Abstract 1238: Comprehensive ctDNA monitoring provides early signal of clinical benefit with a novel personalized neoantigen directed immunotherapy for late-stage cancer patients

Abstract Neoantigen directed immunotherapy holds promise to increase the likelihood of patients with solid tumor devoid of immune infiltration benefiting from immune checkpoint immunotherapy (CPI). A heterologous prime-boost vaccination approach consisting of Chimpanzee Adenovirus (ChAd) prime and multiple self-amplifying mRNA (SAM) boosts, delivering 20 neoantigens, has been evaluated in a Phase 1/2 clinical trial in late-stage solid tumor patients in combination with nivolumab and ipilimumab (NCT03639714). Neoantigen dynamics, tumor burden and genomic correlates of response were studied over time in 20 patients (8 GEA, 2 NSCLC, 10 MSS-CRC). Exome sequences from archival (sample used for neoantigen selection), baseline (start of immunization) and on-treatment biopsies were analyzed for 20, 16 and 10 patients respectively. Paired pre- and post-vaccine tumor transcriptomes were analyzed for 6 patients. Personalized capture baits were designed for all non-synonymous mutations detected in archival biopsies (mean 146; range: 67-402) for ctDNA monitoring. Longitudinal ctDNA samples were collected monthly on treatment (mean 7; range: 1-18). ctDNA duplex UMI libraries were captured and sequenced to a target mean raw depth >80,000x and reduced to 3x per strand consensus duplex reads. The majority of vaccine neoantigens were detected in ctDNA (87%; range 45%-100%) and mean neoantigen variant allele frequency (VAF) strongly correlated with all monitored mutations VAF (R2 = 0.90, p < 0.0001) through treatment. The percentage of vaccine neoantigens detected was higher than that for all monitored mutations in the same samples with a median of 80% (21%-98%) in ctDNA and 70% (44%-100%) in biopsies. Five of 9 MSS-CRC patients with measurable baseline ctDNA achieved molecular responses (MR, >50% reduction in ctDNA from baseline) that correlated with OS and PFS, and in some patients, was accompanied by radiologic tumor shrinkage. One MSS-CRC patient with MR for >7 months acquired novel biallelic loss-of-function mutations in TAP1 following 1 year of study treatment. Differential gene expression analysis from paired pre- and post-vaccine biopsies (including 2 MSS-CRC pairs with MR) demonstrated significant upregulation in gene signatures associated with immune-inflamed tumor microenvironments including interferon alpha and gamma responses. We demonstrate that tumor-informed neoantigen selection and vaccine manufacturing while patients receive chemotherapy is feasible, since the majority of neoantigens are retained in the tumor post-chemotherapy. Further, neoantigen-directed immunotherapy appears to drive clinical benefit in patients with advanced MSS-CRC tumors, where CPI alone has provided minimal benefit. Comprehensive ctDNA longitudinal monitoring enables real time assessment of clinical response and acquired resistance. Citation Format: Desiree Schenck, Rita Zhou, Alexis Mantilla, Oliver Spiro, Taylor Patch, Adrienne Johnson, Daniel Navarro Gomez, Brian S. Henick, Chih-Yi Liao, Sameek Roychowdhury, Steve Maron, Benjamin Solomon, Alexander I. Spira, Daniel V. Catenacci, Andrew R. Fergusson, Raphael F. Rousseau, Karin Jooss, Matthew J. Davis. Comprehensive ctDNA monitoring provides early signal of clinical benefit with a novel personalized neoantigen directed immunotherapy for late-stage cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1238.