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1366 Anti-PD-1/IL-7v bispecific antibody promotes TCF1+ stem like T cells expansion and long-lasting in vivo efficacy
  1. Aurore Morello,
  2. Margaux Seite,
  3. Justine Durand,
  4. Isabelle Girault,
  5. Geraldine Teppaz,
  6. Virginie Thepenier,
  7. Vanessa Gauttier,
  8. Caroline Mary and
  9. Nicolas Poirier
  1. OSE Immunotherapeutics, Nantes, France


Background Immunocytokines can strengthen anti-PD-(L)1 therapy by promoting T-cell survival, but their shortened half-life and systemic toxicity limit their clinical development. We propose to selectively deliver IL-7 to PD-1+ T-cells using a bispecific anti-PD1/IL-7v mutein fused to reinvigorate PD1+IL-7R+ tumor-specific T cells and sustain long-term response. RNAseq and TILs scRNAseq analyses illustrate that IL-7R and IL-7R pathway gene expression is significantly correlated with better long-term OS and/or PFS across several cancers Higher IL-7R and IL-7R pathway expression by tumor-specific T-cell clonotype is significantly correlated with ICI response, higher stemness & proliferative signature,lower exhaustion and apoptosis markers, providing a strong rationale of co-targeting IL-7 to PD-1 to sustain durable tumor-specific T-cells response. Despite low IL-7R expression on Tumor-specific T-cell clonotype a high concentration of IL-7 can rescue them. We propose with the anti-PD-1/IL-7v to cis-target and provide a survival/proliferative specific signal.

Methods Proliferation, IL-7R signaling assays were tested to determine the mechanism. For the suppressive assay, CD4 Treg and autologous CD8 Teff were co-cultured. In vivo experiments were performed in hPD-1KI immunocompetent mice.

Results A high-affinity antagonist anti-PD-1 mAb was fused to a single IL-7 mutein (IL7v) having lower affinity to IL-7R complex allowing a preferential and optimal cis-potentiation of PD-1+ T-cells. Anti-PD1/IL7v restores proliferation and maintains long-term survival of chronically stimulated human T-cells in vitro (over 5 stimulation). scRNAseq and FACs analyses demonstrated that anti-PD1/IL7v triggers the expansion of TCF1+ stem-like memory T-cells (CCR7+PD1+KI67+), whereas IL-2 and IL-15 promote differentiation of T-cells into exhausted T-cells (TCF1-Tim3+Ki67+). Furthermore, anti-PD1/IL7v preferentially stimulated Teff over Treg as opposed to IL-2 & IL-15 and abrogated the Treg suppression by restoring IFN-γ secretion and proliferation of CD8 Teff.

In vivo, anti-PD1/IL-7v has impressive monotherapy efficacy in PD-1 sensitive model (orthotopic mesothelioma,>90%CR) and in a PD-1 resistant model (orthotopic HCC,>65% CR) in which anti-PD-1 or IL-7 has no effect. Further analyses in HCC model demonstrate that anti-PD1/IL7v enhanced quality and biodistribution of T-cells by promoting intratumoral TCF1+CD8+stem-like T-cells proliferation and favoring T-cell migration into the tumor nest whereas anti-PD-1 promotes T-cell exclusion. Combination with sorafenib chemotherapy in HCC model further enhances in vivo efficacy.

Conclusions Our data validate the rational of selective delivery of IL-7 to tumor-specific T-cells to sustain long-lasting response, proliferation, and survival of these key effectors upon ICI therapy. Anti-PD1/IL-7v preferentially cis-potentiates PD1+-tumor-specific-T-cells limiting the risk of I-O/I-O immunotoxicity and induces the expansion of stem-like T-cell capable to strengthen PD-1 therapy efficacy.

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