For over 150 years, scientists and clinicians have been attempting to fight against cancers by utilizing the immune system. In 1866, Wilhelm Busch and Friedrich Fehleisen first discovered that acute inflammation could cause a significant decrease in tumor size. In the 1980s, the “father of immunotherapy”, William Coley attempted to treat tumors by injecting extracts of bacteria to stimulate patients’ immune systems, which was referred to as “Coley toxin” and has been demonstrated to be effective against several types of cancer. In the mid-1970s, it was claimed that immune-stimulating cytokines might reverse the immunosuppression of cancer. The recombinant alpha interferon (IFNα2b) and high-dose interleukin-2 (IL-2) were approved by the FDA for treating hairy cell leukemia in 1986 and metastatic renal cell carcinoma (RCC) in 1992, respectively. However, severe adverse effects were found in clinics. In the 1990s, James P. Allison observed that cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) functions as a brake on T-cell-mediated immune response. Programmed death 1(PD-1) and its ligand PD-L1 were also identified and proven to regulate cancer immunity. The promising outcomes of clinical trials have led to the approval of anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibody blockade therapies. Since 2011, there have been over 83 FDA-approved indications of ICIs in over 17 types of cancers and over 2000 clinical trials in development with checkpoints. In 2008, the Fred Hutchison Cancer Research Center published the first clinical trial that confirmed the safety and effectiveness of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell lymphomas. Until 2017, Novartis' tisagenlecleucel-T (Kymriah) and Kite/Gilead's axicabtagene ciloleucel (Yescarta) were approved by FDA for the treatment of relapsed or refractory AML and lymphomas. Currently, over 20 clinical trials are investigating the efficacy and safety of CAR-NK therapies in cancer.
Immunotherapies, including ICIs, cytokines treatment, tumor vaccines, oncolytic viruses, CAR-T/NK, and others, are known as the fourth pillar of cancer treatment after surgery, radiation therapy, and chemotherapy. The emergence of tumor immunotherapy has greatly revolutionized the cancer treatment.