The Chimeric Co-Stimulatory Receptor Pd1-41bb Enhances The Function Of T Cell Receptor (Tcr)-Modified T Cells Targeting Solid Tumors

Introduction: The use of cellular immunotherapies has led to impressive complete and durable clinical responses in patients with certain types of hematological cancers. However, positive clinical results in solid tumor indications are still rare and many patients are in urgent need of alternative treatment options for several different indications. It has become clear that expression of inhibitory immune checkpoint molecules as well as harsh metabolic conditions in the tumor microenvironment (TME) are responsible for lack of activity of T cell immunotherapies in several settings, especially solid tumors. Here additional strategies are necessary to efficiently employ cellular immunotherapies. With the aim to further enhance the clinical efficacy of TCR-based immunotherapies under immunosuppressive conditions found in tumors, we analyzed the ability of PD1-41BB, a chimeric co-stimulatory receptor, to reverse the natural inhibitory PD-1/PD-L1 interaction into a supporting co-stimulatory signal in TCR-modified T cells encountering tumor cells. Methods: We evaluated the ability of the chimeric co-stimulatory receptor PD1-41BB to improve activity of TCR-modified T cells using 2-dimensional or 3-dimensional in vitro assays that model different immunosuppressive conditions found in tumors. Results: We demonstrate that chronic stimulation as well as several immunosuppressive factors of the TME, such as tumor cell expression of inhibitory immune checkpoint molecules or glucose restriction, impede the ability of TCR-transduced T cells to produce inflammatory cytokines and to efficiently lyse tumor cells. By using a chimeric co-stimulatory receptor consisting of the extracellular part of PD-1 and the co-stimulatory domain of 4-1BB we reversed the naturally occurring inhibitory PD-1/PD-L1 interaction to provide a co-stimulatory signal for improved T cell activity under immunosuppressive conditions or chronic stimulation. Addition of the chimeric co-stimulatory receptor PD1-41BB to TCR-modified T cells led to enhanced release of Interferon-γ, increased tumor cell killing, T cell proliferation and persistence in these T cell-tumor cell models. Conclusions: These preclinical studies support our approach to enhance the clinical efficacy of TCR-T therapies in PD-L1-positive malignancies by reversing naturally occurring inhibitory signals enabling counteraction of checkpoint-mediated dysfunction and metabolic insufficiency. The chimeric co-stimulatory PD1-41BB receptor has the potential to further enhance the clinical efficacy of TCR-modified T cells in patients with PD-L1-positive malignancies. Further preclinical in vitro and in vivo studies are ongoing to investigate the safety and efficacy of PD1-41BB in combination with multiple TCR candidates to explore its feasibility for the treatment of various cancers. Citation Format: Nadja Sailer, Melanie Salvermoser, Maria Gerget, Sarah Thome, Angelika J. Fischbeck, Svenja Ruehland, Luis F. Olguin-Contreras, Maja Buerdek, Christian Ellinger, Elfriede Noessner, Dolores J. Schendel, Patrik Kehler. The chimeric co-stimulatory receptor PD1-41BB enhances the function of T cell receptor (TCR)-modified T cells targeting solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3231.