A Phase I Trial of CD19-targeted Chimeric Antigen Receptor (CAR) T Cells That Constitutively Secrete Interleukin 18 (19-28z/IL-18) in Patients With Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Participants will have a sample of their white blood cells, called T cells, collected using a procedure called leukapheresis. The collected T cells will be sent to a laboratory to be changed (modified) to become 19-28z/IL-18, the CAR T-cell therapy that participants will receive during the study. Making the participants' study therapy will take about 2-4 weeks.

开始日期2024-02-23

申办/合作机构

Memorial Sloan Kettering Cancer Center

100 项与 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center) 相关的临床结果

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100 项与 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center) 相关的转化医学

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100 项与 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center) 相关的专利（医药）

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项与 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center) 相关的文献（医药）

2024-07-11·Blood

IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model

Article

作者: DeWolf, Susan ; Pierce, Jonah ; Massa, Alyssa ; Bogen, Bjarne ; Galiano, Michael ; Manuele, Dylan ; James, Scott E ; van den Brink, Marcel R M ; Lemarquis, Andri L ; Ng, Brandon D ; Kousa, Anastasia I ; Fischman, Jacob S ; Chen, Sophia ; Boardman, Alexander P ; Rajagopalan, Adhithi ; Elias, Harold K

AbstractMultiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18–secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

2024-02-01·Arthritis & Rheumatology

Effects of B Cell Depletion by CD19‐Targeted Chimeric Antigen Receptor T Cells in a Murine Model of Systemic Sclerosis

Article

作者: Tu, Ly ; Guignabert, Christophe ; Boulch, Morgane ; Allanore, Yannick ; Orvain, Cindy ; Avouac, Jérôme ; Bousso, Philippe ; Tilotta, Françoise ; Cauvet, Anne ; Ottaviani, Mina ; Thuillet, Raphaël

ObjectiveOur goal was to study the tolerance and efficacy of two B cell depletion strategies, including one with CD19‐targeted chimeric antigen receptor (CAR) T cells, in a preclinical model mimicking the severe lung damages observed in systemic sclerosis.MethodsB cell depletion strategies were evaluated in the Fra‐2 transgenic (Tg) mouse model. We considered a first group of 16 untreated mice, a second group of 15 mice receiving a single dose of anti‐CD20 monoclonal antibody (mAb), and a third group of 8 mice receiving CD19‐targeted CAR‐T cells in combination with anti‐CD20 monoclonal antibody. After six weeks of clinical evaluation, different validated markers of inflammation, lung fibrosis, and pulmonary vascular remodeling were assessed.ResultsCD19‐targeted CAR‐T cells infusion in combination with anti‐CD20 mAb resulted in a deeper B cell depletion than anti‐CD20 mAb alone in the peripheral blood and lesional lungs of Fra‐2 Tg mice. CAR‐T cell infusion worsened the clinical score and increased mortality in Fra‐2 Tg mice. In line with the above findings, CAR‐T cell infusion significantly increased lung collagen content, the histological fibrosis score, and right ventricular systolic pressure. CAR‐T cells accumulated in lesional lungs and promoted T activation and inflammatory cytokine production. Treatment with anti‐CD20 mAb in monotherapy had no impact on lung inflammation–driven fibrosis and pulmonary hypertension.ConclusionB cell therapies failed to show efficacy in the Fra2 Tg mice. The exacerbated Fra‐2 lung inflammatory burden stimulated accumulation and expansion of activated CD19‐targeted CAR‐T cells, secondarily inducing T cell activation and systemic inflammation, finally leading to disease worsening.

Cancer Immunology, Immunotherapy

Treatment of secondary CNS lymphoma using CD19-targeted chimeric antigen receptor (CAR) T cells

Article

作者: Omili, Destiny ; Koka, Rima ; Dietze, Kenneth A ; Baker, Jillian M ; Hankey, Kim G ; Kallen, Michael E ; Hardy, Nancy M ; Dishanthan, Nishanthini ; Ahmad, Haroon ; Atanackovic, Djordje ; Kline, Kathryn ; Gebru, Etse ; Fan, Xiaoxuan ; Miller, Alexis ; Chen, Wengen ; Yared, Jean A ; Dahiya, Saurabh ; Iraguha, Thierry ; Luetkens, Tim ; Rapoport, Aaron P

AbstractBackgroundAggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported.MethodsWe prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity.ResultsTwo of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4+ central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient’s CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells.ConclusionsOur results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of “fit” and highly tumor-reactive CAR-T with low off-target reactivity into the CNS.

100 项与 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center) 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
费城染色体阳性急性淋巴细胞白血病	临床1期	美国	Memorial Sloan Kettering Cancer Center	2024-02-23
复发性成人急性淋巴细胞白血病	临床1期	美国	Memorial Sloan Kettering Cancer Center	2024-02-23
复发难治性急性淋巴细胞白血病	临床1期	美国	Memorial Sloan Kettering Cancer Center	2024-02-23
难治性 B 细胞急性淋巴细胞白血病	临床1期	美国	Memorial Sloan Kettering Cancer Center	2024-02-23