Browsing by Author "Apetoh, Lionel"

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    Efficacy of novel allogeneic cancer cells vaccine to treat colorectal cancer
    (Frontiers Media, 2024-07-24) Alzeeb, George; Tortorelli, Corinne; Taleb, Jaqueline; De Luca, Fanny; Berge, Benoit; Bardet, Chloé; Limagne, Emeric; Brun, Marion; Chalus, Lionel; Pinteur, Benoit; Bravetti, Paul; Gongora, Céline; Apetoh, Lionel; Ghiringhelli, Francois; Medicine, School of Medicine
    Colorectal cancer (CRC) remains a significant global health burden, emphasizing the need for innovative treatment strategies. 95% of the CRC population are microsatellite stable (MSS), insensitive to classical immunotherapies such as anti-PD-1; on the other hand, responders can become resistant and relapse. Recently, the use of cancer vaccines enhanced the immune response against tumor cells. In this context, we developed a therapeutic vaccine based on Stimulated Tumor Cells (STC) platform technology. This vaccine is composed of selected tumor cell lines stressed and haptenated in vitro to generate a factory of immunogenic cancer-related antigens validated by a proteomic cross analysis with patient's biopsies. This technology allows a multi-specific education of the immune system to target tumor cells harboring resistant clones. Here, we report safety and antitumor efficacy of the murine version of the STC vaccine on CT26 BALB/c CRC syngeneic murine models. We showed that one cell line (1CL)-based STC vaccine suppressed tumor growth and extended survival. In addition, three cell lines (3CL)-based STC vaccine significantly improves these parameters by presenting additional tumor-related antigens inducing a multi-specific anti-tumor immune response. Furthermore, proteomic analyses validated that the 3CL-based STC vaccine represents a wider quality range of tumor-related proteins than the 1CL-based STC vaccine covering key categories of tumor antigens related to tumor plasticity and treatment resistance. We also evaluated the efficacy of STC vaccine in an MC38 anti-PD-1 resistant syngeneic murine model. Vaccination with the 3CL-based STC vaccine significantly improved survival and showed a confirmed complete response with an antitumor activity carried by the increase of CD8+ lymphocyte T cells and M1 macrophage infiltration. These results demonstrate the potential of this technology to produce human vaccines for the treatment of patients with CRC.
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    STING-driven activation of T cells: relevance for the adoptive cell therapy of cancer
    (Shared Science Publishers, 2023-11-14) Richter, Fabian; Paget, Christophe; Apetoh, Lionel; Microbiology and Immunology, School of Medicine
    Adoptive cell therapy (ACT) can successfully treat hematopoietic cancers but lacks efficacy against solid tumors. This is due to insufficient T cell infiltration, high tumor heterogeneity, frequent antigen loss with subsequent tumor escape, and the immunosuppressive tumor microenvironment (TME). Alternative methods to boost the anticancer efficacy of adoptively transferred cells are actively pursued. Among adjuvants that are utilized to stimulate anticancer immune responses, ligands of the stimulator of interferon genes (STING) pathway have received increasing attention. STING activation can trigger dendritic cell (DC) activation and endogenous immune responses, thereby preventing tumor escape. Activation of the STING pathway in the context of ACT was accordingly associated with improved T cell trafficking and persistence in the TME combined with the reduced presence of immunosuppressive cells. Recent findings also suggest cell-intrinsic effects of STING ligands on T cells. Activation of the STING signaling pathway was in this regard shown to enhance effector functions of CD4+ and CD8+ T cells, suggesting that the STING signaling could be exploited to harness T cell anticancer functions. In this review, we will discuss how the STING signaling can be used to enhance the anticancer efficacy of ACT.
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    The Emerging Role of IL-9 in the Anticancer Effects of Anti-PD-1 Therapy
    (MDPI, 2023-04-12) Vinokurova, Daria; Apetoh, Lionel; Microbiology and Immunology, School of Medicine
    PD-1 blockade rescues failing anticancer immune responses, resulting in durable remissions in some cancer patients. Cytokines such as IFNγ and IL-2 contribute to the anti-tumor effect of PD-1 blockade. IL-9 was identified over the last decade as a cytokine demonstrating a potent ability to harness the anticancer functions of innate and adaptive immune cells in mice. Recent translational investigations suggest that the anticancer activity of IL-9 also extends to some human cancers. Increased T cell-derived IL-9 was proposed to predict the response to anti-PD-1 therapy. Preclinical investigations accordingly revealed that IL-9 could synergize with anti-PD-1 therapy in eliciting anticancer responses. Here, we review the findings suggesting an important contribution of IL-9 in the efficacy of anti-PD-1 therapy and discuss their clinical relevance. We will also discuss the role of host factors like the microbiota and TGFβ in the tumor microenvironment (TME) in the regulation of IL-9 secretion and anti-PD-1 treatment efficacy.