Abstract 2507: Drivers of immunotherapy response within the CPI3000+ cohort
Authors: Thakkar Krupa , Castro Andrea , Qian Danwen , Swanton Charles , Litchfield Kevin 
Published: March 2024

Introduction: Multiple genomic and transcriptomic biomarkers have been associated with response to immune checkpoint (CPI) therapy. These markers include tumor mutational burden (TMB), immune infiltration and HLA loss of heterozygosity. Our previously published meta-analysis of biomarkers included over 1000 patients (CPI1000) across multiple cancer types and demonstrated that clonal TMB and CXCL9 expression were the strongest predictors of response pan-cancer. Biomarkers were combined into a multivariable predictor of response which out-performed TMB in three validation cohorts. However, even with an extensive systematic review, the literature and exploratory biomarkers only accounted for ~60% of the variance explained in CPI response. Approach and

Results: Extending the cohort to over 3000 patients from 20 studies, across 11 tumor solid tumor types, we have utilized available genomic and transcriptomic data to further validate the multi-variable predictor of response as well as conduct additional exploratory analysis to uncover the remaining variance explained. The raw data is processed through a robust bioinformatics pipeline and is harmonized across studies. The pipeline developed to process the CPI3000+ cohort will be open-access and available to promote federated learning and collaborations. Firstly, we have expanded the systematic review to include recent biomarkers from literature. The literature review included over 1000 papers, and we identified greater than 200 unique biomarkers which can be quantified and assessed in the CPI3000+ cohort. Data presented on this extensive set of genomic and transcriptomic biomarkers across the cohorts will improve understanding of biomarkers of response to CPI therapy. Second, we will explore novel biomarkers of response including non-classical sources of antigen such as retained introns as well as pathways such as the unfolded protein response. We will also survey the effects of tumor-associated antigens such as those involved in CAR-T cell and vaccine trials in CPI response which was limited in the CPI1000 cohort. We will also be presenting data on emerging checkpoints in late-stage trials across cancer types. Finally, we will be combining the biomarkers into a novel multivariable predictor of response.

Conclusions: Results from this work will highlight the varying determinants of immunotherapy response across solid tumor types, offering insight into tumor intrinsic and extrinsic drivers of immunogenicity. We have shown that sources of tumour antigen are a major group of biomarkers for CPI response, here we expand on this further in a larger cohort as well as identifying novel biomarkers to create an improved multivariable predictor of clinical value.

Citation Format: Krupa Thakkar, Andrea Castro, Danwen Qian, Charles Swanton, Kevin Litchfield. Drivers of immunotherapy response within the CPI3000+ cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2507.