Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy for Treatment of Malignant Pleural Mesothelioma
2019
Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with poor prognosis. CRS-207 is a live-attenuated Listeria monocytogenes engineered to express mesothelin, a tumor-associated antigen highly expressed in MPM. CRS-207 induces anti-tumor immune responses and increase susceptibility of neoplastic cells to immune-mediated killing.
Experimental Procedure: Patients with unresectable MPM, ECOG 0 or 1, and adequate organ and pulmonary function were enrolled in this multicenter, open-label phase-1b study. They received two priming infusions of 1x10 9 CFU CRS-207, followed by pemetrexed/cisplatin chemotherapy, and CRS-207 booster infusions. Primary objectives were safety and induction of immune response. Secondary/exploratory objectives included tumor response, progression-free survival (PFS), overall survival (OS), immune subset analysis and gene expression profiling of tumor.
Results: Of 35 evaluable patients, 89% (31/35) had disease control with one complete response (3%), 19 partial responses (54%) and 10 stable disease (29%). Estimated median duration of response was 5.0 months (95% CI:3.9, 11.5). Median PFS and OS was 7.5 (95% CI:7.0, 9.9) and 14.7 (95% CI:11.2, 21.9) months, respectively. Tumor size reduction was observed post-CRS-207 infusion prior to chemotherapy in 11/35 (31%) patients. No unexpected treatment-related serious adverse events or deaths were observed.
Immunohistochemical analysis of pre and post-CRS-207 treatment tumor biopsies revealed possible reinvigoration and proliferation of T cells, increased infiltration of dendritic and NK cells, increased CD8:Treg ratio, and a shift from immunosuppressive M2-like to proinflammatory M1-like macrophages following CRS-207 administration.
Conclusions: Combination CRS-207 and chemotherapy induced significant changes in the local tumor microenvironment and objective tumor responses in a majority of treated patients. (ClinicalTrials.gov, NCT01675765)
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