Abstract B053: SUMOylation and TIGIT inhibition: a novel immunotherapy combination for pancreatic cancer
Authors: de la Torre Medina Jorge R , Joshi Utsav , Narayanan Jaynath Shankara , Tiriac Herve , Chen Yuan , White Rebekah 
Published: September 2024

Abstract
Introduction: Immune checkpoint inhibitors have shown promise in many other solid tumors but have been disappointing in pancreatic ductal adenocarcinoma (PDAC). Preclinical work demonstrates that the immune checkpoint receptor TIGIT plays a key role in PDAC immune evasion and may be a better therapeutic target than the PD1 or CTLA4 axes. Post-translational small-ubiquitin-like modification (SUMOylation) regulates the activity of numerous proteins involved in cell proliferation. Our laboratory has shown that inhibition of SUMOylation with small molecule TAK-981 favorably modulates the PDAC immune microenvironment and specifically increases the expression of TIGIT binding partners CD226 on immune cells and CD155 on tumor cells. We hypothesized that inhibition of SUMOylation with small molecule TAK-981 would synergize with anti-TIGIT antibody therapy to induce anti-tumor immunity. Methods:All studies utilized a murine PDAC organoid line (KPC46) derived from a liver metastasis in a genetically engineered mouse model (KPC). KPC46 consistently metastasizes to the liver when implanted orthotopically into the tail of the pancreas in immunocompetent mice. Following tumor implantation, mice were surveilled by ultrasound until tumors reached 5-7 mm in diameter, then randomized to one of two treatment groups: TAK-981 + anti-TIGIT or vehicle control (n=10/group). Monotherapies were not included, as each drug alone did not produce significant responses in prior studies using this model. The treatment cohort received 15 mg/kg of TAK-981 and 100 micrograms of anti-TIGIT antibody via intraperitoneal injection every 48 hours starting 14 and 15 days, respectively, post-implantation, for a total of 4 weeks. Complete responders were defined as absence of disease after 2 months of observation. Complete responders and age-matched controls (n=3/group) were rechallenged with subcutaneous tumor injection and monitored for tumor development. Results:Survival of PDAC mice was significantly prolonged in the combination group when compared to the control group (median survival 81 vs 42 days, P&lt;0.05). A total of 4 mice (40%) were deemed complete responders after 2 months of monitoring. The re-challenge experiment produced tumors in all three control mice but none of the treated mice by 4 weeks after implantation. Conclusion:In this study, we explored the combination of two promising immunotherapy agents for PDAC which demonstrated significant additive effects generating durable and complete responses. We were able to confirm the presence of protective immunity. These results are rarely seen in PDAC experiments. Further experiments to better understand and optimize these effects are underway. These drugs are currently in clinical trials for solid tumors and could feasibly be studied in the near future in PDAC.
Citation Format: Jorge R de la Torre Medina, Utsav Joshi, Jaynath Shankara Narayanan, Herve Tiriac, Yuan Chen, Rebekah White. SUMOylation and TIGIT inhibition: a novel immunotherapy combination for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B053.