Background: Small cell lung cancer (SCLC) is a highly aggressive disease for which standard treatment remains virtually unchanged since the 1980s. SCLC has a relatively immunosuppressed phenotype with low levels of infiltrating T-cells and evidence of reduced antigen presentation. Only a minority of SCLC patients responds to programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors as monotherapy. Therefore, though the clinical data is promising, there is a strong need to develop strategies to enhance the efficacy of immunotherapy in SCLC. Our group previously discovered that the DNA damage repair (DDR) protein, checkpoint kinase 1 (CHK1), is overexpressed in SCLC and that CHK1 inhibitors have activity in preclinical models of SCLC. Based on data from others and our group, we hypothesize that tumor associated neoantigen (TAA) expression is suppressed in SCLC by several mechanisms, including DDR machinery, and that targeting CHK1 may enhance antitumor immunity and response to immune checkpoint targeting.
Results: In SCLC models, inhibition of CHK1 by genetic knockdown and small molecule inhibition (LY2606368) induces DNA damage as demonstrated by increased γ-H2AX levels. We also observed increased protein levels of immune checkpoint ligand, PD-L1, following pharmacologic inhibition with LY2606368. We next tested whether co-targeting CHK1+PD-L1 enhances the anti-tumor effect in an immune-competent SCLC model. B6129F1 mice were injected in the flank with TKO.mTmG cells harboring conditional deletion of Trp53, Rb1 and p130. When the tumor volume reached 120mm3, mice were treated with either IgG (control), LY2606368 (10mg/kg, 2/7), anti-PD-L1 (300ug, 1/7) or combination of LY2606368 and anti-PD-L1 antibody. Single agent treatment with anti-PD-L1 antibody did not cause tumor regression in these models with T/C ratio=0.93 (p<0.001) at Day 21. Treatment of single agent LY2606368 at a sub-therapeutic dose significantly delayed tumor growth in these models with T/C=0.31 (p<0.001) at Day 21. However, 3 out of 5 mice treated with anti-PD-L1+LY2606368 had a complete tumor regression within 15 days of treatment with T/C=0.05 (p<0.001) at Day 21. Tumors were collected at the end of 21 days for RPPA analysis, RNA sequencing and flow cytometry to characterize tumor-infiltrating immune cells post treatment with the single agents versus the combination.
Discussion: SCLC has an immunosuppressed phenotype (despite a high mutational burden); however, only a minority of tumors expresses PD-L1, suggesting that immunosuppressive mechanisms other than the PD-1/PD-L1 pathway are likely to contribute. This study shows that targeting CHK1 (by genetic knockdown and pharmacological inhibition) leads to increased DNA damage and increased expression of immune checkpoint ligand, PD-L1. Combining CHK1 inhibition and PD-L1 targeting significantly enhanced the effect of PD-L1 antibody leading to tumor regression in an immune competent SCLC model. Biomarker analyses from these models are ongoing to confirm the expression of immune markers. PD-L1 inhibitors as monotherapy have led to objective responses in only a minority of SCLC patients. The CHK1 inhibitor LY2606368 is currently in clinical trial for SCLC patients. The complementary modes of action of the two promising modalities, immune checkpoint targeting and CHK1 inhibition, suggest intriguing possibilities for therapeutic synergy with combination treatment and warrants further clinical investigation.
Citation Format: Triparna Sen, Limo Chen, Bertha Leticia Rodriguez, Yongbin Yang, You Hong Fan, Catherine Allison Stewart, Bonnie Glisson, Helen Piwnica-Worms, Julien Sage, John V. Heymach, Don L. Gibbons, Lauren A. Byers. Combining immune checkpoint inhibition and DNA damage repair (DDR) targeted therapy in small cell lung cancer (SCLC). [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B72.