Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 10, Issue 2, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-004128
Keywords
hematologic neoplasms; translational medical research; t-lymphocytes; receptors; chimeric antigen; cell engineering
Categories
Funding
- NIH [K08CA241400-01, R01 CA138738-05]
- Carson Family Charitable Trust
- William Lawrence and Blanche Hughes Foundation
- Emerald Foundation
- Experimental Therapeutics Center of MSKCC
- MSKCC Core Facilities Grants [P30 CA008748, U54 OD020355-01]
- Annual Terry Fox Run for Cancer Research by the Canada Club of New York
- Kate's Team
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This report summarizes the preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with heavily pretreated and relapsed or refractory WM, and representing a possible treatment option.
Background Waldenstrom macroglobulinemia (WM) is an incurable disease and, while treatable, can develop resistance to available therapies and be fatal. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies, and is now approved for B cell acute lymphoblastic leukemia and certain B cell lymphomas. However, CAR T therapy has not been evaluated for use in WM. Methods and results We performed preclinical studies demonstrating CAR T cell activity against WM cells in vitro, and developed an in vivo murine model of WM which demonstrated prolonged survival with use of CAR T therapy. We then report the first three patients with multiply relapsed and refractory WM treated for their disease with CD19-directed CAR T cells on clinical trials. Treatment was well tolerated, and observed toxicities were consistent with those seen in CAR T treatment for other diseases, and no grade 3 or higher cytokine release syndrome or neurotoxicity events occurred. All three patients attained at least a clinical response to treatment, including one minimal residual disease-negative complete response, though all three eventually developed recurrent disease between 3 and 26 months after initial treatment. Conclusions This report summarizes preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with WM, and representing a possible treatment option in patients with heavily pretreated and relapsed or refractory WM. Larger studies evaluating CAR T therapy in WM are warranted, along with further evaluation into mechanisms of resistance to CAR T therapy.
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