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.
N1 - Funding Information:
A special thank you is extended to the referring physicians, participating investigators, and most of all the patients and their families. The authors also thank Jocelyn Hybiske, PhD, an independent consultant, for editorial services. This study was sponsored by Aduro Biotech, Inc. (Berkeley, CA). The Coussens laboratory acknowledges support from UL1 TR000128 (T. Tsujikawa) and NCI/ NIH (R01CA15531 and U54CA163123), the Department of Defense Breast Cancer Research Program (W81XWH-11-1-0702), the Susan G Komen Foundation (KG111084), the Brenden-Colson Center for Pancreatic Health, and a Stand Up To Cancer–Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant (SU2C-AACR-DT14-14) to L.M. Coussens. A. Thomas is supported by the intramural program of the NIH (ZIA BC 011793). R. Hassan is supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (ZIA BC010816).
Funding Information:
A special thank you is extended to the referring physicians, participating investigators, and most of all the patients and their families. The authors also thank Jocelyn Hybiske, PhD, an independent consultant, for editorial services. This study was sponsored by Aduro Biotech, Inc. (Berkeley, CA). The Coussens laboratory acknowledges support from UL1 TR000128 (T. Tsujikawa) and NCI/ NIH (R01CA15531 and U54CA163123), the Department of Defense Breast Cancer Research Program (W81XWH-11-1-0702), the Susan G Komen Foundation (KG111084), the Brenden-Colson Center for Pancreatic Health, and a Stand Up To Cancer?Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant (SU2C-AACR-DT14-14) to L.M. Coussens. A. Thomas is supported by the intramural program of the NIH (ZIA BC 011793). R. Hassan is supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (ZIA BC010816).
Funding Information:
H. Kindler is a consultant/advisory board member for AstraZeneca, Aldeyra, Boehringer Ingelheim, Bristol-Myers Squibb, Astellas, Erytech, Five Prime, Ipsen, Kyowa, and Paredox. S. Honarmand is an employee of and holds ownership interest (including patents) in Aduro Biotech, Inc. E.M. Jaffee reports receiving commercial research grants from AduroBiotech and Bristol-Myers Squibb; holds ownership interest (including patents) in AduroBiotech; and is a consultant/advisory board member for CSTONE, DragonFly, and Genocea. L. M. Coussens reports receiving commercial research grants from Acerta Pharma, Deciphera Pharmaceuticals, Roche Glycart AG, and Syndax Pharmaceuticals; reports receiving other commercial research support from Plexxikon, Pharma-cyclics, Acerta Pharma, Deciphera Pharmaceuticals, Genentech, Roche Glycart AG, Cell Signaling Technologies, and NanoString Technologies; and is a consultant/advisory board member for Pharmacyclics, Syndax Pharmaceuticals, Carisma Therapeutics, Verseau Therapeutics, Zymeworks, Melvin and Bren Simon Cancer Center at Indiana Universtiy, Koch Institute for Integrated Cancer Research at MIT, Salk Institute Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Dana-Farber Cancer Center Breast SPORE, Cancer Research Institute, The V Foundation for Cancer Research, Cancer Research United Kingdom, Starr Cancer Consortium, NIH/NCI, and Cell Signaling Technologies. D.G. Brockstedt was an employee of and holds ownership interest (including patents) in Aduro Biotech. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
©2019 American Association for Cancer Research.
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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U2 - 10.1158/1078-0432.CCR-19-0070
DO - 10.1158/1078-0432.CCR-19-0070
M3 - Article
C2 - 31263030
AN - SCOPUS:85072796532
SN - 1078-0432
VL - 25
SP - 5787
EP - 5798
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -