452 Combination treatment using KISIMATM protein-based cancer vaccine and systemic STING agonist results in profound modulation of tumor microenvironment and improved tumor control. (9th November 2020)

• Record Type: Journal Article
• Authors: Rossi, Matteo; Belnoue, Elodie; Carboni, Susanna; Berardino, Wilma Besson-Di; Riva, Erika; Santiago-Raber, Marie-Laure; Derouazi, Madiha
• Is Part Of: Journal for immunotherapy of cancer. Volume 8(2020)Supplement 3
• Page Start: A479
• Page End: A479
• Publication Date: 2020-11-09
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-SITC2020.0452
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: KISIMA TM platform allows the development of protein-based cancer vaccines able to induce a potent, tumor-specific CD8 and CD4 T cells response. While the cell penetrating peptide and the Anaxa portions confer, respectively, the cell delivery and self-adjuvanticity properties, the multiantigenic domain allows the targeting of different cancer antigens, resulting in anti-tumoral efficacy in different murine models. 1 The first clinical candidate developed from KISIMA TM is currently tested, together with anti-PD-1 blockade, in a phase I study in metastatic colorectal cancer patients. Stimulator of interferon genes agonists (STINGa) were shown to induce a potent type I interferon response in preclinical studies. The intratumoral administration of STINGa, to promote tumor inflammation, was shown to result in a protective spontaneous immune response in several murine tumor models. However, the encouraging preclinical results are not supported by recent clinical data, challenging the efficacy of unspecific monotherapy.As it is more and more clear that an effective cancer immunotherapy will require the combination of different treatment strategies, we investigate here the efficacy of combining KISIMA TM cancer vaccine with STINGa treatment. Methods: Mice were vaccinated with subcutaneous (s.c.) injection of KISIMA TM vaccine combined with s.c. administration of STINGa. Safety and immunogenicity were assessed by measuring temperature, serum cytokines and the peripheral antigen-specific response. Anti-tumoral efficacy as well as in depth monitoring of TILs and tumor microenvironment modulation were assessed following therapeutic vaccination in a HPV16 E6 and E7 expressing TC-1 cold tumor model. Results: Combination treatment was well tolerated and promoted the development of circulating antigen-specific CD8 T cells. In TC-1 tumor bearing mice, KISIMA TM therapeutic vaccination resulted in the infiltration of both antigen-specific CD8 and CD4 T cells within the tumor, as well as a switch of tumor associated macrophages polarization toward the more inflammatory type 1. Combination therapy further increased the tumor microenvironment modulation induced by KISIMA TM vaccine, promoting the polarization of inflammatory Thelper 1 CD4 T cells and increasing the effector function of antigen-specific CD8 T cells. The profound modulation of the tumor microenvironment induced by combination therapy enhanced the beneficial effect of KISIMA TM vaccination, resulting in a prolonged tumor control. Conclusions: Combination of KISIMA TM cancer vaccine with systemic STINGa treatment induces the development of a potent, tumor-specific immune response resulting in a profound modulation of the TME. As check-point inhibitor (CPI) therapy is ineffective on poorly infiltrated tumors, combination with therapies able to highly enhance tumor infiltration by T cells could expand CPI indications. Ethics Approval: The study was approved by the Canton of Geneva Ethic Board, under the license number GE165/19 Reference: Belnoue E, et al. Targeting self and neo-epitopes with a modular self-adjuvanting cancer vaccine. JCI Insight 2019. 4:11.