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

Raffit Hassan, Evan Alley, Hedy Kindler, Scott Antonia, Thierry Jahan, Somayeh Honarmand, Nitya Nair, Chan C. Whiting, Amanda Enstrom, Ed Lemmens, Takahiro Tsujikawa, Sushil Kumar, Gina Choe, Anish Thomas, Katherine McDougall, Aimee L. Murphy, Elizabeth Jaffee, Lisa M. Coussens, Dirk G. Brockstedt

Research output: Contribution to journalArticle

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 x 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.

Original languageEnglish (US)
Pages (from-to)5787-5798
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number19
DOIs
StatePublished - Oct 1 2019

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Listeria monocytogenes
Drug Therapy
Neoplasms
Disease-Free Survival
Pemetrexed
Tumor Microenvironment
Survival
Gene Expression Profiling
Neoplasm Antigens
Immunosuppressive Agents
Natural Killer Cells
Cisplatin
Malignant Mesothelioma
mesothelin
Macrophages
T-Lymphocytes
Biopsy
Safety
Lung
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Clinical Response of Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma. / Hassan, Raffit; Alley, Evan; Kindler, Hedy; Antonia, Scott; Jahan, Thierry; Honarmand, Somayeh; Nair, Nitya; Whiting, Chan C.; Enstrom, Amanda; Lemmens, Ed; Tsujikawa, Takahiro; Kumar, Sushil; Choe, Gina; Thomas, Anish; McDougall, Katherine; Murphy, Aimee L.; Jaffee, Elizabeth; Coussens, Lisa M.; Brockstedt, Dirk G.

In: Clinical Cancer Research, Vol. 25, No. 19, 01.10.2019, p. 5787-5798.

Research output: Contribution to journalArticle

Hassan, R, Alley, E, Kindler, H, Antonia, S, Jahan, T, Honarmand, S, Nair, N, Whiting, CC, Enstrom, A, Lemmens, E, Tsujikawa, T, Kumar, S, Choe, G, Thomas, A, McDougall, K, Murphy, AL, Jaffee, E, Coussens, LM & Brockstedt, DG 2019, 'Clinical Response of Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma', Clinical Cancer Research, vol. 25, no. 19, pp. 5787-5798. https://doi.org/10.1158/1078-0432.CCR-19-0070
Hassan, Raffit ; Alley, Evan ; Kindler, Hedy ; Antonia, Scott ; Jahan, Thierry ; Honarmand, Somayeh ; Nair, Nitya ; Whiting, Chan C. ; Enstrom, Amanda ; Lemmens, Ed ; Tsujikawa, Takahiro ; Kumar, Sushil ; Choe, Gina ; Thomas, Anish ; McDougall, Katherine ; Murphy, Aimee L. ; Jaffee, Elizabeth ; Coussens, Lisa M. ; Brockstedt, Dirk G. / Clinical Response of Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 19. pp. 5787-5798.
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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 x 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.",
author = "Raffit Hassan and Evan Alley and Hedy Kindler and Scott Antonia and Thierry Jahan and Somayeh Honarmand and Nitya Nair and Whiting, {Chan C.} and Amanda Enstrom and Ed Lemmens and Takahiro Tsujikawa and Sushil Kumar and Gina Choe and Anish Thomas and Katherine McDougall and Murphy, {Aimee L.} and Elizabeth Jaffee and Coussens, {Lisa M.} and Brockstedt, {Dirk G.}",
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TY - JOUR

T1 - Clinical Response of Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma

AU - Hassan, Raffit

AU - Alley, Evan

AU - Kindler, Hedy

AU - Antonia, Scott

AU - Jahan, Thierry

AU - Honarmand, Somayeh

AU - Nair, Nitya

AU - Whiting, Chan C.

AU - Enstrom, Amanda

AU - Lemmens, Ed

AU - Tsujikawa, Takahiro

AU - Kumar, Sushil

AU - Choe, Gina

AU - Thomas, Anish

AU - McDougall, Katherine

AU - Murphy, Aimee L.

AU - Jaffee, Elizabeth

AU - Coussens, Lisa M.

AU - Brockstedt, Dirk G.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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 x 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.

AB - 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 x 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.

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