Axis (3) Anti-tumor Immunotherapy
Coordinated by N. Labarrière et F. Lang

This axis aims at developing innovative immunotherapeutic strategies, for therapeutic vaccination of adoptive T cell transfer in cancer patients, and also to identify an early immune marker associated with clinical responses to ICB (Immune-check-point blockade) treatments. Concerning our first objective, we are currently working on a research project to improve therapeutic vaccination of melanoma patients based on synthetic long peptides, starting notably from MELOE-1 as a model antigen. In the field of adoptive T cell transfer, our team has a privileged collaboration with the Team of Pr Dreno (Team 2, CRCINA), making easier to set up clinical trials in melanoma patients. As an example, a phase I/II clinical trial of adoptive transfer of Melan-A and MELOE-1 specific CD8 T lymphocytes, originating from our results (Labarriere et al., 2013) and unique in Europe, is currently ongoing at the Nantes University hospital. Another objective of this axis concerns the optimization of the functional properties of specific T cells used for adoptive cell transfer. With this in mind, we are currently developing a research program that aims to inactivate PD-1 and TIGIT genes in effector melanoma-specific T lymphocytes. This program is supported by the « Ligue contre le Cancer » and the BMS foundation.

In this work package, our second objective is to define an early immune marker associated with clinical responses to ICB treatments. Indeed, the definition of an early marker correlated with the efficacy of anti-PD-1 therapy is a crucial issue for anti-tumor immunotherapy. It is now accepted that anti-PD-1 immunotherapies modify the pre-existing anti-tumor T repertoire. We previously documented that, within an antigen- specific peripheral CD8+ T cell repertoire, the emergence of T cells with high functional avidity, identifiable by the co-expression of PD-1 and TIGIT molecules, was associated with clinical responses in melanoma patients under anti-PD-1 therapy (Simon et al., Cancer Res 2017, and Figure 2).
Based on these results, we hypothesized that tumor-specific T lymphocytes amplified upon PD-1 blockade could recirculate and be identified in the periphery within this PD-1+/TIGIT+ fraction. Our project thus aims to characterize circulating T lymphocytes subpopulations (before and after treatment), co-expressing these two markers, in terms of frequency, T cell repertoire, phenotype and functions, in order to evaluate their relevance as an early marker of therapeutic response.

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Analysis of the Vß repertoire of Melan-A specific T cells before and after anti-PD-1 therapy (n=9). Melan-A repertoire diversity before PD-1 treatment (T0) and after 4 cures (M2) was assessed on sorted Melan-A specific T cells using a panel of 24 anti-Vß antibodies. Empty stacks represent the fraction of Vß subfamilies not amplified upon PD-1 therapy, grey stacks illustrate pre-existing Vß subfamilies amplified after therapy, and red stacks represent Vß subtypes only detected after treatment. CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease.