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1370 Anti-PD-1/IL-7v immunocytokine favors proliferation & survival of TCF1+ stem like memory T cells and a durable in vivo efficacy in monotherapy or using combinatorial strategy
  1. Aurore Morello,
  2. Justine Durand,
  3. Margaux Seite,
  4. Isabelle Girault,
  5. Geraldine Teppaz,
  6. Virginie Thepenier,
  7. Cecile Batty,
  8. Ariane Desselle,
  9. Emmanuelle Wilhelm,
  10. Marine Malloci,
  11. Caroline Mary and
  12. Nicolas Poirier
  1. OSE Immunotherapeutics, Nantes, Loire-Atlantique, France
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


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 developed a bifunctional anti-PD-1/IL7v (BICKI®IL7v) to selectively Cis-deliver IL-7 to PD-1+tumor-specific T-cells. RNAseq and TILs scRNAseq analyses demonstrate that IL-7R and IL-7R pathway gene expression prior ICI treatment is significantly correlated with better OS and/or PFS across several cancers. IL-7R expression is correlated with higher stemness and lower apoptosis markers, providing a strong rationale of co-targeting IL-7 & PD-1 to sustain durable tumor-specific-T-cell response. The Anti-PD-1/IL-7v aims to cis-deliver IL-7 and sensitizes PD-1+tumor-specific T-cells to antagonizes PD-1 inhibitory signal and provide long-term survival and proliferative signals.

Methods Efficacy of anti-PD1/IL7v was evaluated in Ectopic tumor (MC38) or orthotopic HCC (Hepa1.6) in hPD1KI mice. Anti-PD1/IL7v effect was evaluated on chronically-stimulated human T-cells by scRNAseq and FACs.

Results Anti-PD-1/IL7v was designed using a high-affinity antagonist anti-PD-1, fused to a single point IL-7 mutein (IL7v) having lower affinity to IL-7R complex, to allow an optimal cis-potentiation of PD-1+T-cells and synergistic activation. Using an in vitro chronic stimulation model of human T cells, we demonstrated that anti-PD-1/IL7v promotes long-term reinvigoration proliferation/survival of stem-like-memory-TCF1+CD8+T-cells (>5 weeks), whereas IL-2/IL-15 promote short-term T-cell survival and differentiation into exhausted phenotype.

Anti-PD1/IL-7v showed significant anti-tumor efficacy in-vivo in responsive and refractory mouse models in monotherapy or combination (8 different orthotopic or ectopic models). In the orthotopic HCC model, anti-PD-1/IL7v induced >60% complete response while anti-PD-1 or IL-7 alone has no effect. Using FTY720 agent blocking ingress of new T-cells within TME, we demonstrated that anti-PD1/IL7v anti-tumor efficacy is mediated by amplification of TILs but also involves migration of fresh T-cells into TME. Further analyses demonstrated that anti-PD1/IL7v enhances quality and biodistribution of T-cells by promoting intratumoral TCF1+stem-like-CD8+T-cell proliferation and T-cell migration into the tumor nest whereas anti-PD-1 induced mostly T-cell exclusion. These data correlate with capacity of anti-PD1/IL7v to induce integrins and adhesion molecules surface expression. Finally, high synergistic efficacy in combination therapy with Sorafenib in HCC model (p=0.023), Oxaliplatin in MC38 model(85%CR) has been observed illustrating the potential of combining chemotherapy with ICI and anti-apoptotic cytokine therapy.

Conclusions Our data validate the rational of selective delivery of IL-7 to PD-1+tumor-specific-T-cells to limit risk of I-O/I-O immunotoxicity and sustain long-lasting proliferation and survival of stem-like CD8+T-cells to strengthen PD-(L)1 therapy. Synergistic anti-tumor efficacy with tyrosine-kinase-inhibitor or chemotherapeutics agents was demonstrated highlighting the potential clinical benefit of combination therapy with anti-PD-1/IL7v.

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