Clinical Cancer Research 2019 July 1 [Link]
Hassan R, Alley E, Kindler H, Antonia SJ, Jahan TM, Honarmand S, Nair N, Whiting C, Enstrom A, Lemmens E, Tsujikawa T, Kumar S, Choe G, Thomas A, McDougall K, Murphy A, Jaffee EM, Coussens LM, Brockstedt DG
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 1×10 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.
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.
Combination CRS-207 and chemotherapy induced significant changes in the local tumor microenvironment and objective tumor responses in a majority of treated patients.