T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma.
By Jennifer N. Brudno, I. Maric, Steven D Hartman, J. Rose, Michael L. Wang, Norris Lam, M. Stetler-Stevenson, Dalia A. Salem, C. Yuan, S. Pavletic and 11 more. Journal of Clinical Oncology, 2018
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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 × 106 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.
Subfields: Hematology, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/6abc9df605015e2953d36874b78755f0b23129ad
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Citations in the corpus
- Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management (2018, background): “Organ system Toxicities Constitutional • Fever • Fatigue and malaise • Headache Cardiovascular • Sinus tachycardia Hypotension • Decreased left ventricular ejection fraction • Arrhythmias • QT prolongation • Troponinemia Respiratory • Hypoxia Dyspnea • Increased respiratory rate Respiratory failure ”
- B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. (2019, background): “Down-modulation of BCMA expression was also observed in at least 1 subject in the NCI study (20), suggesting that it may be a common means of MM cell escape from BCMA-directed CAR T cell therapies.”