Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion

Abstract

Purpose Adoptive cell transfer (ACT) is a promising immunotherapeutic approach for cancer. Host lymphodepletion is associated with favorable ACT therapy outcomes, but it may cause detrimental effects in humans. We tested the hypothesis that IL-15 administration enhances ACT in the absence of lymphodepletion. We previously showed that bioactive IL-15 in vivo comprises a stable complex of the IL-15 chain with the IL-15 receptor alpha chain (IL-15Rα), termed heterodimeric IL-15 (hetIL-15). Experimental Design We evaluated the effects of the combination regimen ACT+hetIL-15 in the absence of lymphodepletion by transferring melanoma-specific Pmel-1 T cells into B16 melanoma-bearing mice. Results hetIL-15 treatment delayed tumor growth by promoting infiltration and persistence of both adoptively transferred Pmel-1 cells and endogenous CD8+ T cells into the tumor. In contrast, persistence of Pmel-1 cells was severely reduced following irradiation in comparison to mice treated with hetIL-15. Importantly, we found that hetIL-15 treatment led to the preferential enrichment of Pmel-1 cells in B16 tumor sites in an antigen-dependent manner. Upon hetIL-15 administration, tumor-infiltrating Pmel-1 cells showed a “non-exhausted” effector phenotype, characterized by increased IFN-γ secretion, proliferation and cytotoxic potential and low level of PD-1. hetIL-15 treatment also resulted in an improved Pmel-1 to Treg ratio in the tumor. Conclusions hetIL-15 administration improves the outcome of ACT in lymphoreplete hosts, a finding with significant implications for improving cell-based cancer immunotherapy strategies.

Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes

“…hetIL-15 has an extended half-life in vivo and stimulates proliferation and cytotoxic commitment of NK cells and CD8 + effector T cells by binding to the IL-2/IL-15βγ receptor. We have shown that recombinant hetIL-15 induces proliferation, activation and increased cytotoxic potential of lymphocytes and, importantly, induces migration of lymphocytes into tumors in a murine model [ 25 ]. Due to these properties and its ability to delay tumor progression in animal models, hetIL-15 has progressed to clinical trials for metastatic cancer (NCT02452268).…”

Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction

“…Tregs in HIV-1-infected INR subjects and allowed dysfunctional cycling CD4 + T cells in INRs to complete the cell cycle and divide. These findings suggest that administration of IL-15, a cytokine in human trials for the treatment of cancer (50,51), could rescue functionally impaired Tregs, which bear features of an exhausted phenotype (52) in INR patients and enhance immune restoration in these subjects.…”

Tissue Resident CD8 Memory T Cell Responses in Cancer and Autoimmunity

“…While TGF-β has come to be known for its roles in promoting tumor growth ( 152 ), suppressing T cell function ( 153 ), and enforcing Treg stability ( 154 ), its key role in T RM cell generation suggests its value in certain immunotherapy contexts. On the other hand, IL-15 has long been recognized for its role in supporting anti-tumor T cell responses ( 155 , 156 ). Studies show that T RM cells preferentially accumulate at sites of high IL-15 production, such as hair follicles in the skin ( 46 , 111 ).…”