Examining IL-15 as an immunotherapy agent in cancer and AIDS

Division Of Basic Sciences - Nci

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Abstract

Understanding of the cellular mechanisms controlling expression shed new light in the biology and regulation of IL-15, led to the identification of the bioactive heterodimeric form of IL-15 and provided methods for the efficient production and clinical application of this cytokine (Bergamaschi, J. Biol. Chem. 283: 4189, 2008; Bergamaschi, Blood 120: e1-8, 2012; Bergamaschi, Cancers 13, 2021). We have shown that hetIL-15 greatly increases lymphocyte infiltration in several tumors in mouse models and in macaques, suggesting a general method to increase lymphocyte infiltration, which is associated with anti-tumor activity. We have performed first-in-human clinical trials of hetIL-15 in metastatic cancers (Conlon, JITC:e003388. 2021) and also in combination with anti-PD-1 check point inhibitor (NCT02452268; collaboration with Novartis). hetIL-15 is extensively studied in mouse tumor models where we demonstrated the rapid interaction of lymphoid and myeloid cell networks resulting in changes in numbers and migration of different cell populations. Extensive transcriptomics and proteomics analysis has revealed additional pathways affected by hetIL-15 (Bergamaschi, J. Immunother. Cancer: 8:e000599, 2020; Bergamaschi, Cancers 13, 2021). We have studied the effects of hetIL-15 in the number and properties of Dendritic Cells (DC) in tumors which increase upon hetIL-15 treatment. DC participate in a network of cells that are induced during hetIL-15 treatment and in turn support more recruitment of effector cells in tumor sites. Studies in mouse orthotopic models show that DC populations correlate with tumor regression and reveal additional beneficial effects of hetIL-15 in inducing or enhancing long term protective immune response against tumors. Thus, hetIL-15, a cytokine directly affecting lymphocytes and inducing cytotoxic cells, has also an indirect rapid and significant effect on the recruitment of myeloid cells, initiating a cascade for tumor elimination though innate and adoptive immune mechanisms. In addition to cancer immunotherapy, IL-15 has generated strong interest for clinical use to treat HIV infection, especially in protocols targeting viral eradication or a functional cure. The use of IL-15 as an immune therapeutic agent against HIV infection is based on its effects as a growth factor and key regulator of cytotoxic responses mediated by both the innate (NK cells) and the adaptive (CTL) arms of the immune system. Importantly, hetIL-15 treatment promotes the entrance of cytotoxic (GrzB+) CD8+ T cells in the B cell follicles, areas within the LN where CTL are typically excluded and where SIV/HIV infected follicular helper CD4+ T cells reside. hetIL-15 treatment led to significant decrease in cell-associated viral RNA within the LN as well as in plasma viremia in SHIV infected macaques (Watson, PLoS Pathog. 14: e1006902, 2018). In a collaborative effort, we further reported that a IL-15 transcriptional signature response to a viral RhCMV/SIV vaccine strongly correlated with protection (Barrenas, PLoS Pathog 17:e1009278; 2021). We have expanded this concept and are testing the contribution of a combinatorial treatment including hetIL-15 in reducing reservoir in the SIV infected ART-treated macaques.