Abstract 2241: Immune-modulatory therapeutic cancer vaccines against IDO1 and PD-L1 control tumor growth through target specific changes in the tumor microenvironment

Abstract Despite the established clinical efficacy of checkpoint inhibitors such as blocking antibodies against Programmed Death protein (PD)-1 and Programmed Death Ligand (PD-L)1, drug resistance remains a significant obstacle in various cancer types. Indoleamine 2, 3-dioxygenase 1 (IDO1) and PD-L1 are critical immunosuppressive drivers in the tumor microenvironment (TME) that favor cancer progression. The development of immune-modulatory vaccines against IDO1+ and PD-L1+ immune suppressive and/or tumor cells in the TME (IO102-IO103) has revealed promising clinical results1 and is now being investigated in a Phase 3 clinical trial in advanced melanoma. Using preclinical models, the present study aims to further characterize the mode of action of these vaccines and compare it with conventional checkpoint inhibitors. Anti-tumor efficacy of the vaccines was evaluated by monitoring tumor growth in syngeneic murine models after treatment with IDO1 or PD-L1 peptides in Montanide adjuvant. Tumor tissues, spleens and lymph nodes were collected and processed for flow cytometry or functional readouts. T cell activity was assessed using IFNγ Elispot assay. Gene expression analysis was performed using the Nanostring nCounter PanCancer IO360 Panel on bulk tumors from animals treated with IDO1 or PD-L1 vaccines; or anti-PD1/PD-L1. Vaccination against IDO1 and PD-L1 induced specific T-cell expansion in splenocytes, associated with reduced tumor growth. In particular, PD-L1 specific T cells were also detected in lymph nodes and tumor infiltrating lymphocytes from MC38 tumor-bearing animals. Target specific activation of T cells was confirmed ex vivo upon restimulation of cells by the detection of IFNγ and TNFα within CD8+ cells. Gene expression analysis of tumors revealed distinct immune signatures for each treatment group, either supporting cytotoxic T-cell activity (PD-L1 vaccine) or reducing the immune suppression within the TME (IDO1 vaccine). Comparison with samples from animals treated with anti-PD-1 or anti-PD-L1 showed non-overlapping gene expression changes induced by PD-L1 vaccine. Our results from murine models show that IDO1 and PD-L1 peptide vaccines each contribute to tumor growth control through the activation of target specific T cells and their recruitment at tumor site. Gene expression analysis suggests that this is achieved through changes in the expression of immune-suppressive markers and enhanced T cell activation and cytotoxic activity. The gene expression changes observed were different from the signatures of anti-PD-L1 and anti-PD1, suggesting a complementary mode of action to those therapeutics. Altogether, our data support the clinical potential of IDO1 and PD-L1 immune-modulatory vaccines to improve existing therapeutics in cancer. 1.Kjeldsen et al. Nat Med 2021 DOI:10.1038/s41591-021-01544-x Citation Format: Marion Chapellier, Anne Madsen, Rasmus Agerholm-Nielsen, Lea Svendsen, Inés Lecoq, Evelina Martinenaite, Shih-Chun Shen, Erika Sutanto-Ward, James DuHadaway, Souvik Dey, Dema Ghaban, Mads Hald Andersen, Alexander J. Muller, Ayako Wakatsuki Pedersen. Immune-modulatory therapeutic cancer vaccines against IDO1 and PD-L1 control tumor growth through target specific changes in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2241.