Immune checkpoint therapy is a type of treatment that enhances anti-tumor immune responses by modulating T cell activity. In the latest issue of Science, Padmanee Sharma and James P. Allison from the MD. Anderson Cancer Center in the United States analyzed the development of immunological checkpoint therapy in a review article.

At present, immune checkpoint therapy has been added to the "anti-cancer army" only next to surgery, radiotherapy, chemotherapy, and targeted therapy. One of the three immunotherapeutic drugs approved by the FDA is an antibody drug that specifically binds to the CTLA-4 receptor on the surface of T cells, called ipilimumab, which was approved in 2011. The other two are antibody-based drugs that specifically bind to the PD-1 receptor on the surface of T cells, called pembrolizumab and nivolumab respectively, which were approved in 2014.

These three drugs have completely different properties compared to previous anti-cancer drugs.
First, they do not directly act on tumor cells, but indirectly kill tumor cells by acting on T cells; in addition, they are not specific to the tumor cells surface, but systematically enhance the systemic anti-tumor immune response. Specifically, in a small number of specific cancer types, CTLA-4 antibody drugs have been effective in extending patient life for up to ten years.

The rapid development of basic science over the past 20 years has led to a significant increase in the treatment of some cancers. We use high-throughput sequencing screens to find specific mutations in cancer cells in specific patients. These specific mutations can be thought of as "cancer molecular markers" carried by patients. "Individualized medicine" for cancer can be achieved by designing specific drugs. For example, by designing some small molecule drugs to block some of the necessary signaling pathways of cancer cells. For example, melanoma patients carry a mutation in BRAF V600E, which allows the BRAF signaling pathway to remain on. These patients can be treated with a BRAF inhibitor drug. It has been proven that this treatment can significantly extend the life of the patient.

Tumor microenvironment: tumor cell and host immune response

Tumors are composed of many different cell types, including primitive cells after genetic variation and a large number of other types of cells, such as epidermal cells, fibroblasts, and the like. Initially there may be only a small number of immune cells entering the interior of the tumor, but NK cells and macrophages will slowly appear, followed by T cells. T cells are important components that kill tumor cells that express tumor-specific antigens. The main mode of action is through the interaction of the TCR on its surface with the MHC-antigen complex on the surface of tumor cells. Tumor-specific antigens may be composed of oncogenic viruses, differentiation antigens, epigenetic regulatory molecules, and new antigens produced during carcinogenesis. T cells are screened, looking for tumor-specific antigens, and then begin to divide and proliferate, eventually killing these cells. However, the activation process of T cells is much more complicated than that described because of the many molecules involved in both positive and negative regulation. The interaction of TCR with the MHC-antigen complex is not sufficient by itself to activate T cells. Some stimulating factors are needed. After activation of the signal, T cells can achieve a killing effect near the tumor.

Regulation of T cell response

Since then, some in-depth studies of the complex regulatory mechanisms of T cells have helped explain why simple vaccination patterns do not work to treat cancer. In the mid-1990s, people gradually learned that the activation of T cells is subject to a variety of complex signal regulation. CTLA-4, a class of molecules highly homologous to CD28, is also expressed on the surface of T cells. CTLA-4 binds to CD80/CD86 and binds more strongly than CD28. On top of this, scientists have shown that CTLA-4 is completely opposite to CD28, which inhibits the activation of T cells. Subsequent clues are: CTLA-4 is highly expressed after T cell activation, and such molecules accumulate on the cell membrane, and then further activation of T cells is blocked by binding to CD80/CD86.

Based on the understanding of the function of CTLA-4, people began to wonder whether the effect of spectrally killing tumors could be achieved by liberating endogenous T cell activation without having to consider specific antigenic substances. Many laboratories have validated this conjecture through a mouse model and eventually contributed to the advent of the CTLA-4 blocking antibody ipilimumab. The advent of ipilimumab opened the door of immune checkpoint therapy. Now we know more immune checkpoint inhibitors (molecules), including PD-1. PD-1 also has two ligands, PD-L1 and PD-L2, which are expressed on the surface of various types of cells. Unlike CTLA-4, PD-1 does not block co-stimulatory signals, but directly suppresses signals downstream of the TCR.

Clinical effect of immune checkpoint therapy

Phase I/II clinical trial results show that Ipilimumab can effectively inhibit the deterioration of melanoma, renal cell carcinoma, prostate cancer, urinary tract cancer and ovarian cancer. In stage III clinical trials, Ipilimumab was used to treat patients with advanced melanoma, and the results showed a significant increase in patient life. Importantly, the arousal of the immune response was found in more than 20% of patients with a life span of more than 4 years.
Similarly, anti-PD1 antibody drugs have also achieved significant therapeutic effects.

Since CTLA-4 and PD-1 have different mechanisms of action, it means that the combination of the two drugs may lead to better therapeutic effects. Experiments on mouse models have indeed confirmed this hypothesis. In 2013, the results of Phase I clinical trials demonstrated that anti-CTLA-4 (ipilimumab) combined with anti-PD-1 (nivolumab) inhibited tumor progression in 50% of patients with advanced melanoma.

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