Tumor antigens are the core of tumor immunity, and the recognition of tumor antigens is the theoretical and material basis of specific active immunotherapy.  The identification and selection of early tumor antigens mostly focus on tumor cell consensus antigens, which is suitable for a wider range of cancer patients. However, these shared antigens also have some expression in normal tissues or embryo tissues, which may lead to antigen peptides. The immune tolerance of a high affinity effect of an MHC-T cell antigen receptor limits the therapeutic effect. On the other hand, due to its great heterogeneity and genetic instability, tumors have long been subjected to immune selection pressure in the body environment, and only those tumor cells that are not antigenic are able to survive. Therefore, tumor antigens are generally characterized by low immunogenicity. How to enhance the antigenicity of tumor cells is the key to effective immunotherapy.

 Specific immunotherapy includes phagocytic cells including monocytes and macrophages. In addition to phagocytosis and antigen presentation, various cytokines such as interleukin (IL-1 can be secreted after activation, IL-6, IL-8, IL-12, TNF. Similarly, in addition to direct cell killing, NK cells can also secrete cytokines such as interferon (IFN), TNF-α, granulocyte-macro-phage colony stimulating factor (GM-CSF), IL-3 and macrophage colony-stimulating factor (M-CSF). These cytokines have a promoting effect on T cells, B cells, APC cells and the like. Therefore, the use of non-specific immune-stimulants or direct administration of related cytokines may achieve the purpose of regulating immune cell activation, proliferation and functional activity.

Non-specific immune-stimulants include endotoxin, lipid A, trehalose, thymosin, and some Chinese herbal ingredients. More successful non-specific immune-stimulants, such as BCG for bladder infusion for bladder cancer, and levamisole and 5-fluorouracil in combination with colon cancer shows a certain degree of effect. Advances in genetic engineering have made it possible to mass produce cytokines. To date, dozens of clinical studies have analyzed whether immune-stimulatory cytokines can safely and effectively activate tumor-specific immune responses, either alone or in combination with conventional chemotherapy. Recombinant cytokines are approved by the FDA as anti-tumor immune-stimulants, namely IFN-a2a, IFN-a2b and IL-2. In addition, granulocyte colony stimulating factor (GM-GSF) and GM-CSF are clinically used as immune-remodeling agents for transplant patients or post-chemotherapy cancer patients. The main problem is that the systemic application of cytokines has a large side effect, rapid failure, low concentration in the tumor, and poor efficacy. In recent years, attempts have been made to introduce cytokines into the body via a vector or to bind to a monoclonal antibody to enhance its targeting and reduce systemic side effects. More efforts should be made for the development of promising combination therapies, including combination with Toll-like receptor agonists, immunological checkpoint inhibitors, and immunogenic chemotherapy.

Adoptive cell transfer therapy (ACT) extremely active tumor immunotherapy field for more than a decade, which inoculate in vitro activated autologous or allogeneic immune effector cells to a patient to kill tumor cells in the patient. ACT is more suitable for patients with low cellular immune function, such as high-dose chemotherapy, post-radiotherapy, bone marrow transplantation, and the number and function of immune cells in viral infection, especially in patients with blood or immune system tumors.

There are three main strategies for ACT treatment. 1. Tumor infiltrating lymphocyte (TIL) treatment is the separation of lymphocytes with anti-tumor activity from tumor tissues, cultured in vitro by IL-2, and then re-introduced into the cell therapy of patients. The main limitation is that preparation of clinical therapeutic amount of cells needs to be cultured in vitro for 4 to 7 weeks, which is time consuming, laborious and easy to be contaminated. Preparation of TIL is difficult, requiring specialized production equipment and technicians. Related research is currently underway to shorten cell culture time and make the separation of tumor-specific cells easier. 2. T cell receptor (TCR) treatment, is to collect patient T cells, using genetic engineering to introduce new receptors, to identify specific tumor antigens and to kill tumor cells, which can also introduce immune factors, and trigger other cells to attack tumor cells. The main problem is that the TCR must match the patient's immune type. Studies have reported that the human melanocyte differentiation antigen MART-1 and the tumor/testis antigen NY-ESO-1 have achieved certain therapeutic effects in patients with melanoma and synovial cell tumor, respectively. 3. A chimeric antigen receptor (CAR) encodes a gene of a pseudo-like protein that binds to a tumor cell surface antigen in a T cell by genetic engineering. As an antibody to a common cancer antigen, a cell receptor fragment or a T cell proliferation stimulating factor has an advantage that it does not need to match the type of immunity of a patient. At present, only CAR T cell therapy targeting CD19 protein on B cells has a positive result in small-scale clinical trials. CD19 protein is also expressed on normal cells, so the occurrence of side effects is unavoidable. Further research is needed to identify cell surface antigens that target but do not damage normal tissues, and to investigate whether ACT therapy is applicable to a wider range of cancer types and how it can be integrated with other cancer immunotherapies, such as immunological checkpoint inhibitors.

