부산대학교 도서관

Objectives: In previous clinical studies using a murine-derived CAR construct targeted to mesothelin (SS1 CAR), we observed limited persistence and efficacy. To improve the outcome, we created a fully human anti-mesothelin scFV fused to the intracellular signaling domains 4-1BB (CD137) and TCR zeta (M5 CAR). Pre-clinical evaluation of the M5 CAR revealed enhanced in vivo antitumor activity compared to the SS1 CAR. Methods: Fourteen patients with mesothelin-expressing tumors (ovarian, lung, malignant mesothelioma) were treated with the M5 CAR. Three patients received a single IV dose of 3 x 107 CART-meso cells/m2 (Cohort 1), three patients received a single IV dose of 3 x 107 CART-meso cells/m2 following lymphodepletion (Cohort 2), and two patients received a single IV dose of 3 x 108 CART-meso cells/m2 (Cohort 3). Due to toxicity, the last six patients received lymphodepletion and an initial IV dose of 3 x 107 CART-meso cells/m2 followed by up to two additional IV doses spaced 21-42 days apart (Cohort 4). Results: The infusions were well tolerated. M5 CART cells were detectable in blood one hour after infusion and expanded to a peak at Day 7-10. Higher levels were detected in patients treated with the higher dose CART cells and with lymphodepletion. M5 CART cells persisted up to 28-42 days in all subjects and at three and six months in two patients. M5 CART cells were trafficked to tumors in nine of the 14 patients. At 28-35 days after treatment, eight patients showed stable disease (8/14, 57%) per RECIST criteria. One patient had SD for three months; another had SD for nine months. Four subjects experienced cytokine release syndrome (CRS) (three grade 3 and one grade 4), and related AEs included hypoxia, hypotension, hyponatremia, fatigue, and febrile neutropenia. In Cohort 3, both subjects had acute respiratory SAEs. One patient experienced grade 3 SAEs (CRS, hypotension, hypoxia) but fully recovered. The other patient, with extensive pulmonary tumor burden and residual PD-1 blockade, suffered fatal respiratory failure. Due to these SAEs, the MTD was defined at 3 x 107 CART-meso cells/m2 and six subsequent patients had no pulmonary SAEs. Conclusions: This dose-escalation trial demonstrates the feasibility of treating multiple tumor types with M5 CART cells. The M5 CART cells engrafted and expanded in the blood of all subjects but persisted at relatively low blood levels and for short time periods. CART trafficking into tumors was identified in 9/14 patients. Short-term stable disease was noted in the majority of patients, but no clinical responses were seen. Pulmonary toxicity was seen when given at the 3 x 10 8 CART cells/m2 dose. These preliminary results may help guide future M5 CART clinical trials, such as loco-regional delivery or modifications to the CART cells to improve safety and enhance trafficking and persistence. [ABSTRACT FROM AUTHOR]