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

• Published in: Clinical cancer research 2017-06, Vol.23 (11), p.2817-2830
• Main Authors: Ng, Sinnie Sin Man, Nagy, Bethany A, Jensen, Shawn M, Hu, Xintao, Alicea, Candido, Fox, Bernard A, Felber, Barbara K, Bergamaschi, Cristina, Pavlakis, George N
• Format: Article
• Language: English
• Subjects: Adoptive Transfer - methods; Animals; Cancer; Cancer immunotherapy; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cell proliferation; Chains; Cytotoxicity; Effector cells; Experimental design; Humans; Immunotherapy; Immunotherapy, Adoptive; Infiltration; Interleukin 1; Interleukin 15; Irradiation; Low level; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Metastases; Mice; PD-1 protein; Receptors, Interleukin-15 - genetics; Receptors, Interleukin-15 - immunology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; γ-Interferon
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-1808

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 IL15 administration enhances ACT in the absence of lymphodepletion. We previously showed that bioactive IL15 comprises a stable complex of the IL15 chain with the IL15 receptor alpha chain (IL15Rα), termed heterodimeric IL15 (hetIL15). We evaluated the effects of the combination regimen ACT + hetIL15 in the absence of lymphodepletion by transferring melanoma-specific Pmel-1 T cells into B16 melanoma-bearing mice. hetIL15 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 with mice treated with hetIL15. Importantly, we found that hetIL15 treatment led to the preferential enrichment of Pmel-1 cells in B16 tumor sites in an antigen-dependent manner. Upon hetIL15 administration, tumor-infiltrating Pmel-1 cells showed a "nonexhausted" effector phenotype, characterized by increased IFNγ secretion, proliferation, and cytotoxic potential and low level of PD-1. hetIL15 treatment also resulted in an improved ratio of Pmel-1 to Treg in the tumor. hetIL15 administration improves the outcome of ACT in lymphoreplete hosts, a finding with significant implications for improving cell-based cancer immunotherapy strategies. .