Clinical Response of Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma

Abstract

Purpose: 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 antitumor immune responses and increases susceptibility of neoplastic cells to immunemediated killing.Patients and Methods: Patients with unresectable MPM, ECOG 0 or 1, and adequate organ and pulmonary function were enrolled in this multicenter, open-label phase Ib study. They received two priming infusions of 1 Â 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.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%). The estimated median duration of response was 5.0 months (95% CI, 3.9-11.5). The median PFS and OS were 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 of 35 (31%) patients. No unexpected treatment-related serious adverse events or deaths were observed. IHC analysis of pre-and post-CRS-207 treatment tumor biopsies revealed possible reinvigoration and proliferation of T cells, increased infiltration of dendritic and natural killer cells, increased CD8:T reg ratio, and a shift from immunosuppressive M2-like to proinflammatory M1-like macrophages following CRS-207 administration.Conclusions: Combination of CRS-207 and chemotherapy induced significant changes in the local tumor microenvironment and objective tumor responses in a majority of treated patients.

Clinical Experience and Recent Advances in the Development of Listeria-Based Tumor Immunotherapies

“…As CRS-207 targets mesothelin, a tumor antigen highly expressed in MPM, a Phase I clinical trial was conducted to determine safety and tolerability of CRS-207 in combination with pemetrexed and cisplatin. In contrast to its efficacy on PDAC, 89% of patients receiving CRS-207 in combination with pemetrexed and cisplatin experienced tumor reduction (60). While the median OS was comparable to chemotherapy at 14.7 months, the OS rate at 1 year of 64.9% was more comparable to ICI-treated MPM patients.…”

Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future

“…The phase I trial NCT01675765 evaluated the sequential administration of the cancer vaccine CRS-207, an attenuated form of Listeria monocytogenes expressing MSLN, with or without cyclophosphamide followed by consolidation CT, to stimulate an innate and adaptive immunity against MSLN-expressing cells. The cyclophosphamide arm showed acceptable toxicity and a DCR of 89%, a PR of 54%, an SD of 29%, and a median PFS and OS of 7.5 and 14.7 months, respectively (116).…”

Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?

“…Reduction of tumor size was also observed post-CRS-207 infusion prior to chemotherapy in 11 patients and no treatment-related serious adverse events or deaths were observed. These results suggested that combining CRS-207 with traditional chemotherapy might potentially result in increased anti-tumor activity (78). However, after a phase II trial had showed no clinical activity of the combination of CRS-207 with PD-1 inhibition (NCT03175172), clinical development of this therapy was discontinued.…”