DNA damaging therapy and immune response in small cell lung cancer subtypes

PROJECT SUMMARY Small cell lung cancer (SCLC) is a highly aggressive disease for which there remains a critical need for therapies that provide durable benefit and biomarkers to guide treatment selection. While immunotherapy provides clinical benefit for some patients, overall survival with current chemotherapy-immunotherapy combinations in unselected patient populations remains only ~12 months. A particularly understudied feature of SCLC is therapeutic approaches to enhance immune-mediated responses for this largely immune “cold” cancer. Our group has previously identified promising drug targets, strategies to enhance immunotherapy response, and candidate predictive biomarkers for SCLC (including PARP and other DNA damage response inhibitors alone an in combination with immunotherapy). These have been rapidly translated into clinical trials. To address current research gaps (outlined in the NCI’s SCLC Progress Working Group report), including (1) investigation of the SCLC microenvironment (including the potential and limitations of immunotherapy), (2) tumor heterogeneity, (3) characterization of longitudinal patient samples, (4) models of newly identified subtypes, and (5) development of blood-based biomarker approaches, we have assembled a multidisciplinary team with scientific, clinical, translational, and computational expertise in the field of SCLC and cancer immunology. Together with our Thoracic Bioinformatics Working Group, we recently found that there are four distinct, expression-based molecular subsets of SCLC, including a novel “Inflamed” subtype (Gay et al, Cancer Cell, 2021). Importantly, these SCLC subtypes (SCLC-ASCLC, NEUROD1, POU2F3, and SCLC-Inflamed) have distinct therapeutic vulnerabilities that can be leveraged to enhance response to ICB combinations. We have generated and profiled new patient-derived xenograft models from biopsies and circulating tumor cells (“CDXs”) representing the major SCLC subtypes. These, together with an established humanized mouse model system, will enable us to deeply characterize mechanisms of immune response to combinations of ICB and DNA damaging therapies. Based on our data, we hypothesize that SCLC subtypes and SLFN11 status will determine distinct, immune mediated responses to DNA damaging therapies and ICB and that novel combinations targeting replication stress may enhance ICB response in immune “cold” SCLC. To address these hypotheses, in Aim 1, we will determine the SCLC molecular subtype-specific immune modulatory effects of DNA damaging therapy in co-clinical trials in vivo and in patient specimens before and after treatment. In Aim 2, we will investigate cancer cell SLFN11 as a predictive biomarker and its role in STING pathway activation and anti-tumor immunity. Lastly, in Aim 3, we will assess methods to overcome resistance, including alternative DNA damaging agents combined with ICB. The overall hypothesis is that molecular subtyping of SCLC tumors, paired with strategies to enhance immunotherapy response, will improve survival for patients with SCLC by providing a personalized, biomarker-informed approach to therapy.