Phase 1 study of CAR-37 T cells in patients with relapsed or refractory CD37+ lymphoid malignancies

医学 耐火材料(行星科学) 内科学 淋巴瘤 肿瘤科 癌症研究 生物 天体生物学
作者
Matthew J. Frigault,Charlotte Graham,Trisha R. Berger,Julie Ritchey,Nora Horick,Areej El‐Jawahri,Irene Scarfò,Andrea Schmidts,Nicholas J. Haradhvala,Marc Wehrli,Won‐Ho Lee,Aiyana L. Parker,Hadley R. Wiggin,Amanda A. Bouffard,Aonkon Dey,Mark B. Leick,Katelin Katsis,Eva L. Elder,Maria Dolaher,Daniella Cook,Alena A. Chekmasova,Lu Huang,Sarah Nikiforow,Heather Daley,Jerome Ritz,Myriam Armant,Fred Preffer,John F. DiPersio,Valentina Nardi,Yi‐Bin Chen,Kathleen Gallagher,Marcela V. Maus
出处
期刊:Blood [American Society of Hematology]
卷期号:144 (11): 1153-1167 被引量:3
标识
DOI:10.1182/blood.2024024104
摘要

Abstract We report a first-in-human clinical trial using chimeric antigen receptor (CAR) T cells targeting CD37, an antigen highly expressed in B- and T-cell malignancies. Five patients with relapsed or refractory CD37+ lymphoid malignancies were enrolled and infused with autologous CAR-37 T cells. CAR-37 T cells expanded in the peripheral blood of all patients and, at peak, comprised >94% of the total lymphocytes in 4 of 5 patients. Tumor responses were observed in 4 of 5 patients with 3 complete responses, 1 mixed response, and 1 patient whose disease progressed rapidly and with relative loss of CD37 expression. Three patients experienced prolonged and severe pancytopenia, and in 2 of these patients, efforts to ablate CAR-37 T cells, which were engineered to coexpress truncated epidermal growth factor receptor, with cetuximab were unsuccessful. Hematopoiesis was restored in these 2 patients after allogeneic hematopoietic stem cell transplantation. No other severe, nonhematopoietic toxicities occurred. We investigated the mechanisms of profound pancytopenia and did not observe activation of CAR-37 T cells in response to hematopoietic stem cells in vitro or hematotoxicity in humanized models. Patients with pancytopenia had sustained high levels of interleukin-18 (IL-18) with low levels of IL-18 binding protein in their peripheral blood. IL-18 levels were significantly higher in CAR-37–treated patients than in both cytopenic and noncytopenic cohorts of CAR-19–treated patients. In conclusion, CAR-37 T cells exhibited antitumor activity, with significant CAR expansion and cytokine production. CAR-37 T cells may be an effective therapy in hematologic malignancies as a bridge to hematopoietic stem cell transplant. This trial was registered at www.ClinicalTrials.gov as #NCT04136275.
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