus, Notocupes], Zygadenia homora (Lin, 1986), comb. nov. [Conexicoxa, Notocupes], Zygadenia issykkulensis (Ponomarenko, 1969), comb. nov. [Notocupes], Zygadenia jurassica (Hong 1983), comb. nov. [Chengdecupes], Zygadenia kezuoensis (Hong 1987), comb. nov. [Chengdecupes], Zygadenia khasurtuiensis (Strelnikova, 2019), comb. nov. [Notocupes], Zygadenia khetanensis (Ponomarenko, 1993), comb. nov. [Notocupes], Zygadenia kirghizica (Ponomarenko, 1969), comb. nov. [Notocupes], Zygadenia laeta (Lin, 1976), [Tetraphalerus], Zygadenia laiyangensis (Hong et Wang, 1990), comb. nov. [Forticupes, Notocupes], Zygadenia lapidaria (Ponomarenko, 1968), comb. nov. [Notocupes], Zygadenia laticella (Ponomarenko, 1969), comb. nov. [Notocupes], Zygadenia lata (Ponomarenko, 1969), comb. nov. [Notocupes], Zygadenia lenta (Ren, Lu, Guo et Ji, 1995), comb. nov. [Tetraphalerus], Zygadenia lini (Ponomarenko, Yan, Wang et Zhang, 2012), comb. nov. [Notocupes], Zygadenia longicollis (Ponomarenko, 1994), comb. nov. [Notocupes], Zygadenia ludongensis (Wang et Liu, 1996), comb. nov. [Notocupes], Zygadenia minuscula (Tan, Ren, Shih et Ge, 2006), comb. nov. [Amblomma, Notocupes], Zygadenia mongolica (Ponomarenko, 1994), comb. nov. [Notocupes], Zygadenia nigrimonticola (Ponomarenko, 1968), comb. nov. [Notocupes], Zygadenia oxypyga (Ponomarenko, 1969), comb. nov. [Notocupes], Zygadenia patula (Ponomarenko, 1985), comb. nov. [Notocupes], Zygadenia pingi (Ponomarenko et Ren, 2010), comb. nov. [Notocupes], Zygadenia porrecta (Tan, Ren, Shih et Ge, 2006), comb. nov. [Amblomma, Notocupes], Zygadenia protensa (Tan, Ren, Shih et Ge, 2006), comb. nov. [Amblomma, Notocupes], Zygodenia psilata (Tan, Ren et Liu, 2005), comb. nov. [Amblomma, Notocupes], , Zygadenia pulchra Ponomarenko, 1968, comb. nov. [Notocupes], Zygadenia reticulata (Oppenheim, 1888), comb. nov. [Procarabus, Notocupes], Notocupes rostrata (Ponomarenko, 1969), comb. nov. [Notocupes], Zygadenia rudis (Tan, Ren et Liu, 2005), comb. nov. [Amblomma, Notocupes], Zygadenia shiluoensis (Hong 1984), comb. nov. [Chengdecupes], Zygadenia sogutensis (Ponomarenko, 1969), comb. nov., Zygadenia stabilis (Tan, Ren et Liu, 2005), comb. nov. [Amblomma, Notocupes], Zygadenia tenuis (Ponomarenko, 1969), comb. nov. [Notocupes], Zygadenia tripartita (Oppenheim, 1888), comb. nov. [Procarabus, Notocupes], Zygadenia tuanwangensis (Hong et Wang, 1990), comb. nov. [Picticupes, Notocupes], Zygadenia valida (Lin, 1976), comb. nov. [Sinocupes, Notocupes], Zygadenia vitimensis (Ponomarenko, 1966), comb. nov. [Notocupes].

