T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor with a CD28 Costimulatory Moiety Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma

B-cell maturation antigen (BCMA) is expressed by normal plasma cells and the malignant plasma cells of multiple myeloma (MM). We developed the first anti-BCMA chimeric antigen receptor (CAR-BCMA). CAR-BCMA includes an anti-BCMA single-chain variable fragment, a CD28 costimulatory domain, and a CD3-zeta T-cell activation domain (Carpenter et al. Clinical Cancer Research 2013. Vol. 19. 2048-2060). We used a gamma-retroviral vector to genetically modify autologous T cells to express CAR-BCMA. We are conducting a phase I clinical trial of CAR-BCMA T cells. On this trial, patients receive a chemotherapy regimen of 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine on days -5 to -3 followed by an infusion of CAR-BCMA T cells on day 0. Chemotherapy is administered to increase the activity of CAR T cells by depleting endogenous leukocytes. Twenty-three patients have received CAR-BCMA T cells on one of 4 dose levels, 0.3x10⁶, 1x10⁶, 3x10⁶, and 9x10⁶ CAR+ T cells/kg of bodyweight. All patients treated on the lower dose levels and 2 patients treated on the highest dose level have been reported previously (Ali et al. Blood 2016. 128(13). 1688-1700). This abstract exclusively covers the 13 patients treated to date on the highest dose level of 9x10⁶CAR-BCMA T cells/kg.

The median age of the 13 patients was 54 years (range 43-66). The patients had a median of 11 prior lines of therapy. Five patients (12, 19, 20, 23, and 25), had a history of the poor-prognosis chromosome 17p-deletion prior to protocol enrollment. The monoclonal protein produced by each patient's MM and the number of prior therapies of each patient are shown in the table.

Toxicities were consistent with prior reports of cytokine-release syndrome (CRS) after infusions of CAR T cells. The most prominent, signs of CRS were fever, tachycardia, hypotension, and reduced cardiac function. CRS grades are in the table. Of thirteen patients, 4 received the interleukin (IL)-6-receptor antagonist tocilizumab to treat CRS; 2 of these 4 patients also received corticosteroids. While CAR-BCMA T-cell toxicity was severe in some cases, the toxicities were mainly limited to the first 2 weeks after CAR-BCMA T-cell infusion. Because of Grade 3 and 4 CRS experienced by some patients with high bone marrow myeloma burdens, we modified the clinical protocol to only allow enrollment of patients with lower myeloma burdens defined as MM making up 30% or less of bone marrow cells. Two patients (16 and 18) experienced delayed neutropenia and thrombocytopenia that started approximately 1 month after CAR T-cell infusion when blood counts had recovered from the chemotherapy administered before CAR-BCMA T-cell infusions. These patients were treated with filgrastim, eltrombopag, and prednisone based on the hypothesis that the cytopenias were caused by CAR T cells in the patient's bone marrow. At the time of delayed cytopenias, 15 percent of Patient 16's bone marrow T cells were CAR+, and 16.5 percent of Patient 18's bone marrow T cells were CAR+. In both cases, cytopenias resolved after approximately 1 month.

CAR-BCMA T cells exhibited clear anti-myeloma activity. Nine of 11 evaluable patients obtained objective anti-myeloma responses with 2 stringent complete responses, 5 very good partial responses, and 2 partial responses; the duration of responses varied. The longest response to date is 66 weeks (Table). Eight of 10 evaluable patients obtained minimal residual disease negative status by bone marrow flow cytometry. Consistent with BCMA-specific T-cell activity, plasma cells were reduced on bone marrow core biopsies in all 8 evaluated patients and absent in 4 of these patients 2-3 months after CAR-BCMA T-cell infusion.

CAR+ cell levels have been quantified in the blood of patients. CAR T cell levels peaked in the first 2 weeks after infusion and persisted at lower levels for many months in some cases. Cytokines were measured in the serum of all patients. In patients with CRS, multiple cytokines including interferon-gamma, IL-6, IL-8, and IL-17A were consistently elevated in the serum.

These results demonstrate that CAR-BCMA T cells can induce responses in poor-prognosis MM. Accrual to this trial continues. Toxicity was significant but limited in duration and controllable. A compelling atribute of CAR T-cells is that they have a mechanism of action different from other MM therapies. The results reported here should encourage research to improve CAR T-cell therapies for MM.

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