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A first-in-human trial with CAR T cells followed by pembrolizumab showed feasibility, safety and evidence of antitumor efficacy in malignant pleural mesothelioma
A combination immunotherapy with CAR T cell therapy and anti-PD-1 agents shows promising results in solid tumors: the strategy is feasible, safe and has evidence of an antitumor activity in patients with malignant pleural mesothelioma, as revealed by a first-in-human study recently published on Cancer Discovery.
CAR T-cell therapy induces durable and curative responses in patients with hematologic malignancies, but attempts to treat solid tumors with this approach have so far met with limited success due to heterogeneous antigen expression, an inability to achieve T-cell infiltration of the tumor, and inhibition of CAR T-cell function by an immunosuppressive microenvironment. Authors therefore developed a locally delivered mesothelin-targeted CAR T-cell therapy, choosing mesothelin as a target cell-surface antigen because of its overexpression and association with aggressiveness; they combined this CAR-T cell therapy with an anti-PD-1 agent as pembrolizumab because in mouse model they observed that CAR-T cells became functionally exhausted when faced with large tumor burdens, in part because of inhibitory PD-1/PD-L1 signaling.
For this first-in-human trial the authors administered into the pleura 0.3M to 60M CAR-T cells/kg in 27 patients; the procedure was safe and well tolerated, with CAR-T cells detectable in peripheral blood for over 100 days in 39% of patients. Eighteen patients received pembrolizumab safely and among those patients median overall survival from CAR T-cell infusion was 23.9 months, with a 1-year overall survival of 83%. Stable disease was sustained for 6 months or more in 8 patients and 2 exhibited complete metabolic response on PET scan. «Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors», conclude the authors.