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 |
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Authors: | Triparna Sen Carminia M Della Corte Snezana Milutinovic Robert J Cardnell Lixia Diao Kavya Ramkumar Carl M Gay C Allison Stewart Youhong Fan Li Shen Ryan J Hansen Bryan Strouse Michael P Hedrick Christian A Hassig John V Heymach Jing Wang Lauren A Byers |
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Institution: | 1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas;2. Sierra Oncology, Vancouver, British Columbia, Canada;3. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas;4. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas |
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Abstract: | IntroductionDespite 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 ResultsHere, 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.ConclusionsGiven 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. |
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Keywords: | Corresponding author Address for correspondence: Lauren A Byers MD 1515 Holcombe Blvd Unit 0432 Houston Texas 77030 SCLC DNA damage response Immune checkpoint blockade Low-dose gemcitabine |
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