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.

Start Date23 Feb 2024

Sponsor / Collaborator

Memorial Sloan Kettering Cancer Center

100 Clinical Results associated with 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center)

100 Translational Medicine associated with 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center)

100 Patents (Medical) associated with 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center)

Literatures (Medical) associated with 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center)

11 Jul 2024·Blood

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

Article

Author: Elias, Harold K ; 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 ; DeWolf, Susan

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.

01 Feb 2024·Arthritis & Rheumatology

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

Article

Author: Tu, Ly ; Guignabert, Christophe ; Boulch, Morgane ; Allanore, Yannick ; Orvain, Cindy ; Bousso, Philippe ; Avouac, Jérôme ; 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.

Haematologica

Outcomes of patients with primary central nervous system lymphoma following CD19-targeted chimeric antigen receptor T-cell therapy

Article

Author: Hamadani, Mehdi ; Sica, Alejandro R ; Hong, Sanghee ; Allbee-Johnson, Mariam ; Sauter, Craig S ; Herrera, Alex F ; Ganguly, Siddhartha ; Pawarode, Attaphol ; Mercadal, Santiago ; Shadman, Mazyar ; Murthy, Hemant ; Ustun, Celalettin ; Geethakumari, Praveen Ramakrishnan ; Solh, Melhem ; Malone, Adriana ; Ahn, Kwang Woo ; Lee, Catherine J

100 Deals associated with 19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center)

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Indication	Highest Phase	Country/Location	Organization	Date
Philadelphia positive acute lymphocytic leukaemia	Phase 1	US	Memorial Sloan Kettering Cancer Center	23 Feb 2024
Recurrent Adult Acute Lymphoblastic Leukemia	Phase 1	US	Memorial Sloan Kettering Cancer Center	23 Feb 2024
refractory acute lymphoid leukemia in relapse	Phase 1	US	Memorial Sloan Kettering Cancer Center	23 Feb 2024
Refractory B Acute Lymphoblastic Leukemia	Phase 1	US	Memorial Sloan Kettering Cancer Center	23 Feb 2024

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19-28z/IL-18 CAR T cells(Memorial Sloan Kettering Cancer Center)

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