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 immune-mediated 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 × 109 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:Treg 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.

Trial registration: ClinicalTrials.gov NCT01675765.

©2019 American Association for Cancer Research.

Figures

Figure 1.

Response to treatment. A, Maximum tumor volume change on study (% change; N = 35*) 35/38 patients posttumor measurement availablea,b; best overall response (BOR): N = 35 evaluable subjects; complete response (CR): 1/35 (3%); partial response (PR): 19/35 (54%); stable disease (SD): 10/35 (29%); progressive disease (PD): 5/35 (14%). aOne patient with clinical progression (BOR, PD), but no postbaseline tumor measurement and is not represented on the graph. bThree patients were not evaluable for response (BOR, not evaluable), one of whom is included on the graph due to a single post-tumor measurement of SD but did not meet the minimum duration of response for BOR evaluation. B, Percent change in target lesion from baseline over treatment course. C, Percent change in tumor measurement prior to chemotherapy. Change in tumor measurement from baseline following administration of two doses of CRS-207 and prior to administration of pemetrexed/cisplatin. Tumor size reduction ranged from −1% to −39% in 11/36 (31%) patients. Solid, nonresponder (SD or PD); checkered, responder (PR or CR).

Figure 2.

Serum mesothelin as a biomarker of patient response to treatment. The level of serum mesothelin was determined in 31 patients over the course of treatment. A, Shown is a waterfall plot of the change in serum mesothelin at the final time point available for analysis for each patient (2–25 weeks posttreatment), compared with baseline. B, Shown is the concentration of serum mesothelin over time during CRS-207 priming, chemotherapy, and CRS-207 boost treatments. Black, complete responder; green, partial responder; blue, stable disease; red, progressive disease; white, not evaluable.

Figure 3.

Multicolor flow cytometry of circulating immune cells pre- and posttreatment. Multicolor flow cytometry enumeration of the longitudinal changes in circulating immune cells pre- and posttreatment. Shown are the systemic immune cell subsets that changed significantly over the course of treatment in individual patients (n = 27), as determined by ANOVA. The frequencies of T cells, CD8 Tcm (central memory), naïve CD8 T cells, CD4 Tem (effector memory), mDCs, pDCs, and monocytes changed significantly in patients during CRS-207 priming, chemotherapy or CRS-207 boost treatments. Blue, stable disease; red, progressive disease; green, partial response; blank, complete response. P values were determined by ANOVA. *, P < 0.05; ***, P < 0.001.

Figure 4.

Multiplex IHC-based quantification depicting longitudinal changes of immune cell characteristics comparing pre and post dosing biopsies. A, Percentages and ratios of T cells, NK cells, CD68+ CSF1R+ macrophages, and DCs, comparing pre- and posttreatment status. B and C, Representative images showing post-therapeutic increase of CD8+ T cells (B) and CD83+ DCs (C). Boxed areas identify magnified areas below. Bars, 100 μm.