Unveiling Temporal Dynamics of IL-2-Driven PD-1+CD8+ T Cell Responses in Tumor Immunity

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Sarah Amar1¥, Yulia Liubomirski2¥, Galia Tiram2, Koren Salomon2, Eilam Yeini2, Michael Monsonego1, Tomer Weiss1, Anshika Katyal2, Opal Avramoff2, Anne Krinsky2, Keren Reshef1, Shai Dulberg1, Ayelet Kaminitz1, Dana Bar On3, Inbal Ben Eliezer3, Ortal Iancu3, Safra Rudnick-Glick3, Trang Vuong3, Kim Yap3, Tetsuya Taura3, David Wilson3, Paul Ayton*3, Ronit Satchi-Fainaro*2,4, Asaf Madi*1

 

1 Department of Pathology, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.

2 Department of Physiology and Pharmacology, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.

3 Teva Pharmaceutical Industries Ltd., Tel Aviv 6944020, Israel

4 Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel.

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PD-1+CD8+ tumor-infiltrating T cells are essential players in cancer immunotherapy, serving as key mediators of anti-tumor immune responses. Interleukin-2 (IL-2) is a critical cytokine that supports T-cell growth and function, but its therapeutic application is limited due to severe systemic toxicities at high doses and preferential activation of regulatory T cells (Tregs) at low doses. To address these limitations, we engineered αPD1-attIL2, a novel therapeutic combining a modified IL-2 with reduced receptor potency and a non-blocking anti-PD-1 antibody. This fusion molecule selectively activates PD-1+ T cells within the tumor microenvironment, demonstrating robust anti-tumor activity without inducing toxicity.

 

In a colorectal cancer model, αPD1-attIL2 achieved complete tumor regression and enhanced efficacy in additional tumor models. Early after treatment, CD8+ T cells, rather than Tregs, exhibited increased proliferation and activation, along with reduced expression of exhaustion markers. Over the course of treatment, αPD1-attIL2 induced macrophage M1 polarization, sustained effector T-cell responses, and promoted the formation of memory T cells, indicating a durable anti-tumor immune response. In comparison, monotherapy with an anti-PD-1 blockade elicited distinct cellular effects but showed less pronounced anti-tumor activity. Notably, combining αPD1-attIL2 with anti-PD-1 blockade further improved therapeutic efficacy, underscoring the additive effect of these approaches.

 

These findings highlight the promise of targeting PD-1+CD8+ T cells with IL-2-based immunotherapy. By overcoming the challenges of traditional IL-2 treatment, αPD1-attIL2 represents a powerful strategy to enhance tumor immunity and improve outcomes across multiple cancers.