The efficacy of adoptive T cell transfer following expansion with different cytokine cocktails
Donahue, Michael J.
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Immunotherapy is a compelling modality to treat cancer offering systemic durable protection against tumor targets. Adoptive T cell therapy (ACT) has emerged as a promising treatment in advanced cancer patients. ACT is a personalized cancer treatment where T cells are removed from the suppressive tumor microenvironment and expanded ex vivo and then reinfused into the patient. Although ACT has shown strong efficacy in many patients the overall response rate is still limited. Thus there is a need to create stronger and more effective T cells. These studies focus on what immune contexture yields the most effective T cell populations. A critical determinant in T cell activation is what cytokines act on the T cell during activation, directing the activation response and proliferative capacity. Traditionally T cells in the clinic are expanded using interleukin-2 (IL-2), however additional cytokines have been suggested to support T cell growth and development. Therefore, we compared 4 different cytokine cocktails: IL-2 alone, IL-2, 12, 18; IL-2, 7, 15; and IL- 2, 12, 21. The effectiveness of each cocktail was examined for three endpoints; total T cell expansion, the phenotype of the activated cells and the ability of the T cells to delay tumor growth. Tumor growth studies were performed using the B16-OVA/OT-I tumor model system. IL-7, 15 had the highest proliferative rate while the other cytokine cocktail proliferative rates were similar. Following expansion, the phenotype of the expanded T cells was examined ex vivo using flow cytometry. While all groups predominately induced the development of effector phenotype T cells the cocktail IL-7, 15 favored the T cells naïve state, while IL-12, 21 and IL-12, 18 favored central memory and effector T cell types. All treatment groups showed significant tumor growth delay over untreated mice with preliminary survival data suggesting that the combination of IL-12, 21 was the most effective, with 40% survival. This could suggest that the more central memory type is more effective at mediating tumor cell killing. These studies will provide important information to develop more robust ACT treatment protocols in the clinical treatment of advanced disease.