Визначено, що основною, принциповою відмінністю публічного управління від будь- яких інших видів управління є попередня розробка цілісної моделі проекту, її аналіз, узгодження, затвердження, і потім вже реалізація. В рамках управління проектом моделі являють собою не тільки інструменти пізнавальної діяльності, а й інструменти реального управління. Стосовно публічного управління територіальним розвитком необхідно доповнити відповідними моделями екологічної, етнічної, економічної динаміки, а також моделями загального розвитку територіальної системи. Застосування таких моделей дозволяє прогнозувати, планувати і контролювати, перш за все, динаміку територіальної системи. В рамках цієї дисертації за доцільне обмежитися аналізом лише основних видів моделювання. Зазначено, що моделі передбачають, що кожна з конкуруючих технологічних систем має здатність до вдосконалення, а ефективність експлуатують виробництв з часом підвищується. Передбачається, що кожна з двох альтернативних технічних систем освоюється як новаторами, що діють в її рамках, так і імітаторами, готовими до сприйняття нововведень як даної, так і альтернативної системи (умовно – імітатори першого і другого типу). Динамічні моделі і теорії в економіці з’явилися у зв’язку з активним вивченням динамічних процесів в економічних системах, в першу чергу економічного зростання та економічних циклів. Надалі в міру вивчення динаміки економічних систем в економічній теорії стали з’являтися нерівноважні економічні моделі, які на сьогодні слід визнати найбільш адекватними умовами розвитку територіальних систем. Ухвалення концепції стійкості в економічному аналізі було значною мірою обумовлено розвитком природничих наук, де для проведення осмисленого аналізу динамічних систем була потрібна їх стійкість. Для експериментальних наук це означає, що дескриптивні моделі повинні призводити до одних і тих же якісних результатів, якщо експеримент повторюється при малих змінах умов. Мета статті. Метою проведеного в поданій статті дослідження є вивчення досвіду моделювання процесів управління соціально-економічним територіальним розвитком, що прописана в фундаментальних офіційних документах ООН, Євростату, Світового банку щодо еколого-економічного й екосистемного моделювання. Методологія. У фаховій зарубіжній та вітчизняній літературі існує чималий масив розробок щодо моделювання процесів управління соціально-економічним територіальним розвитком за авторством J. Wang, F. Soulard, Zhiyun Ouyang, Changsu Song, Hua Zheng, S.Polasky, Yi Xiao, M. Ruckelshaus, Weihua Xu, C. Daily, А.В Невєрова, А.А. Тишкова, О.Є.Медведєвої, Д.В.Касимова, В.В. Юрак, Н.В. Дегтярь, І.П. Соловія, Л.Д. Загвойської, G. Sandoval, D. Barton та інших, які своєю чергою спираються на відповідну керівну методику, що прописана в фундаментальних офіційних документах ООН, Євростату, Світового банку щодо еколого-економічного й екосистемного моделювання. Наукова новизна. Процес моделювання процесів управління соціально-економічним територіальним розвитком розглянуто через призму ухвалення концепції стійкості в економічному аналізі, що обумовлено розвитком природничих наук, де для проведення осмисленого аналізу динамічних систем була потрібна їх стійкість. Висновки. Визначено, що динамічні моделі і теорії в економіці з’явилися у зв’язку з активним вивченням динамічних процесів в економічних системах, в першу чергу економічного зростання та економічних циклів. Надалі в міру вивчення динаміки економічних систем в економічній теорії стали з’являтися нерівноважні економічні моделі, які на сьогодні слід визнати найбільш адекватними умовами розвитку територіальних систем.

New Generation Chimeric Antigen Receptor T-Cell Therapy ( CoupledCAR ) Induces High Rate Remissions in Solid Tumor Yu Liu1,Song Li2,Youli Luo3,Haixia Song4,Chengfei Pu5, Zhiyuan Cao 5, Cheng Lu5,Yang Hang5,Xi Huang5,Xiaogang Shen5 ,Xiaojun Hu3 , Renbin Liu1,Xiuwen Wang2,Junjie Mao3,Shihong Wei4 ,Zhao Wu5and Lei Xiao5* 1.The Third Affiliated Hospital, SUN YAT-SEN University 2.Qilu Hospital of Shandong University 3.The Fifth Affiliated Hospital, SUN YAT-SEN University 4.Gansu Procincial Cancer Hospital 5.Innovative Cellular Therapeutics *Corresponding to: Lei Xiao, xiaolei@ictbio.com Chimeric antigen receptor (CAR) T cell therapy made significant progress for treating blood cancer such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges, such as physical barrier, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and cell expansion in vivo for treatment of solid tumors Conventional CAR T cell therapy showed weak CAR T expansion in patients and thus achieved no or little response for treating solid tumors. Here, we generated "CoupledCAR" T cells including an anti-TSHR CAR molecule. Compared with conventional CART cells,these "CoupledCAR" T cells successfully improved the expansion of CART cells more than 100 times and enhanced CAR T cells' migration ability, allowing the CAR T cells to resist and infiltrate the tumor microenvironment and killed tumor cells. To verify the effect of "CoupledCAR" T cells on solid tumors, we have completed several clinical trials for