Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy

Abstract

Background Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy against both B-cell malignancies and some types of solid tumors. Interleukin (IL) -15 is an important immune stimulator that may provide ideal long-term persistent CAR-T cells. However, higher base line or peak serum IL-15 levels are also related to severe toxicity, such as cytokine release syndrome (CRS), graft-versus-host disease (GVHD), and neurotoxicity. Methods We successfully constructed CD19 specific armored CAR-T cells overexpressing IL-I5 and IL-15 receptor alpha (IL-15Ra). In vitro cell differentiation and viability were monitored by flow cytometry, and an in vivo xenograft mouse models was used to evaluate the anti-tumor efficiency and liver damage of CAR-T cells. Results CAR-T cells overexpressing IL-15 alone demonstrated enhanced viability, retarded exhaustion in vitro and superior tumor-inhibitory effects in vivo. However, these tumor-free mice had lower survival rates, with serious liver injuries, as a possible result of toxicity. As expected, CAR-T cells overexpressing IL-15 combined with IL-15Ra had reduced CD132 expression and released fewer cytokines (IFNγ, IL-2 and IL-15) in vitro, as well as had the tendency to improve mouse survival via repressing the growth of tumor cells and keeping livers healthier compared to CAR-IL-15 T cells. Conclusions These results indicated the importance of IL-15 in enhancing T cells persistence and IL-15Ra in reducing the adverse effects of IL-15, with superior tumor retardation during CAR-T therapy. This study paves the way for the rapid exploitation of IL-15 in adoptive cell therapy in the future.

Combined therapy of CAR-IL-15/IL-15Rα-T cells and GLIPR1 knockdown in cancer cells enhanced anti-tumor effect against gastric cancer

“…It enhances the proliferation of human NK, CD4 + and CD8 + T cells in humanized mice [ 28 , 29 ], and exhibits potent immunostimulatory effects on NK, NKT and CD8 + T cells [ 30 , 31 ]. It is demonstrated that CAR-T cells secreting IL-15/IL-15Ra complex display comparable efficacy as secreting IL-15 alone with reduced adverse effects in hematological cancer [ 32 ]. In this study, we constructed the IL-15Rα into the extracellular region of CAR structure, which enhanced the anti-tumor effects of CAR-T cells against gastric cancer compared with conventional CAR-T.…”

New insights into the stemness of adoptively transferred T cells by γc family cytokines

“…To further prolong the persistence of infused T cells, stable IL-15/IL-15Rα complexes were incorporated to induce and sustain the expansion of the CD62L + and CCR7 + central memory T cell (Tcm) phenotype ex vivo resulting in augmented efficacy of adoptive immunotherapy [ 114 ]. As a result, efforts have been made to optimize the IL-15/IL-15Rα structure to achieve a higher proportion of infused T cells with stemness and greater antitumor potency in ACT [ 115 ]. In addition to its incorporation in ex vivo precultures, IL-15 and its receptor complex have been integrated into CAR engineering to maintain T SCM expansion in vivo for durable responses [ 116 – 122 ].…”

Emerging Immunotherapy Approaches for Treating Prostate Cancer

“…Other strategies to improve the efficacy of CAR-T therapy in metastatic prostate cancer include developing dual-antigen CARs to mitigate antigen escape and tumor heterogeneity [ 116 ]. Moreover, “armored” CARs, co-expressing cytokines such as IL-12, IL-15, or IL-7/Chemokine (C-C motif) ligand 19 (CCL19), have demonstrated superior proliferative capacity, metabolic fitness, persistence, and anti-tumor efficacy compared to conventional CARs devoid of cytokine support [ 117 , 118 ]. The strategic combination of prostate cancer-targeted CAR T cells with PD-1 checkpoint inhibition or immunomodulatory drugs has also been studied in pre-clinical models [ 119 ].…”