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.

Grant Number: 5R01CA207295-09
NIH Institute/Center: NIH
Principal Investigator: Lauren Byers