different solid tumors, including two patients with thyroid cancer. Immunohistochemistry (IHC) results showed that thyroid stimulating hormone receptors (TSHR) were highly expressed in thyroid cancer cells. In vitro co-culture experiments showed that TSHR CAR T cells specifically recognized and killed TSHR-positive tumor cells. Animal experiments showed that TSHR CAR T cells inhibited the proliferation of TSHR-positive tumor cells. Therefore, we designed "CoupledCAR" T cells expressing a binding domain against TSHR. Further,we did clinical trials of two group patients that were successfully treated using conventional TSHR CAR T cells and the "CoupledCAR" T cells, respectively. In the first group using conventional TSHR CAR T cells, patients showed weak cell expansion and less migration ability. In the group using TSHR "CoupledCAR" T cells, patients showed rapid expansion of CAR T cells and killing of tumor cells. One month after infusion (M1), the patient was evaluated as PR(Partial Response): the lymph node metastasis disappeared, and thoracic paratracheal tumors decreased significantly. Three months after infusion (M3), the patient was evaluated as a durable response, and the tumor tissue was substantially smaller than M1. Further, two patients with colonrectal cancer were enrolled in this trial and infused "CoupledCAR" T cells. One patient achieved PR and the other one achieved SD (Stable Disease). Therefore, "CoupledCAR" T cells can effectively promote expansion, migration and killing ability of CAR T cells in patients with thyroid cancer. "CoupledCAR" T cell technology is a technological platform, which may be used to treat other cancer types. Next, we are recruiting more patients with solid tumors in clinical trials using "CoupledCAR" T cells. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Disease relapse is common with peripheral T-cell lymphomas (PTCL) or cutaneous T-cell lymphomas (CTCL). Adoptive immunotherapy with CD19 directed CAR-T cells is a standard option for B cell lymphoid malignancies in the relapsed setting. This study assesses the safety and preliminary efficacy of CD4 targeting autologous CAR-T, LB1901, in patients (pts) with CD4+ relapsed or refractory (R/R) TCL. A pre-clinical study showed LB1901 exhibited potent anti-tumor activity without off-target effects (Zeng 2021). Methods: This is a phase 1, open-label, multicenter, multicohort study of LB1901 (NCT04712864; currently enrolling). Eligible pts are ≥18 years with histologically confirmed CD4+ PTCL-NOS (not otherwise specified); or CD4+ AITL (angioimmunoblastic T-cell lymphoma); or CD4+ CTCL (either MF [mycosis fungoides] or SS [Sézary syndrome]). In Part A (dose escalation), pts with SS must have ≤2,000 circulating Sézary cells/µL to ensure safety of pts with higher disease burden. In Part B, pts with >2,000 Sézary cells/µL is allowed. CD4 expressed on tumor cells must be confirmed within 3 months prior to apheresis. Other inclusion criteria include: R/R disease with ≥2 prior lines of systemic antineoplastic therapy; for pts with PTCL-NOS or AITL, ≥1 measurable lesion according to IWG Response Criteria (Cheson 2014) and for pts with CTCL, ≥stage IIB on TNMB-ISLC/EORTC staging system; identified HSCT donor available prior to enrollment (in the event of severe recurrent infections and prolonged lymphopenia for which pt may need an allogeneic HSCT as a safety rescue); and ECOG status of 0 or 1. Response will be evaluated based on IWG response criteria for PTCL and Global Composite Response for CTCL (Olsen 2007). The study will be conducted in 2 parts (Part A: dose escalation and Part B: dose expansion). Three dose levels (0.3 X 106, 1.0 X 106, and 3.0 X 106 CAR+ viable T cells/kg) will be evaluated (N=3-6 for each dose level) with an optional dose level minus 1 (0.1 X 106 CAR+ viable T cells/kg). Part B will include 2 cohorts, PTCL and CTCL (N=12-20 for each), after the recommended dose for expansion (RDE) has been identified in Part A. Enrolled pts will undergo apheresis for PBMC collection. LB1901 will be manufactured from autologous CD8+ T cells. Pts may receive optional bridging therapy and receive lymphodepleting chemotherapy with fludarabine 30mg/m2/day and cyclophosphamide 300mg/m2/day (Flu-Cy), for 3 days followed by LB1901. Primary endpoints are incidence, duration, and severity of AEs and laboratory abnormalities (Parts A and B) and DLT at each dose level (Part A). Secondary endpoints include overall response rate; duration of response; CAR-positive T cell counts and CAR transgene level in blood; and presence of anti-CAR antibody response. Exploratory endpoints include preliminary efficacy, pharmacokinetics, and CD4+ T cell counts. Citation Format: Swaminathan P. lyer, David G. Maloney, Nora Bennani, Auris Huen, Muhammad Akram, Soo Kim, Chuan Wang, Zhiyin Liang, Henry Castro, Lida Pacaud, Mehdi Hamadani. LB1901: A phase 1, open-label, multicenter, multicohort study of CD4-targeted chimeric antigen receptor T cells (CD4-CAR-T) in relapsed or refractory T-cell lymphoma (TCL) [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 CT215.