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

• Published in: Journal of thoracic oncology 2019-12, Vol.14 (12), p.2152-2163
• Main Authors: Sen, Triparna, Della Corte, Carminia M., Milutinovic, Snezana, Cardnell, Robert J., Diao, Lixia, Ramkumar, Kavya, Gay, Carl M., Stewart, C. Allison, Fan, Youhong, Shen, Li, Hansen, Ryan J., Strouse, Bryan, Hedrick, Michael P., Hassig, Christian A., Heymach, John V., Wang, Jing, Byers, Lauren A.
• Format: Article
• Language: English
• Subjects: DNA damage response; Immune checkpoint blockade; Low-dose gemcitabine; SCLC
• ISSN: 1556-0864; 1556-1380
• DOI: 10.1016/j.jtho.2019.08.009

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. 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. 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.