Enhanced lymphodepletion is insufficient to replace exogenous IL-2 or IL-15 therapy in augmenting the efficacy of adoptively transferred effector CD8 ⁺ T cells

Abstract

Effector CD8 ⁺ T cells conditioned with IL-12 during activation mediate enhanced antitumor efficacy after adoptive transfer into lymphodepleted hosts; this is due in part to improved IL-7 responsiveness. Therefore, we hypothesized that increasing the intensity or type of lymphodepletion would deplete more IL-7-consuming host cells and improve the persistence and antitumor activity of IL-12-conditioned CD8 ⁺ T cells. Using cyclophosphamide (CTX), fludarabine (FLU), and total body irradiation (TBI, 6 Gy) either individually or in combination, we found that combined lymphodepletion best enhanced T cell engraftment in mice. This improvement was strongly related to the extent of leukopenia, as post-transfer levels of donor T cells inversely correlated to host cell counts after lymphodepletion. Despite the improvement in engraftment seen with combination lymphodepletion, dual-agent lymphodepletion did not augment the antitumor efficacy of donor T cells compared to TBI alone. Similarly, IL-7 supplementation after TBI and transfer of tumor-reactive T cells failed to improve persistence or anti-tumor immunity. However, IL-15 or IL-2 supplementation greatly augmented the persistence and antitumor efficacy of donor tumor-reactive T cells. Our results indicate that the amount of host IL-7 induced after single agent lymphodepletion is sufficient to potentiate the expansion and antitumor activity of donor T cells, and that the efficacy of future regimens may be improved by providing post-transfer support with IL-2 or IL-15.