TY - JOUR
T1 - Combination Treatment of the Oral CHK1 Inhibitor, SRA737, and Low-Dose Gemcitabine Enhances the Effect of Programmed Death Ligand 1 Blockade by Modulating the Immune Microenvironment in SCLC
AU - Sen, Triparna
AU - Della Corte, Carminia M.
AU - Milutinovic, Snezana
AU - Cardnell, Robert J.
AU - Diao, Lixia
AU - Ramkumar, Kavya
AU - Gay, Carl M.
AU - Stewart, C. Allison
AU - Fan, Youhong
AU - Shen, Li
AU - Hansen, Ryan J.
AU - Strouse, Bryan
AU - Hedrick, Michael P.
AU - Hassig, Christian A.
AU - Heymach, John V.
AU - Wang, Jing
AU - Byers, Lauren A.
N1 - Funding Information:
Disclosure: Drs. Milutinovic, Hansen, Strauss, Hedrick, and Hassig are full time employees of Sierra Oncology. Dr. Heymach has received grants from AstraZeneca, Bayer, GlaxoSmithKline, and Spectrum; has received personal fees from Spectrum; and serves on advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GlaxoSmithKline, Guardant Health, Hengrui, Lilly, Novartis, Spectrum, EMD Serono, and Synta. Dr. Byers has received grants from Sierra Oncology; and has a patent pending on Combination of Gemcitabine + SRA737 and Anti?PD-L1. The remaining authors declare no conflict of interest.This work was supported by research funding from Sierra Oncology (L.A.B.); National Institutes of Health (NIH)/National Cancer Institute (NCI) award U01-CA213273 (J.V.H. L.A.B.); NIH/NCI award 1-R01-CA207295 (L.A.B.); NIH/NCI CCSG P30-CA016672 (shRNA and ORFeome Core, Boinformatics Shared Resource); The University of Texas-Southwestern and MD Anderson Cancer Center Lung SPORE (5 P50 CA070907) (J.V.H. J.W. L.A.B.); NIH/NCI T32 CA009666 (C.M.G.); the Lung Cancer Research Foundation (T.S.); through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (J.V.H. J.W. L.A.B.); MD Anderson Cancer Center Physician Scientist Award (L.A.B.); and The Rexanna Foundation for Fighting Lung Cancer (J.V.H. L.A.B.).
Funding Information:
This work was supported by research funding from Sierra Oncology (L.A.B.); National Institutes of Health (NIH)/ National Cancer Institute (NCI) award U01-CA213273 (J.V.H., L.A.B.); NIH / NCI award 1-R01-CA207295 (L.A.B.); NIH / NCI CCSG P30-CA016672 (shRNA and ORFeome Core, Boinformatics Shared Resource); The University of Texas-Southwestern and MD Anderson Cancer Center Lung SPORE ( 5 P50 CA070907 ) (J.V.H., J.W., L.A.B.); NIH / NCI T32 CA009666 (C.M.G.); the Lung Cancer Research Foundation (T.S.); through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (J.V.H., J.W., L.A.B.); MD Anderson Cancer Center Physician Scientist Award (L.A.B.); and The Rexanna Foundation for Fighting Lung Cancer (J.V.H., L.A.B.).
Publisher Copyright:
© 2019 International Association for the Study of Lung Cancer
PY - 2019/12
Y1 - 2019/12
N2 - Introduction: Despite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC. Methods and Results: Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti–programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti–PD-L1/anti–PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNβ, and chemokines, CCL5 and CXCL10. Conclusions: Given that anti–PD-L1/anti–PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.
AB - Introduction: Despite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC. Methods and Results: Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti–programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti–PD-L1/anti–PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNβ, and chemokines, CCL5 and CXCL10. Conclusions: Given that anti–PD-L1/anti–PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.
KW - DNA damage response
KW - Immune checkpoint blockade
KW - Low-dose gemcitabine
KW - SCLC
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UR - http://www.scopus.com/inward/citedby.url?scp=85073736124&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2019.08.009
DO - 10.1016/j.jtho.2019.08.009
M3 - Article
C2 - 31470128
AN - SCOPUS:85073736124
SN - 1556-0864
VL - 14
SP - 2152
EP - 2163
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 12
ER -