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CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial
- Source :
- Nature Medicine
- Publication Year :
- 2020
-
Abstract
- 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.<br />Bispecific CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in patients with large B cell lymphoma and B cell acute lymphoblastic leukemia, with relapses associated with loss of CD19 but not CD22.
- Subjects :
- 0301 basic medicine
Oncology
Adult
medicine.medical_specialty
Lymphoma, B-Cell
Lymphoma
medicine.medical_treatment
Sialic Acid Binding Ig-like Lectin 2
Antigens, CD19
Cancer immunotherapy
Immunotherapy, Adoptive
General Biochemistry, Genetics and Molecular Biology
CD19
Article
03 medical and health sciences
0302 clinical medicine
Antigen
immune system diseases
Recurrence
Phase I trials
Internal medicine
hemic and lymphatic diseases
medicine
Humans
B-cell lymphoma
B cell
Aged
Acute lymphocytic leukaemia
biology
business.industry
General Medicine
Immunotherapy
Middle Aged
medicine.disease
Chimeric antigen receptor
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
biology.protein
Disease Progression
business
Progressive disease
Subjects
Details
- ISSN :
- 1546170X
- Volume :
- 27
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Nature medicine
- Accession number :
- edsair.doi.dedup.....02a9f608b206e9336d2cdf9c23ecab41