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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