Abstract A009: Synergistically overcoming KRAS-driven radioresistance and immune evasion in PDAC with alpha particle radiotherapy and anti-CTLA-4

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer mortality in the United States, with over 90% of cases presenting mutant KRAS (mt KRAS). Increased radioresistance and upregulated Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) expression are among the hallmarks induced by mt KRAS. While dose escalation may increase overall survival, the low radiation tolerability of surrounding organs remains the main challenge when treating PDAC patients with high doses of radiation. Additionally, although CTLA-4 upregulation appears to be a promising therapeutic target, PDAC's complex immunosuppressive tumor microenvironment renders it poorly responsive to immune checkpoint blockade. In this study we propose to sensitize a mt KRAS murine PDAC model (KPC cell line) to CTLA-4 inhibition (aCTLA-4) and overcome its intrinsic radioresistance by using Diffusing Alpha-emitters Radiation Therapy (Alpha DaRT), an intratumoral source of highly ionizing alpha particles with over 1, 000 times more ionizing power than photons, to deliver localized doses of alpha particles to the tumor while sparing surrounding healthy tissue. To access local tumor response, mice were challenged with 5×105 cells subcutaneously in the left leg and after 7 days (day 0) one DaRT source (inert or active) was implanted. aCTLA-4 or IgG was injected intraperitoneally every 3 days starting on day 3 (4 doses). Animals with complete tumor regression (100 days tumor free) were re-challenged on day 130. To access systemic immunity response, mice were challenged with 5×105 cells in the left leg and 1×105 in the right leg and one DaRT source was implanted in the left leg tumor 10 days after tumor challenging (day 0). The same schedule for aCTLA-4 was followed, but 6 doses were administered. The combined therapy (Alpha DaRT+aCTLA-4) induced significantly (p0. 05) higher tumor growth delay compared to control and monotherapies from day 25 on. By day 39, all mice in the control and monotherapies groups had reached euthanasia criteria, whereas 70% of the combined therapy group were still alive. 40% of combined treatment group mice reached complete tumor regression by day 30 and upon rechallenge on day 130, no tumors regrew for any mouse. A significant (p0. 0001) synergistic effect was observed between Alpha DaRT and aCTLA-4. For systemic immunity, the combined therapy also induced greater tumor growth delay in the primary irradiated tumor as well for the secondary unirradiated tumor compared to control and monotherapies. In conclusion, Alpha DaRT combined with aCTLA-4 synergistically induces durable local control and systemic antitumor immunity in a mt KRAS PDAC model, highlighting a promising strategy to overcome KRAS-driven radioresistance and immune evasion. Citation Format: Marco Reis, Poliana Marinello, Alexandre Rubinstein, Walison Brito, Vered Bachar, Ronen Segal, Gabriel Sawakuchi. Synergistically overcoming KRAS-driven radioresistance and immune evasion in PDAC with alpha particle radiotherapy and anti-CTLA-4 abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr A009.