Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial
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Published:2024-01-18
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ISSN:1078-8956
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Container-title:Nature Medicine
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language:en
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Short-container-title:Nat Med
Author:
Marin David, Li YeORCID, Basar Rafet, Rafei HindORCID, Daher MayORCID, Dou Jinzhuang, Mohanty VakulORCID, Dede MerveORCID, Nieto Yago, Uprety Nadima, Acharya Sunil, Liu Enli, Wilson Jeffrey, Banerjee Pinaki, Macapinlac Homer A., Ganesh Christina, Thall Peter F.ORCID, Bassett RolandORCID, Ammari Mariam, Rao Sheetal, Cao KaiORCID, Shanley MayraORCID, Kaplan MecitORCID, Hosing Chitra, Kebriaei Partow, Nastoupil Loretta J.ORCID, Flowers Christopher R., Moseley Sadie Mae, Lin PaulORCID, Ang Sonny, Popat Uday R., Qazilbash Muzaffar H., Champlin Richard E., Chen KenORCID, Shpall Elizabeth J., Rezvani KatayounORCID
Abstract
AbstractThere is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
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1. Promising early results with CAR NK cells;Nature Reviews Clinical Oncology;2024-02-01
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