An IL-15 superagonist ALT803 in combination with an anti-PD-L1 monoclonal antibody mediates significant anti-tumor efficacy and markedly enhances CD8+ T cell and NK cell responses in murine breast carcinoma
An IL-15 superagonist ALT803 in combination with an anti-PD-L1 monoclonal antibody mediates significant anti-tumor efficacy and markedly enhances CD8+ T cell and NK cell responses in murine breast carcinoma
Karin M. Knudson1, Kristin C. Hicks1, Jeffrey Schlom1 and Sofia R. Gameiro1 1Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
IL-15 is a promising cancer therapeutic due to its potent stimulation of CD8+ T cell and NK cell activation and function. ALT803, a complex of an IL-15 superagonist mutant and dimeric IL-15RalphaSushi-FC fusion protein, exhibits anti-tumor efficacy in murine myeloma, glioblastoma, and breast cancer models. It is possible that the anti-tumor effects of ALT803 can be enhanced by directly targeting immunosuppression within the tumor microenvironment, especially since IL-15 is known to upregulate the expression of checkpoint molecule PD-L1. The PD-L1/PD-1 checkpoint axis is known to regulate both CD8+ T cell and NK cell function in the tumor. Here, we examined the antitumor efficacy and immunomodulatory effects of combining ALT803 with a monoclonal antibody targeting PD-L1.
ALT803 monotherapy, while significantly preventing lung metastasis compared to PBS treatment, did not improve anti-tumor efficacy versus anti-PD-L1 monotherapy in the 4T1 murine model of triple-negative breast cancer. The combination of ALT803 and anti-PD-L1 promoted a significant reduction in primary 4T1 tumor growth and spontaneous lung metastasis as compared to PBS- and -anti-PD-L1-treated mice, resulting in an increase in median overall survival in those animals treated with the combination of ALT803 and anti-PD-L1.
CD8+ T cells and NK cells from the spleen and lung displayed a more active phenotype after treatment with ALT803 plus anti-PD-L1 combination. This effect appeared to be dependent on the ALT803 component of the combination therapy, as the CD8+ T cells and NK cells from anti-PD-L1-treatment did not display this phenotype. In addition, ALT803 plus anti-PD-L1 combination promoted the generation of an inflammatory milieu. Serum cytokine levels of TNF-alpha and IFN-gamma correlated with a more activated CD8+ and NK cell phenotype upon ALT803 plus anti-PD-L1 treatment, with significant increases observed only in the ALT803 plus anti-PD-L1 combination-treated mice.
Taken together, these findings offer a preclinical proof of concept for future studies employing the combination of ALT803 and aPD-L1. This also offers rationale supporting clinical use of ALT803 in combination with checkpoint inhibitors and potentially other immunotherapies.
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