T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma

Abstract

Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 × 10 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a γ-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease-negative status. High peak blood CAR cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8 T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…As a consequence, the FDA recently approved two commercial CAR-T cell therapies for relapsed/refractory B-ALL and relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) (tisagenlecleucel) [101 & ,102] and for the second-line treatment of DLBCL (axicabtagene ciloleucel) [103 & ,104]. Their development is now being expanded and explored through other malignancies targeting CD5 [105] and CD7 [106] in T cell malignancies, FLT3, CD33, CD38, CD56, CD117, CD123, NKG2DL and Lewis-Y in AML [107], CD30 in Hodgkin lymphoma [108] or B-cell maturation antigen (BCMA) (breakthrough therapy designation by the FDA), CD19, CD38, CD138, TACI and SLAMF7 in multiple myeloma patients [109,110].…”

A review of chimeric antigen receptor T-cells in lymphoma

“…Clinical trials in multiple myeloma targeting B-cell maturation antigen (BCMA) have proven efficacy and safety of the use of CAR-T in this population [64]. Signaling lymphocyte-activating molecule F7 (SLAMF7), the monoclonal antibody target of elotuzumab, is another promising target in multiple myeloma given its lack of expression outside of hematologic cell line; however, CAR-T targeting this antigen has yet to be used in human clinical trials [65,66].…”

Cellular therapy: Immune‐related complications

“…Recent efforts have been aimed at developing CAR‐T directed toward other antigens and in other indications. The most developed program is a B‐cell maturation antigen (BCMA) directed CAR‐T in clinical trials for relapsed/refractory multiple myeloma . Additional B‐cell targeted single antigen therapy CAR‐T directed at TSLPR and CD38 are under development, though these are in earlier stages of development as compared with BCMA directed CAR‐T .…”