Abstract B074: Combination TIGIT and PD-1 inhibition with VEGFR-2 based therapy induces potent response in patient derived immune competent xenograft model with gastroesophageal adenocarcinoma

Abstract Background: Immune checkpoint inhibitors (ICI) have significantly improved survival outcomes in selected patients with advanced gastroesophageal adenocarcinoma (GEA). However, not all patients benefit, and for those tumors which initially respond, long term survival is rare. There are ongoing efforts to design rational immunotherapy combinations for these cancers. Targeting TIGIT is an area of interest for the treatment of GEA. Combining anti-angiogenic therapy with ICIs may normalize aberrant tumor vasculature and promote better tumor immune cell infiltration. This study evaluates the combination of anti-TIGIT tiragolumab (T), anti PD-1 nivolumab (N), anti-VEGFR2 DC101 (D), and paclitaxel (Pac) in a humanized mouse model with patient derived gastroesophageal junction adenocarcinomas. Methods: Humanized or Human Immune System BRGS (BALB/c, Rag2−/−, IL2RγC−/−, SIRPαNOD) mice were generated by engraftment with human CD34+ cells isolated form umbilical cord blood and subsequently injected with MSS gastroesophageal junction adenocarcinoma PDX (hPDX) in bilateral flanks. Drug treatment groups were as follows: Vehicle, D+Pac, N+D+Pac, and T+N+D+Pac. Treatments began when tumors reached 225-500mm 3 and tumors were measured twice weekly. At the end of study, sera, lymph nodes, spleen, and tumor tissue were collected for immunohistochemistry, single cell suspensions, and flow cytometry analysis. Results: Mice treated with Quadruplet (T+N+D+Pac) and triplet (N+D+Pac) had significant tumor growth inhibition compared to vehicle and doublet (D+Pac). Notably, there were 4/8 complete regressions in the quadruplet compared to triplet (2/7) and doublet (2/6) and vehicle (1/4). All groups experienced minimal toxicity with limited weight loss. Flow cytometric analysis demonstrated an increase in human TNFa and IFNg CD4 and CD8 T cells in tumors treated with quadruplet therapy. Conversely, there were fewer TIM-3 exhausted T cells and Tregs within the TILS as well as decreased human myeloid cells in tumors treated with quadruplet therapy. An increased MHC I expression on tumor cells was noted with the quad therapy. Across all groups, IFNg CD8 T cells and MHC Class I upregulation on the tumor correlated to slower tumor growth. CD25+FoxP3 CD8 regulatory T cells were strongly correlated to tumor growth. Conclusions: Quadruplet therapy with tiragolumab, nivolumab, DC101, and paclitaxel resulted in significant tumor growth inhibition with 4/8 complete responses in this immune competent humanized mouse PDX model. These pre-clinical results support further development of this combination in clinical trials. Citation Format: Sunnie S. Kim, Stacey M. Bagby, Zander Kostka-Newman, John Rhey Mhar Garcia, Emily Baiyee Toegel, S. Lindsey Davis, Alexis D. Leal, Robert W. Lentz, Christopher H. Lieu, Wells A. Messersmith, Martin D. McCarter, Adrian TA. Dominguez, Cameron Binns, Stephen G. Smoots, Marilyn M. Jackson, Benedetto Mungo, Megan Marsh, Julie Lang, Todd M. Pitts. Combination TIGIT and PD-1 inhibition with VEGFR-2 based therapy induces potent response in patient derived immune competent xenograft model with gastroesophageal adenocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B074.