Abstract
Exogenous cytokines are widely applied to enhance the anti-tumor ability of immune cells. However, systematic comparative studies of their effects on chimeric antigen receptor (CAR)-engineered T (CART) cells are lacking. In this study, CART cells targeting folate receptor-alpha were generated and expanded ex vivo in the presence of different cytokines (IL-2, IL-7, IL-15, IL-18, and IL-21), and their expansion, phenotype and cytotoxic capacity were evaluated, in vitro and in vivo. Moreover, the effect of the administration of these cytokines along with CART cells in vivo was also studied. IL-2, IL-7, and IL-15 favored the ex vivo expansion of CART cells compared to other cytokines or no cytokine treatment. IL-7 induced the highest proportion of memory stem cell-like CART cells in the final product, and IL-21 supported the expansion of CART cells with a younger phenotype, while IL-2 induced more differentiated CART cells. IL-2 and IL-15-exposed CART cells secreted more proinflammatory cytokines and presented stronger tumor-lysis ability in vitro. However, when tested in vivo, CART cells exposed to IL-2 ex vivo showed the least anti-tumor effect. In contrast, the administration of IL-15 and IL-21 in combination with CART cells in vivo increased their tumor killing capacity. According to our results, IL-7 and IL-15 show promise to promote ex vivo expansion of CART cells, while IL-15 and IL-21 seem better suited for in vivo administration after CART cell infusion. Collectively, these results may have a profound impact on the efficacy of CART cells in both hematologic and solid cancers.
Highlights
Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CARs) is an attractive strategy for cancer treatment
In the presence of IL-2, IL-7, or IL-15, activated and transduced CAR-modified T (CART) cells expanded about 150 fold over the subsequent two weeks, while those grown with IL-18, IL-21 or in the absence of cytokines only expanded 30 to 50 fold (Figure 1C)
We found that IL-2 significantly enhanced the accumulation of CART cells and their cytotoxic capacity in vitro
Summary
Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CARs) is an attractive strategy for cancer treatment. Various strategies are being explored to further enhance the efficacy of CART cell therapy, including the incorporation of new signaling domains, co-expression of cytokine genes along with CARs, optimization of the conditions for CART cell expansion ex vivo and supplementation with exogenous cytokines [3, 4]. The paradoxical finding that T cells with a less differentiated phenotypic and functional profile have an increased propensity to persist after infusion, generate memory and mediate cancer regression, has fostered efforts to generate, induce or selectively enrich T cells with these attributes [5,6,7]. IL-2 has been the most widely studied as an immunotherapeutic agent for cancer and has shown to enhance the antitumor activity of CD19-specific CART cells in patients [9]. Administration of IL-18 is safe and well-tolerated, even at a dose as high as 1000μg/kg [15], making it a good candidate to boost the antitumor activity of CART cells
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