Abstract 1126: Disease monitoring with comprehensive genomics provides evidence of mechanism of action and immune evasion in patients receiving an individualized neoantigen cancer vaccine (2023)

Abstract Therapeutic vaccines hold promise to broaden the potency of immune checkpoint blockade (ICB) therapy in tumors lacking immune reactivity. A heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based individualized neoantigen vaccine regimen in combination with nivolumab 480 mg IV and ipilimumab 30mg SC (NCT03639714) has previously demonstrated safety, durable immunogenicity, and clinical benefit in patients with previously treated metastatic disease. Genomic correlates of response were studied over time in 29 patients (13 MSS-CRC, 13 GEA, 3 NSCLC) to understand novel mechanisms of action. Exome and transcriptome sequencing from archival biopsies was used for neoantigen selection. Monthly circulating tumor DNA (ctDNA) samples were collected for monitoring using a comprehensive tumor-naïve and tumor-informed hybrid-capture based ctDNA assay. Paired pre- and post-vaccine tumor transcriptomes were analyzed for 10 patients with 6 having accompanying DNA T cell receptor Β CDR3 repertoire sequencing (TCRseq) in biopsies and longitudinal PBMCs. Prior to vaccination patient tumors were not enriched for immune infiltration or tumor mutation burden (TMB), median 4.3 mut/Mb (range: 2-17 mut/Mb). Minimal neoantigen and mutation drift was observed with a median of 92.5% of neoantigens (range: 45-100%) and a median of 84% (range: 24-99%) of individual mutations detected in biopsies and ctDNA. Notably, paired pre- and post-vaccine biopsy gene expression analyses show upregulation in gene signatures associated with immune infiltration aligning with evidence of T cell expansion measured by significantly expanding CDR3 clonotypes (p &amp;lt0.01). Longitudinal TCRseq in PBMCs demonstrate vaccine induced TCR repertoire dynamics and expanding and contracting clones observed in tumor biopsies could be monitored throughout treatment. In 4 patients the most drastic TCR repertoire changes were observed at time points measured after a 2nd dose of ChAd68. Lastly, we observe evidence of acquired immune evasion through ctDNA monitoring in two patients each following a year of study treatment. One GEA patient acquired HLA-LOH after remaining stable on treatment and one MSS-CRC with a molecular response (MR) for &amp;gt7 months acquired novel biallelic loss-of-function mutations in TAP1 following 1 year of study treatment. We demonstrate that our neoantigen-directed immunotherapy regimen drives durable immune pressure on the tumor in patients with advanced disease where CPI alone has provided minimal benefit. Further, the evidence of acquired resistance supports the induction of immune pressure on tumors following individualized neoantigen vaccination. Comprehensive ctDNA longitudinal monitoring enables real-time assessment of clinical response and acquired resistance. Citation Format: Desiree Schenk, Rita Zhou, Olivia Petrillo, Alexis Mantilla, Italo Faria do Valle, Steven Maron, Brian S. Henick, Chih-Yi Liao, Daniel V.T. Catenacci, Sameek Roychowdhury, Benjamin Solomon, Alexander I. Spira, Ankur Dhanik, Andrew R. Fergusson, Karin Jooss, Matthew Davis. Disease monitoring with comprehensive genomics provides evidence of mechanism of action and immune evasion in patients receiving an individualized neoantigen cancer vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1126.