Abstract 2955: Anti-PD-1/IL-7v bispecific antibody promotes TCF1+ stem like CD8 T cells expansion and long-lasting in vivo efficacy
Authors: Morello Aurore , Seite Margaux , Durand Justine , Girault Isabelle , Mary Caroline , Thepenier Virginie , Teppaz Geraldine , Wilhem Emmanuelle , Desselle Ariane , Poirier Nicolas 
Published: April 2023

Immunocytokines can strengthen anti PD(L)1 therapy by promoting T-cell survival, but their shortened half-life and systemic toxicity limit clinical development. We propose to selectively deliver IL7 to PD1+ T cells using a bispecific anti PD1/IL7 mutein (BICKI®IL7v) to reinvigorate PD1+IL7R+ tumor specific T cells. RNAseq and TILs scRNAseq analyses (n=1036 patients) demonstrated that IL7R and IL7R pathway gene expression prior ICI treatment is significantly correlated with better long term OS and/or PFS across several cancers. Importantly, IL7R expression is correlated with higher stemness and lower apoptosis markers, providing a strong rationale of cotargeting IL7 & PD1 to sustain the durable tumor-specific T cell response. Despite low IL7R expression on tumor T cell clonotype, a high concentration of IL7 can rescue them. The anti PD1/IL7v aims to cis-deliver IL7 and sensitize PD-1+ tumor-specific T cells to provide a long-term survival & proliferative specific signal while simultaneously antagonizing PD1 inhibitory signal. The Anti PD1/IL7v is constructed with a high affinity antagonist anti PD1 fused to a single IL7 mutein (IL7v) having lower affinity to IL7R complex to allow an optimal cis-potentiation and synergistic activation of PD1 expressing T cells. Using an in vitro chronic stimulation model (5 STIM) a,d scR, we demonstrated that anti PD1/IL7v promotes long-term reinvigoration proliferation/survival of stem-like memory TCF1+CD8+ T cells (&gt;5 weeks) whereas IL2 and IL15 promote short term survival. scRNAseq and phenotypic analyses confirmed that chronically stimulated Anti PD1/IL7v treated T cells significantly expressed the hallmark of stemness genes while IL2 and IL15 treatments induced T cell differentiation into exhausted phenotype. Interestingly, higher tumor and lymph node retention markers were significantly induced on chronically stimulated T cells after anti PD1/IL7v treatment. T cell engraftment into immunodeficient mice, confirmed the stem-like property of IL7 treated T cells capable of self-autorenewal compared to IL2 treated exhausted T cells that no longer proliferate and engraft in vivo. In an orthotopic HCC mouse model, we confirmed that anti PD1/IL7v promotes intratumoral proliferation of TCF1+ stem-like CD8+T cell and migration into the tumor nest, associated with significant anti-tumor efficacy (&gt; 55% CR). In contrast, anti PD1 or IL7 treatment had no efficacy and induced T-cell exclusion. Anti PD1/IL7v also showed significant anti-tumor efficacy in second-line treatment post-anti-PD-(L)1 treatment in the MC38 mouse model, highlighting the clinical potential of anti PD1/IL7v in ICI resistant patients. Our data validate the rationale of selective delivery of IL7 to PD1 tumor-specific T cells to limit the risk of I-O/I-O immunotoxicity and sustain a long lasting proliferation and survival of stem-like CD8 T cells to strengthen PD(L)1 therapy.

Citation Format: Aurore Morello, Margaux Seite, Justine Durand, Isabelle Girault, Caroline Mary, Virginie Thepenier, Geraldine Teppaz, Emmanuelle Wilhem, Ariane Desselle, Nicolas Poirier. Anti-PD-1/IL-7v bispecific antibody promotes TCF1+ stem like CD8 T cells expansion and long-lasting in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2955.