Treatment of Aggressive T Cell Lymphoblastic Lymphoma/leukemia Using Anti-CD5 CAR T Cells

Feng, Jia; Xu, Hai-chan; Cinquina, Andrew; Wu, Zehua; Chen, Qi; Zhang, Ping; Wang, Xingen; Shan, Huiming; Xu, Lei; Zhang, Qian; Sun, Lihua; Zhang, Wenli; Pinz, Kevin G.; Wada, M.; Jiang, Xun; Hanes, William; Ma, Yupo; Zhang, Hongyu

doi:10.1007/s12015-020-10092-9

Cited by 52 publications

(42 citation statements)

References 32 publications

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“…Genetic strategies to improve T cell costimulation include modified TCRs incorporating costimulatory domains ( 155 ) and coexpression of costim-only CARs ( 214 ) or domain swapped inhibitory receptors ( 215 ). Finally, several genetic strategies are also being explored to maintain T cell homeostatic cytokine signaling, including auto-secreting IL-15 or IL-12 elements ( 216 – 219 ) and a constitutively active IL-7 receptor ( 220 ).…”

Section: Clinical Landscape Of Tcr T Therapiesmentioning

confidence: 99%

Cancer Therapy With TCR-Engineered T Cells: Current Strategies, Challenges, and Prospects

2022

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To redirect T cells against tumor cells, T cells can be engineered ex vivo to express cancer-antigen specific T cell receptors (TCRs), generating products known as TCR-engineered T cells (TCR T). Unlike chimeric antigen receptors (CARs), TCRs recognize HLA-presented peptides derived from proteins of all cellular compartments. The use of TCR T cells for adoptive cellular therapies (ACT) has gained increased attention, especially as efforts to treat solid cancers with ACTs have intensified. In this review, we describe the differing mechanisms of T cell antigen recognition and signal transduction mediated through CARs and TCRs. We describe the classes of cancer antigens recognized by current TCR T therapies and discuss both classical and emerging pre-clinical strategies for antigen-specific TCR discovery, enhancement, and validation. Finally, we review the current landscape of clinical trials for TCR T therapy and discuss what these current results indicate for the development of future engineered TCR approaches.

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Section: Clinical Landscape Of Tcr T Therapiesmentioning

confidence: 99%

Cancer Therapy With TCR-Engineered T Cells: Current Strategies, Challenges, and Prospects

2022

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“…Recently, subcutaneous injection of recombinant human IL15 was tested in patients with advanced solid tumors, although the treatment produced substantial increases in circulating NK and CD8 + T cells, nonetheless, no objective responses were observed ( 130 ). However, when IL-15/IL-15Rα sushi-domain was co-expressed on CD5-specific CAR-T cells, and tested in a patient with relapsed T-lymphoblastic lymphoma with CNS infiltration, a rapid ablation of the CNS lymphoblasts to undetectable levels within 4 weeks and disease remission was observed ( 131 ). To address IL-15-induced immune checkpoint activation, IL-15 can also be combined with anti-PD-(L)1 and anti-CTLA-4 antibodies ( 132 ).…”

Section: Overcoming the Challenges Of Tcr-t Cancer Immunotherapymentioning

confidence: 99%

Emerging Strategies in TCR-Engineered T Cells

et al. 2022

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Immunotherapy of cancer has made tremendous progress in recent years, as demonstrated by the remarkable clinical responses obtained from adoptive cell transfer (ACT) of patient-derived tumor infiltrating lymphocytes, chimeric antigen receptor (CAR)-modified T cells (CAR-T) and T cell receptor (TCR)-engineered T cells (TCR-T). TCR-T uses specific TCRS optimized for tumor engagement and can recognize epitopes derived from both cell-surface and intracellular targets, including tumor-associated antigens, cancer germline antigens, viral oncoproteins, and tumor-specific neoantigens (neoAgs) that are largely sequestered in the cytoplasm and nucleus of tumor cells. Moreover, as TCRS are naturally developed for sensitive antigen detection, they are able to recognize epitopes at far lower concentrations than required for CAR-T activation. Therefore, TCR-T holds great promise for the treatment of human cancers. In this focused review, we summarize basic, translational, and clinical insights into the challenges and opportunities of TCR-T. We review emerging strategies used in current ACT, point out limitations, and propose possible solutions. We highlight the importance of targeting tumor-specific neoAgs and outline a strategy of combining neoAg vaccines, checkpoint blockade therapy, and adoptive transfer of neoAg-specific TCR-T to produce a truly tumor-specific therapy, which is able to penetrate into solid tumors and resist the immunosuppressive tumor microenvironment. We believe such a combination approach should lead to a significant improvement in cancer immunotherapies, especially for solid tumors, and may provide a general strategy for the eradication of multiple cancers.

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“…This was the first clinical trial to demonstrate that CAR T cells expressing transgenic membrane-bound IL-15 were well tolerated and effective in treating B-ALL (Table 4). Meanwhile, a phase I study reported that administration of CD5-IL15/IL15sushi CAR also led to rapid reduction of malignant cells within 4 weeks post-infusion with grade I CRS and a brief, transient T-cell aplasia in the patient [86] (Table 4). These results suggest that incorporating IL-15 and its receptor complex may be a safe and useful approach to potentiate CAR T cell therapy.…”

Section: Il-15-armored Car T Cellsmentioning

confidence: 99%

Interleukin 15 in Cell-Based Cancer Immunotherapy

Zhou

Husman

et al. 2022

IJMS

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Cell-based cancer immunotherapy, such as chimeric antigen receptor (CAR) engineered T and natural killer (NK) cell therapies, has become a revolutionary new pillar in cancer treatment. Interleukin 15 (IL-15), a potent immunostimulatory cytokine that potentiates T and NK cell immune responses, has demonstrated the reliability and potency to potentially improve the therapeutic efficacy of current cell therapy. Structurally similar to interleukin 2 (IL-2), IL-15 supports the persistence of CD8+ memory T cells while inhibiting IL-2-induced T cell death that better maintains long-term anti-tumor immunity. In this review, we describe the biology of IL-15, studies on administrating IL-15 and/or its derivatives as immunotherapeutic agents, and IL-15-armored immune cells in adoptive cell therapy. We also discuss the advantages and challenges of incorporating IL-15 in cell-based immunotherapy and provide directions for future investigation.

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Treatment of Aggressive T Cell Lymphoblastic Lymphoma/leukemia Using Anti-CD5 CAR T Cells

Cited by 52 publications

References 32 publications

Cancer Therapy With TCR-Engineered T Cells: Current Strategies, Challenges, and Prospects

Cancer Therapy With TCR-Engineered T Cells: Current Strategies, Challenges, and Prospects

Emerging Strategies in TCR-Engineered T Cells

Interleukin 15 in Cell-Based Cancer Immunotherapy

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