New Combination of Immunotherapy PD-1 and GITR Provides More Effective Cancer Therapy

There is no doubt that the clinical use of "inhibitory immune checkpoints" for cancer treatment is the most important advance in anti-cancer treatment over the past 10 years. Blocking antibodies against the co-suppressor immunoreceptor PD-1 (or its ligand PD-L1) and CTLA-4 (cytotoxic T lymphocyte-associated protein 4) as a single drug has shown itself to be powerful in many cancers including melanoma, renal cell carcinoma, and non-small cell lung cancer. Meanwhile, some of the patients treated have achieved a complete cure.   Therefore, PD-1/PD-L1 antibodies (anti-PD-1/PD-L1) and anti-CTLA-4 antibodies (anti-CTLA-4) constantly rewrite the criteria for clinical cancer treatment. But even if immune checkpoint inhibitors have dramatically changed the treatment status of many cancers, the response rate of patients is still only 20% to 25% when used alone.   The response rate of patients will be greatly increased by combining anti-PD-1/PD-L1 and anti-CTLA-4 drugs, however, it will also produce more powerful side effects, such as autoimmune diseases, diabetes, and myocarditis, and even the patients will die in severe cases. Therefore, it is imperative to explore new immunotherapies. Recently, a new combination of immunotherapy targeting PD-1 with GITR has been strongly listed on the front page in the Journal of Science Immunology.   The researchers have proved with powerful evidence that anti-PD therapy combined with GITR agonists can reduce the risk of side effects while improving patient outcomes (GITR is a co-stimulatory receptor glucocorticoid-induced tumor necrosis factor receptor).   In the case of inefficient use of single drugs, combination therapy has become an extremely valuable anti-cancer path. In 2017 alone, more than 450 new trials based on the combination of anti-PD-1/PD-L1 have been launched in various research centers and hospitals. But unfortunately, the results of these tests are not ideal. In this new study, the researchers presented convincing preclinical research data. In studies of colorectal cancer in mice, the use of anti-PD-1 + anti-GITR produced greater anti-tumor effects, far more effective than the use of any single immunological checkpoint antibody alone, meanwhile, the same therapeutic effect was observed in kidney cancer mice.   The reason why this study can achieve such a great synergy is theoretically based on the principle of immunology. Anti-PD-1 + anti-GITR can act on CD8+ + T cells at the same time, killing cancer cells directly through CD8+ + T cells, while other inhibitory cancer cells can be recruited to gather near the middle stream for killing.  

  In activated CD8+ T cells from untreated tumor-bearing mice, PD-1 inhibits the activation of co-stimulatory receptor CD226 by phosphatase SHP-2 and TIGIT, preventing CD226 from binding to its ligand CD155 renders the CD226 signal unconductive. These effects result in limited tumor-specific CD8+ T cell responses and allow rapid tumor growth. (Anti-PD-1) When mice were treated with anti-PD-1 antibodies only, the activation function of CD226 was enhanced by improved CD226 signaling. (Anti-GITR) In contrast, when mice were treated with agonistic antibodies to GITR, the activation function of CD226 was enhanced by a decrease in TIGIT expression, which also enhanced CD226 signaling.   Anti-GITR also inhibits the function of T reg cells and further contributes to the improvement of CD8 + T cell responses. Single anti-PD-1 or single anti-GITR is not sufficient to improve CD8+ T cell function and tumor control. (Anti-PD-1 + anti-GITR) In mice treated with the anti-PD-1 + anti-GITR combination, the activation function of CD226 is enhanced by the cumulative effect of the two antibodies on CD226 signaling. These combined effects result in significantly improved tumor-specific CD8+ T cell responses and tumor control.   With the clinical role of immunotherapy being further highlighted, a variety of therapies are expected to be combined with immunotherapy. However, in fact, if we need to make immunotherapy take effect, the new combination therapy must be based on the basic principles of immunology in order to help patients in combination applications.