T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma
| Autor: | Irina Maric, David F. Stroncek, Jennifer A. Kanakry, Brenna Hansen, Jennifer N. Brudno, Lekha Mikkilineni, Dalia A. Salem, Rashmika Patel, Norris Lam, James N. Kochenderfer, Steven Hartman, Judith Lawrence, Frances T. Hakim, Ronald E. Gress, Michael Wang, Steven A. Feldman, Maryalice Stetler-Stevenson, Constance M. Yuan, Syed Abbas Ali, Jeremy J. Rose, Steven Z. Pavletic |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Transplantation Conditioning Cyclophosphamide T-Lymphocytes medicine.medical_treatment Immunotherapy Adoptive 03 medical and health sciences 0302 clinical medicine Antigen Antineoplastic Combined Chemotherapy Protocols medicine Humans B-Cell Maturation Antigen Multiple myeloma Receptors Chimeric Antigen business.industry Immunotherapy ORIGINAL REPORTS Prognosis medicine.disease Minimal residual disease Chimeric antigen receptor Editorial 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research Cytokines Bone marrow Multiple Myeloma business Vidarabine CD8 medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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