Journal
NATURE MEDICINE
Volume 27, Issue 8, Pages 1419-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-021-01436-0
Keywords
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Funding
- California Institute for Regenerative Medicine [CLIN2-10846]
- National Cancer Institute [5P30CA124435, U54 CA232568-01, 2P01CA049605-29A1]
- Stanford University Cancer Immunotherapy Program
- Virginia and D.K. Ludwig Fund for Cancer Research
- National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) [75N92019D00018]
- American Society of Hematology Research Training Award
- Maternal and Child Health Research Institute
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Despite impressive progress in CAR-T cell therapy, more than 50% of patients treated with CD19-targeting CAR-T cells experience disease progression, often associated with antigen loss. To address this issue, researchers tested a bispecific CAR targeting CD19 and/or CD22, which showed high efficacy in preventing relapse in patients with B-ALL and LBCL. Antigen loss was identified as a major cause of CAR T cell resistance, emphasizing the importance of engineering multi-specific CAR T cells with equivalent potency and cytokine production as a quality indicator for potency.
Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19- or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial (NCT03233854) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19-/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22-/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.
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