RESUMO
BACKGROUND: Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma. METHODS: In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×106, 150×106, 450×106, or 800×106 CAR-positive (CAR+) T cells in the dose-escalation phase and 150×106 to 450×106 CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety. RESULTS: Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10-4 nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion. CONCLUSIONS: We report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.).
Assuntos
Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Imunoterapia Adotiva , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Adulto , Idoso , Relação CD4-CD8 , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Intervalo Livre de Progressão , Linfócitos T/metabolismoRESUMO
BACKGROUND: Single-agent gemcitabine and vinorelbine have activity in treatment of patients with soft-tissue sarcomas. The combination of gemcitabine plus vinorelbine has activity against several forms of metastatic carcinoma with acceptable toxicity. This study evaluated the efficacy and tolerability of gemcitabine plus vinorelbine in advanced soft-tissue sarcoma. METHODS: A single academic center performed this phase II trial. Eligible patients had unresectable or metastatic soft-tissue sarcomas, Eastern Cooperative Group performance status of 0-2, adequate organ function, and