Enhanced Lymphodepletion Is Insufficient to Replace Exogenous IL2 or IL15 Therapy in Augmenting the Efficacy of Adoptively Transferred Effector CD8+ T Cells

Abstract

Effector CD8 T cells conditioned with IL12 during activation mediate enhanced antitumor efficacy after adoptive transfer into lymphodepleted hosts; this is due in part to improved IL7 responsiveness. Therefore, we hypothesized that increasing the intensity or type of lymphodepletion would deplete more IL7-consuming host cells and improve the persistence and antitumor activity of IL12-conditioned CD8 T cells. Using cyclophosphamide, fludarabine, 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 posttransfer 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 with TBI alone. Similarly, IL7 supplementation after TBI and transfer of tumor-reactive T cells failed to improve persistence or antitumor immunity. However, IL15 or IL2 supplementation greatly augmented the persistence and antitumor efficacy of donor tumor-reactive T cells. Our results indicate that the amount of host IL7 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 posttransfer support with IL2 or IL15. The relationship between lymphodepletion and cytokine support plays a critical role in determining donor T-cell engraftment and antitumor efficacy. .

Lymphodepletion – an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle

“…Furthermore, not only individual therapy options are considered, Flu/Cy pre-treatments in pre-clinical models are also combined compared to the clinical regimens [16]. While a single-dose cyclophosphamide as well as Flu/Cy regimens induce strong leukopenia in mice, a single-dose fludarabine alone does not affect the leukocyte compartment (129).…”

Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells

“…Aligned with this pre-clinical approach, a series of clinical trials at the NCI were conducted using TIL in patients and giving them various regimens of total body irradiation [9]. Yet, most individuals given ACT are preconditioned with nonmyeloablative chemotherapies, including cyclophosphamide (CTX) and/or fludarabine (FLU), as TBI at a dose of 1200 cGy in humans has been associated with toxicities including more profound neutropenia and thrombotic microangiopathy [17, 32]. In mice, it was reported that escalating the intensity of lymphodepletion by increasing doses of fractionated TBI stepwise elevated features of toxicity in animals, based on heightened cytokine storm signatures and translocation of gut microbes [33].…”

“…Previous research has shown that lymphodepletion via TBI or cyclophosphamide is an effective regimen to enhance the anti-tumor activity of transferred anti-melanoma CD8 + T cells [17]. Lymphodepletion transiently ablates immunosuppressive host cells, such as regulatory T cells and myeloid derived suppressor cells, which actively blunt CD8 + T cell functionality [18][19][20].…”

“…Non-myeloablative total body irradiation (TBI) is a common method to mediate host lymphodepletion in mice prior to ACT therapy [17,[27][28][29][30][31]. Aligned with this preclinical approach, a series of clinical trials at the NCI were conducted using TIL in patients and giving them various regimens of total body irradiation [9].…”

Late Events After CD-19 CAR-T Treatment

“…Therefore, it is best to consider the adverse events associated with the preparative chemotherapy regimen separately from the CD19 CAR T cell adverse events. There are reports in animal models Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org of strategies to maintain T cell persistence following adoptive transfer without the need for lymphodepletion [6,7]. Such strategies, if proven to not reduce the efficacy of the CD19 CAR T cells, would reduce any long-term non-B cell cytopenias, potential for secondary bone marrow-related malignancies, and the overall cost of the CD19 CAR T therapy.…”