Simultaneous blockade of multiple immune system inhibitory checkpoints enhances antitumor activity mediated by interleukin-15 in a murine metastatic colon carcinoma model.

Interleukin 15 (IL-15) is a promising cytokine for immunotherapy of cancer due to its ability to stimulate the immunity of natural killer, B, and T cells. Its effectiveness, however, may be limited by inhibitory checkpoints and pathways that can attenuate immune responses. Finding strategies to abrogate these negative regulators and enhance the efficacy of IL-15 is a critical challenge. In a preclinical study, we evaluated IL-15 combined with antibodies to block the negative immune regulators cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in a metastatic murine CT26 colon carcinoma model. IL-15 treatment resulted in a significant prolongation of survival in mice with metastatic tumor. Administration of IL-15, however, also increased expression of PD-1 on the surface of CD8(+) T cells including CD8(+)CD44(high) memory phenotype T cells. Moreover, IL-15 also increased the secretion of the immunosuppressive cytokine, IL-10. Combining IL-15 with anti-PD-L1 and anti-CTLA-4 (multiple immune checkpoint blockade) exhibited greater CTL killing and IFNγ secretion. Moreover, this combination resulted in a significant reduction in surface expression of PD-1 on CD8(+) T cells, a decrease in IL-10 secretion, and led to significantly longer survival of tumor-bearing animals compared with mice treated with IL-15 alone or combined singularly with anti-PD-L1 or anti-CTLA-4. Combining the immune stimulatory properties of IL-15 with the simultaneous removal of 2 critical immune system inhibitory checkpoints, we showed enhancement of immune responses leading to increased antitumor activity.

Yu P ，Steel JC ，Zhang M ，Morris JC ，Waldmann TA ... -  《-》

Braking bad: blockade of inhibitory pathways improves interleukin-15 therapy.

Blockade of the CTLA-4 and PD-1 inhibitory pathways in T cells via the administration of neutralizing antibodies at the time of interleukin (IL)-15 therapy markedly enhanced the survival of tumor-bearing mice as compared with those receiving IL-15 alone or IL-15 in combination with just one of the antibodies.

Carson WE 3rd 《-》

Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model.

Yu P ，Steel JC ，Zhang M ，Morris JC ，Waitz R ，Fasso M ，Allison JP ，Waldmann TA ... -  《-》

Targeting interferon signaling and CTLA-4 enhance the therapeutic efficacy of anti-PD-1 immunotherapy in preclinical model of HPV(+) oral cancer.

Dorta-Estremera S ，Hegde VL ，Slay RB ，Sun R ，Yanamandra AV ，Nicholas C ，Nookala S ，Sierra G ，Curran MA ，Sastry KJ ... -  《Journal for ImmunoTherapy of Cancer》

IL-6 and PD-L1 blockade combination inhibits hepatocellular carcinoma cancer development in mouse model.

Limited efficacy of immune checkpoint inhibitors in hepatocellular carcinoma (HCC) was observed in clinical trials, thus prompting investigation into combination therapy. Interleukin-6 (IL-6) has important roles in modeling immune responses in cancers. Here, we hypothesized that IL-6 blockade would enhance antitumor immunity of HCC and synergize with anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor in treating HCC. The sources and immune modulating effects of IL-6 were investigated in HCC models. Combination of anti-IL-6 and anti-PD-L1 was tested in HCC bearing mice. We found that IL-6 is mainly secreted by cancer associated fibroblast (CAFs), but not tumor cells in HCC. High IL-6 expression CAFs could induce strong immunosuppression in HCC microenvironment by recruiting immunosuppressive cells, such as myeloid derived suppressive cells. In addition, high IL-6 expression CAFs also impaired tumor infiltrating T-cell function via upregulating inhibitory immune checkpoints. Using IL-6 blockade could reverse anti-PD-L1 resistance in HCC tumor model. In conclusion, our study indicates that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in HCC, providing a potential strategy to overcoming anti-PD-L1 resistance in HCC.

Liu H ，Shen J ，Lu K 《-》