3. Immune Checkpoint Inhibitors

Anti-programmed death 1 (PD-1) antibody is currently the most studied and the fastest growing clinical immunotherapy. PD-1 acts in the phase of the immune response, which is expressed in activated T cells, B cells and myeloid cells with two ligands, programmed death ligand 1, PD. -L1) and PD-L2. PD-L1/L2 is expressed in antigen presenting cells, and PD-L1 is also expressed in various tissues. The binding of PD-1 to PD-L1 mediates the co-suppression signal of T cell activation, inhibits the killing function of T cells, and negatively regulates the immune response of humans. The research showed that the PLA-L1 was highly expressed in tumor tissues and regulated the function of tumor-infiltrating CD8+ T cells. Therefore, immunomodulation targeting PD-1/PD-L1 has important implications for tumors. The PD-1/PD-L1 inhibitor can specifically bind to PD-L1 on tumor cells to inhibit its expression, thereby enabling T cells with suppressed function to restore recognition function to tumor cells, thereby achieving anticancer effects. In recent years, a variety of PD-1/PD-L1 monoclonal antibodies have been rapidly developed in the clinical study of tumor immunotherapy. Currently, PD-1 inhibitors Pembrolizumab and Nivolumab have been approved by the FDA for advanced melanoma, non-small cell lung cancer, kidney cancer, Hodgkin's lymphoma, and head and neck squamous cell carcinoma. Nivolumab is also approved by the FDA for the treatment of renal and urothelial carcinoma. In addition, monoclonal antibodies such as PD-L1 inhibitors Atezolizumab and Durvalumab have also entered multiple phase III clinical studies covering multiple tumors such as non-small cell lung cancer, melanoma, and bladder cancer.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a transmembrane protein expressed on the surface of activated T cells. CTLA-4 acts on the initiation phase of the immune response, and its activation inhibits the initiation of the T cell immune response, resulting in a decrease in activated T cells and prevention of memory T cell production. The study found that tumor cells can activate CTLA-4, inactivate the activated T cells, thus achieving the tumor's own immune escape. Several preclinical studies have found that blocking CTLA-4 can restore T cell activity and prolong the survival time of memory T cells, thereby restoring the body's immune function to tumor cells, resulting in improved tumor control rate. Currently, two CTLA-4 inhibitors, have been approved by the FDA for the adjuvant treatment of stage III melanoma and the treatment of advanced melanoma, and the clinical studies of Ipilimumab and Tremelimumab in kidney cancer, prostate cancer, and lung cancer have been widely carried out. Early clinical studies have shown that both monoclonal antibodies are safe and effective, either alone or in combination with IL-2, PD-1/PD-L1 inhibitors or chemotherapy.

4. Oncolytic Viruses

Oncolytic viruses are capable of infecting and selectively replicating in cancer cells, eventually leading to cell death without harming healthy cells. There was renewed interest in oncolytic vitro-therapy in the 1990s after the first genetically engineered oncolytic virus, a herpes simplex virus (HSV529 vaccine)-1 thymidine kinase mutant, was reported in 1991. Over the last two decades great progress has been made in this field, and several oncolytic viruses have entered into clinical trials. This special issue on oncolytic viruses addresses challenges to achieve success in the clinic.

Oncolytic viruses can be delivered into cancer patients or preclinical animal models by a number of routes including intratumoral, intra, intrapleural, intraperitoneal delivery and hepatic artery infusion. Oncolytic virus is the most needed, effective therapy for the treatment of patients with metastatic or inaccessible diseases

In recent years, tumor immunotherapy has achieved encouraging results, especially for patients with advanced cancer.

Reference

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