Abstract A047 Synergy between polarized dendritic cells, radiation and PD-1 blockade in effective treatment of rhabdomyosarcoma

Abstract Introduction: Clinical effectiveness of immune checkpoint inhibitor (ICI) therapy depends on tumor-infiltrating cytotoxic T lymphocytes (CTLs) resulting in the need for new tools to convert “cold” tumors which lack CTLs, into CTL-infiltrated “hot” tumors. Radiation therapy (RT) is known to modulate the solid tumor microenvironment (TME) and induce a systemic immune response via enhanced tumor antigen release, production of type I interferons (IFN), intratumoral attraction and activation of DCs, and enhanced tumor recognition by natural killer (NK) cells. Thus, local irradiation of a tumor can be advantageous for both the local treatment of a tumor as well as the prevention of distant metastases. Since previous studies have shown that RT can synergize with ICI and that IL-12 producing DCs administered intratumorally also impart a clinical advantage with ICI, we tested if ST-αDC1s, a DC type designed to produce high levels of IL-12 and CTL-attracting chemokines, can enhance the combination of RT plus anti-PD-1 therapy of mouse rhabdomyosarcoma. Methods: Mice (10-15 mice per group) were inoculated with syngeneic orthotopic (gastrocnemius) M3-9-M rhabdomyosarcoma. At day 13, when tumors reached ∼200 mm3, animals started RT with single fraction of 6 Gy (225 peak kVp) using the Precision X-Rad 320 irradiator. Four doses of anti-PD-1 treatment were given on days 13, 15, 18, and 20. ST-αDC1s were given intratumorally either early (Day 13) or late (Day 20). Surviving animals were challenged with 2.5x higher number of cancer cells on day 90-100 and followed for evidence of tumor recurrence. Results: Anti-PD1 treatment alone was not effective. Control groups receiving PBS injection or anti-PD-1 alone had no survivors at day 90, with most animals succumbing to tumors within 4 weeks. RT alone improved the outcomes, yielding 15% of day-90 survivors (2/13 animals). RT plus anti-PD-1 treatment increased the fraction of survivors to 54% (7/13 animals) , while RT plus anti-PD-1 and early ST-αDC1 treatment resulted in 70% of survivors (7/10 animals). Late ST-αDC1 treatment did not enhance the survival beyond the RT plus anti-PD1 combination. The correlative studies and rechallenge studies will be presented. Citation Format: Ajay Gupta, Eoghan Connors, Michael Moser, Bryan Gillard, Katie Kokolus, Per Basse, Pawel Kalinski. Synergy between polarized dendritic cells, radiation and PD-1 blockade in effective treatment of rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A047.