Abstract A083: Personalized targeted circulating tumor DNA (ctDNA) and T-cell responses after combined neoantigen vaccine and immune checkpoint blockade in ovarian cancer
Authors: MacLean C. Sellars, Rebecca Porter, Ruolin Liu, Alexis A. Howard, Kan Xiong, Andela Crnjac, Nabihah Tayob, Derin Keskin, Vicktor Adalsteinsson, Catherine Wu, Panagiotis Konstantinopoulos
Journal: Cancer Research (2024)

Abstract Background: Circulating tumor DNA (ctDNA) offers the potential to non-invasively track neoantigen dynamics and monitor tumor genomic features over narrow windows of time. Here, we aimed to test the ability of serial ctDNA samples to measure neoantigen evolution and immunologic response in patients with recurrent platinum sensitive ovarian cancer (OC) enrolled in a phase 1 trial of personalized neoantigen vaccines (NeoVax) and nivolumab following platinum-based chemotherapy (NCT04024878). Methods: Peripheral blood was prospectively collected from OC patients enrolled in the NeoVax with nivolumab clinical trial at various time points during treatment (yielding up to 80ml serum per sample). Whole genome sequencing (WGS) of tumor and paired normal tissue (60x coverage) was used for variant calling. Probes for up to 1000 prioritized SNVs were used for variant enrichment from serum cfDNA and analyzed by high throughput sequencing. Results: Transient decline or stabilization in CA125 was observed closely following vaccine boost in 4 of 7 patients treated on study, suggesting vaccine activity. A total of 20 plasma samples collected from the first 4 patients yielded detectable ctDNA with a median tumor fraction of 2.26% (range: 0.04%-16.39%). Baseline samples harbored a median tumor fraction of 0.20% (range: 0.04%-1.37%). ctDNA tumor fraction positively correlated with serum CA125 across all samples (n=15, r=0.661, p=0.007, r2=0.437) and mirrored CA125 stabilization post-vaccine boost. A median of 64.6% (range: 33.3%-73.3%) of SNVs included in each patient's vaccine was detected in baseline samples and a median of 85% (range: 44.4% to 87.5%) was detected at least once throughout treatment. Vaccine-targeted neoantigens were quantified in serial ctDNA samples for four patients with available ex vivo and in vitro T cell response data. In two patients with CA125 and ctDNA decline or stabilization, T cell responses to vaccine were detected (to 8 of 15 (pt 1), and 5 of 17 (pt 2), peptides). In two patients with no appreciable CA125 or ctDNA response, only 1 of 2 patients exhibited T cell responses (to 4 of 7 peptides (pt 3)). In patient 2, for whom a recurrence biopsy was available, vaccine-targeted mutations exhibited a 56% reduction vs. a 24% reduction in non-targeted mutations at recurrence, when compared with primary tumor. Further analyses of immune responses and initial and recurrence biopsies will be presented at the time of the meeting. Conclusions: Personalized targeted sequencing of cfDNA in OC patients detects ctDNA at robust tumor fractions that correlates with serum CA125 and allows quantification of specific neoantigen VAFs over time and treatment course. These analyses reveal preliminary correlations between neoantigen dynamics and neoantigen-specific T cell responses, suggesting that ctDNA may provide a sensitive measure of immune response to advanced immunotherapies in ovarian cancer patients. Funded by the Dana-Farber/Harvard Cancer Center Specialized Program of Research Excellence (SPORE) in Ovarian Cancer (NIH/NCI 2P50CA240243–01A1). Citation Format: MacLean C. Sellars, Rebecca Porter, Ruolin Liu, Alexis A. Howard, Kan Xiong, Andela Crnjac, Nabihah Tayob, Derin Keskin, Vicktor Adalsteinsson, Catherine Wu, Panagiotis Konstantinopoulos. Personalized targeted circulating tumor DNA (ctDNA) and T-cell responses after combined neoantigen vaccine and immune checkpoint blockade in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A083.