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 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 ... -  《-》

Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical background: CTLA-4 and PD-1 blockade.

Much of the recent excitement in the translational field of tumor immunology and immunotherapy has been generated by the recognition that immune checkpoint proteins can be blocked by human antibodies with profound effects in vitro, in animal tumor systems, and in patients. Promising clinical data have already been generated in melanoma and other tumor types with human antibodies directed against cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1). The preclinical data that supported the clinical development of these two antibodies will be discussed in detail in this review, showing that many of the therapeutic effects of these two agents were predicted by the animal models, as were the immune-related side effects noted with these drugs. In contrast, much of the early work with anti-CTLA-4 antibodies indicated that it had a potent therapeutic effect only when combined with granulocyte-macrophage colony-stimulating factor (GM-CSF)-transduced tumor vaccines, and that the antibody alone was effective only in the most immunogenic tumor models in mice. Intriguingly, in patients, the drug alone clearly has had important therapeutic effects, but the addition of vaccines has not added to its clinical benefit. Murine experiments also suggested that CTLA-4 abrogation might function via important effects on natural T-regulatory cells that were CD4(+), CD25(+high), and FOXp3(+), but this has not been borne out in experiments using peripheral blood mononuclear cells from patients treated with anti-CTLA-4 antibodies, and unlike in animals, in humans the exact mechanism(s) by which CTLA-4 abrogation induced an anti-tumor effect is still unclear. Abrogation of PD-1 functions via different immune signaling pathways than CTLA-4 and is likely to have a different spectrum of effects than blocking CTLA-4. For PD-1 blockade, murine experiments have suggested that the antibody alone and combined with adoptive cell transfer or vaccine approaches would be therapeutically beneficial, and that clear effects on T-cell proliferation and activation, as well as T-regulatory cell function would be observed in patients. The clinical development of anti-PD-1 antibody so far has shown that it has a potent effect when administered alone, and trials of vaccines with anti-PD-1 are just being initiated to test the idea that the predicted effects of that antibody observed in animal systems also would be seen in patients. These observations support the idea that animal preclinical therapeutic experiments are an important guide to the conduct of trials employing abrogation of immune checkpoint proteins in T cells in patients. Nonetheless, clinical investigators must be flexible and prepared to find that the biology of those systems may be very different in humans compared to mice.

Weber J 《-》

Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy.

Mangsbo SM ，Sandin LC ，Anger K ，Korman AJ ，Loskog A ，Tötterman TH ... -  《-》

Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy.

Peggs KS ，Quezada SA ，Allison JP 《-》