T cells secreting nanobody-based immune checkpoint inhibitors

Background: Cancer therapy is experiencing a paradigm shift due to the clinical success of immune checkpoint inhibitors (ICI), notably anti-PD-L1 antibodies, yet efficacy remains limited to a few tumor types and a minority of patients. One of the main determinants of clinical response to ICI is the tumor infiltration by anti-tumoral lymphocytes. The main side effects are autoimmune toxicities related to CD8 T cell activation upon ICI treatment. These side effects become almost prohibitive when using ICI combination. Adoptive cell transfer (ACT) of in vitro expanded tumor infiltrating lymphocytes (TILs) is another modality of immunotherapy that has proven clinical benefit in patients with a good safety profile. Aim : We propose to perfom ACT with TILs expanded in vitro and transduced for the secretion of an anti-PD-L1 nanobody in order to obtain a high tumor infiltration by lymphocytes and to reduce the systemic exposure to ICI. Nanobodies offer the advantage of a good penetration ability at the tumor site while displaying a very short half-life in the blood stream due to renal filtration. Results : We successfully established a model of adoptive transfer of TILs in Balb/c mice bearing CT26 tumors. Using viral transduction we managed to obtain lymphocytes secreting anti-PD-L1 nanobodies that bind to PD-L1 and block the PD-1/PD-L1 interaction. We are ready to perfom in vitro and in vivo evaluation of nanobody-secreting lymphocytes in different mouse models