In the past few decades, immunotherapy has been at the forefront of cancer treatment. Accompanying the continuing development of tumor immunotherapy for centuries, there are many important discoverers.

As early as 1777, people tried to inject various pathogens to elicit an immune response against tumors. In 1891, William Coley, the "father of immunotherapy", completed the first successful experiment. He injected streptococcus into patients with metastatic soft tissue sarcoma and observed the tumor regression.

However, it was not until the 1950s that the concept of immune surveillance was proposed. Burnet and Thomas are considered to be the heroes of the immune surveillance hypothesis, in which the immune system actively recognizes and eliminates tumors through tumor-associated antigen (TAA) recognition. The immune surveillance of cancer mainly focuses on aspects of elimination, balance, and escape. "Eliminate" refers to the recognition and destruction of tumor cells through innate immunity and adaptive immunity, "balance" refers to the immune attack on tumor cells and the mutation and remodeling of tumor cells at the same time to resist attack, and finally, the mutated tumor cells "escape" from the recognition by the immune system and continue to proliferate. This interaction between cancer cells and immune surveillance remains critical to the success of immunotherapies (https://www.creative-biolabs.com/immuno-oncology/).

Cytokine Therapy
Early discovery in the field of tumor immunotherapy is the role of cytokines. In 1974, the T cell growth factor IL-2 was discovered, which is produced by CD4+ and CD8+ T cells and plays a key role in T cell differentiation and growth, immune memory, and maintenance of regulatory T cells to prevent autoimmunity. IL-2 was later cloned in 1983 and studied in a syngeneic mouse model (https://www.creative-biolabs.com/immuno-oncology/syngeneic-models.htm
), and it was found that it can promote the regression of metastatic malignant tumors such as syngeneic sarcoma and melanoma. This eventually led the FDA to approve it for the treatment of metastatic kidney cancer in 1992, making IL-2 the first cancer immunotherapy drug in humans. However, IL-2 also has obvious toxicity, including capillary leak syndrome and multiple organ dysfunction, which limits its application.

Checkpoint Suppression
Soon after IL-2 was approved, checkpoint inhibitors came to the forefront of cancer research. The discovery of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) paved the way for the discovery of all checkpoint inhibitors in the future. CTLA-4 is expressed on T cells and helps control immune activation and host damage.

This checkpoint was discovered by James Allison. In 2011, ipilimumab was approved for the treatment of metastatic melanoma and became the first checkpoint inhibitor, which is an anti-CTLA-4 monoclonal antibody that directly blocks CTLA-4, opening up a way for downstream T cell activation, proliferation, and ultimate tumor destruction.

After the discovery of CTLA-4, Ishida et al. discovered programmed death receptor-1 and programmed death ligand-1 (PD-1/PD-L1) in 1992. Currently, there are a variety of approved PD-1 inhibitors, including pembrolizumab, nivolumab, and cemiplimab, as well as PD-L1 inhibitors atezolizumab, avelumab, and durvalumab, which have become the cornerstone of tumor immunotherapy.

Combination therapy with checkpoint inhibitors, such as simultaneous blockade of CTLA-4 and PD-1, can inhibit tumor development through different mechanisms. At present, the FDA has approved the combination of ipilimumab and nivolumab to treat a variety of malignant tumors, including the first-line treatment of NSCLC with PDL-1 expression greater than 1%. However, increased toxicity is still an obstacle to many combined therapies. At present, more than 2000 trials of PD-1/PD-L1 inhibitor combination drugs for various malignant tumors are underway, highlighting the great concern for this breakthrough therapy.

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