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 《-》

Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor--secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors.

Li B ，VanRoey M ，Wang C ，Chen TH ，Korman A ，Jooss K ... -  《CLINICAL CANCER RESEARCH》

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 ... -  《-》

Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals.

Blockade of CTL-associated antigen-4 (CTLA-4), an inhibitory immunomodulatory molecule on T cells, has been shown to enhance T-cell responses and induce tumor rejection, and a number of clinical trials with anti-CTLA-4 blocking monoclonal antibody (mAb) are under way. However, accumulating evidence indicates that anti-CTLA-4 mAb increases the number of CD4+CD25+Foxp3+ regulatory T cells (Treg) and that anti-CTLA4 mAb alone is often insufficient to reject established tumors in mice and humans. Thus, finding maneuvers to control Tregs and other immunosuppressive mechanisms remains a critical challenge. The potential to enhance antitumor immune responses by combining anti-CTLA-4 mAb with anti-glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) mAb, a costimulatory molecule that abrogates directly/indirectly Treg-mediated immune suppression or anti-CD25 mAb that depletes Tregs was analyzed with two tumor models, CT26 (a murine colon carcinoma cell line) and CMS5a (a murine fibrosarcoma cell line). Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8+ T cells infiltrating tumor sites in anti-CTLA-4 mAb-treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8+ T cells with strongly upregulated CD25 expression in anti-GITR mAb-treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling. This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic.

Mitsui J ，Nishikawa H ，Muraoka D ，Wang L ，Noguchi T ，Sato E ，Kondo S ，Allison JP ，Sakaguchi S ，Old LJ ，Kato T ，Shiku H ... -  《-》

Combination of CTL-associated antigen-4 blockade and depletion of CD25 regulatory T cells enhance tumour immunity of dendritic cell-based vaccine in a mouse model of colon cancer.

Saha A ，Chatterjee SK 《-》