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A growing arm of adoptive immunotherapy for cancer involves the isolation, expansion and reinfusion of autologous tumor infiltrating leukocytes or TILs. TILs are enriched for tumor-reactive cytotoxic cells that are rendered inactive or anergic by multiple immunosuppressive mechanisms operating in solid tumors. Their separation from the tumor microenvironment followed by ex vivo activation and expansion in the presence of T cell receptor stimulation and interleukin-2 (IL-2) has been described to reverse this dysfunction and control tumor growth in some patients. Unfortunately, a large number of patients achieve no response or clinical benefit suggesting that TIL immunotherapy could benefit from refinement and improvement. Part of the limitation involves the reliance on IL-2 to support T cell expansion both in vitro and in vivo as this cytokine can result in substantial expansion and activation of regulatory T cells (Tregs) that limit the efficacy of immunotherapy. We have recently described a novel re-targeted form of IL-2, which utilizes NKG2D rather than α chain of IL-2R to form the high affinity receptor complex for β and γ chain signal transduction. This redirected cytokine fusion protein consists of a cowpox virus encoded NKG2D ligand called orthopoxvirus major histocompatibility complex class I-like protein or OMCP along with non-IL-2R-α binding mutant form of IL-2 (OMCPmutIL-2). To evaluate the effect of NKG2D-redirected cytokine delivery on TIL expansion, we isolated TILs from progressively growing B16ova melanoma and expanded them with transient anti-CD3/CD28 stimulation in the presence of continuously replenished wild-type IL-2 or OMCPmutIL-2. Compared to wild-type IL-2 the use of OMCPmutIL-2 resulted in specific and preferential expansion of NK cells, CD8+ T cells as well as γδ T cells after 2 weeks of culture. Significantly higher expansion was observed in CD8+ T (p=0.037), antigen-specific CD8+ tetramer+ (p=0.0014), NK cells (p We conclude that the use of the NKG2D retargeted common γ-chain cytokine, called OMCPmutIL-2, facilitates expansion of multiple lineages of TIL-resident cytotoxic lymphocytes and improves adoptive transfer immunotherapy over wild-type IL-2. Our data thus suggests that retargeting stimulation away from the traditional IL-2R-α chain represents a rational approach to TIL immunotherapy. Citation Format: Anirban Banerjee, Yizhan Guo, Lea Paragas, Jacqueline Slobin, Bayan Mahgoub, Dongge Li, Sarah Hein, John Westwick, Eric Lazear, Alexander S. Krupnick. Targeted expansion of NKG2D-expressing tumor infiltrating leukocytes improves adoptive transfer immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 878.