Abstract
BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.
Highlights
B-cell maturation antigen (BCMA) targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma
By performing single-cell transcriptome profiling on serially collected bone marrow (BM) samples, we show biallelic loss of BCMA as one of the resistance mechanisms to antiBCMA CAR T-cell therapy with Idecabtagene Vicleucel in a patient with initial response but relapse with resistance to retreatment with the same CAR T-cell product
The patient was enrolled in a Phase I trial (CRB-401 ClinicalTrials.gov number, NCT02658929) of antiBCMA CAR T-cell therapy with Idecabtagene Vicleucel and received 150 × 106 CAR+ T cells at day 0 following lymphodepletion with fludarabine (30 mg/m2 per day) and cyclophosphamide (300 mg/m2 per day) on days −5, −4, and −3, as reported in ref
Summary
BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. Among the small number of patients retreated with the same CAR T cell product at the time of progression, responses have been infrequent[4,5]. This highlights development of acquired resistance mechanisms[6,7], which may preclude effectiveness of the second CAR T infusion, and may explain relapse following the initial CAR T-cell therapy. Our results highlight that MM cells may develop alternative paths to survive without BCMA
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