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------  Tumor Immunity  ------

Normally, the immune system can recognize and eliminate tumor cells from the tumor microenvironment; however, tumor cells can suppress the human immune system using different strategies for survival and growth, so the tumor cells cannot be killed normally, thus surviving in all stages of the anti-tumor immune response. These features of tumor cells are called immune escape. The concept of tumor-immune cycle was born in order to better understand the complexity of multiple links and procedures of tumor immunity. The tumor-immune cycle includes the following seven links: 1. Tumor antigen release; 2. Tumor antigen presentation; 3. Initiation and activation of effector T cells; 4. Migration of T cells to tumor tissues; 5. Infiltration of T cells in tumor tissues; 6. Recognition of tumor cells by T cells; 7. Clearance of tumor cells. Abnormalities in any of these links may lead to immune escape due to failure of the anti-tumor-immune cycle. The immune system may be suppressed in the effective recognition and killing of tumor cells by abnormalities in different links by different tumors, resulting in immune tolerance, and even acceleration of the occurrence and development of tumors.

Tumor immunotherapy is a therapeutic strategy involving reinitiating and maintaining tumor immune cycle and restoring the body's normal anti-tumor immune responses so as to inhibit tumor growth and eliminate tumor cells. Examples of such products include monoclonal antibody immune checkpoint blockades, therapeutic antibodies, cancer vaccines, cell therapies, and small molecule inhibitors. In the last few years, numerous achievements in the field of tumor immunotherapy. Many immunotherapeutic products have exhibited potent anti-tumor activity in the treatment of several solid tumors such as melanoma, non-small cell lung cancer, kidney cancer and prostate cancer and have been granted approvals for clinical use by FDA. Tumor immunotherapy was awarded as the most important scientific breakthrough by Science in 2013 for its excellent efficacy and innovation.

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(I) Monoclonal Antibody Immune Checkpoint Blockade

1. PD-1/PD-L1 Pathway and PD-1/PD-L1 Inhibitors

Anti-programmed death protein-1 (PD-1) antibody is an immunotherapy that has been studied at most and clinically developed fastest. PD-1 is expressed in activated T cells, B cells and myeloid cells during the effector phase of immune response. PD-1 has two ligands PD-L1 and PD-L2. Both PD-L1 and PD-L2 are expressed in antigen-presenting cells, and PD-L1 is also expressed in many tissues. Binding of PD-1 to PD-L1 mediates the co-inhibitory signal of T cell activation, inhibits killing of T cells, and negatively regulates the human immune response. Chen Lab (Ethnic Chinese scientist Lieping Chen) first found that PD-L1 is highly expressed in tumor tissues and regulates the tumor-infiltrating CD8+ T cells. Therefore, immune modulation targeting PD-1/PD-L1 has a significance against tumors.

PD-1/PD-L1 inhibitors can specifically bind to PD-L1 on tumor cells to inhibit their expressions so as to restore recognition of tumor cells by suppressed T cells, thereby achieving anti-cancer effects through the autoimmune system.

In recent years, many PD-1/PD-L1 monoclonal antibodies have been studied rapidly in tumor immunotherapy. Currently, the PD-1 inhibitors Pembrolizumab and Nivolumab have been approved for treatment of advanced melanoma, non-small cell lung cancer, Hodgkin lymphoma, and head and neck squamous cell carcinoma by FDA, and Nivolumab has also been approved for the treatment of renal and urothelial cancers by FDA. In addition, monoclonal antibodies such as PD-L1 inhibitors Atezolizumab and Durvalumab have also entered many Phase III clinical studies, covering multiple tumor types such as non-small cell lung cancer, melanoma, bladder cancer, etc.

2. CTLA-4 Inhibitors

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a transmembrane protein expressed on activated T cells. CTLA-4 acts at the initiation phase of the immune response, and its activation inhibits the initiation of the T cell immune response, thus resulting in a decrease in activated T cells and preventing the generation of memory T cells. As shown in studies, tumor cells can activate CTLA-4 and inactivate the activated T cells, thereby realizing immune escape of the tumor itself.

Several preclinical studies showed that blockade of CTLA-4 restores the activity of T cells and prolongs the survival of memory T cells, thereby restoring the body's immune function to tumor cells, resulting in improved tumor control. A specific monoclonal antibody against CTLA-4 has been developed on this basis.

Currently, two CTLA-4 inhibitors, Ipilimumab and Tremelimumab, have been approved for the adjuvant treatment of stage III melanoma and for the treatment of advanced melanoma by the FDA. Clinical studies have been widely conducted for Ipilimumab and Tremelimumab in treatment of renal cell carcinoma, prostate cancer and lung cancer. Results of early clinical studies showed that both monoclonal antibodies demenstrated safety and efficacy, either as monotherapy or in combination with IL-2, PD-1/PD-L1 inhibitors, or chemotherapy.

3. Other Types of Monoclonal Antibodies

Other monoclonal antibodies, such as OX40, CD40, and 4-1BB monoclonal antibodies of the TNF receptor family, are still under development, which enhance the second signaling of T cells to promote activation and proliferation of tumor-specific T cells.

4. Common Adverse Reactions and Management of Immune Checkpoint Blockade

The immune checkpoint blockade therapy relieves the suppression of the immune system by killing tumors by utilizing the body's own immune system, so the immune checkpoint immune-related adverse events involve almost all organs, such as skin (maculopapular rash, vitiligo, psoriasis, Lyell's syndrome, drug-related multiple organ delayed hypersensitivity), gastrointestinal tract (enterocolitis, gastritis, pancreatitis, coeliac disease), endocrine organs (hyperthyroidism or hypothyroidism, hypophysitis, adrenal insufficiency, diabetes), lung (immune pneumonia, pleuritis, pulmonary sarcoma), peripheral and central nervous system (peripheral neuropathy, aseptic meningitis, Guillain-Barre syndrome, cranial neuropathy, myelitis, meningoencephalitis, myasthenia), liver (immune hepatitis), kidney (interstitial nephritis, lupus glomerulonephritis), blood system (hemolytic anemia, thrombocytopenia, granulocytopenia, trilineage hypopenia), musculoarticular system (arthritis, muscle lesions), heart (pericarditis, myocarditis), eyes (uveitis, conjunctivitis, retinitis, choroiditis, blepharitis, periorbital myositis), etc. The resulting toxicity events were different in severity, among which some were mild symptoms and easy to control, and some were severe symptoms and could be life-threatening. The overall incidence of immune-related adverse reactions was lower than that of chemotherapy, the tolerance was good, and the most common treatment-emergent adverse reactions were fatigue, decreased appetite, nausea, weakness, and rash. The overall incidence of serious adverse reactions (Grade 3/4 adverse reactions) was 7-13%. Most adverse reactions were reversible and manageable. Prevention, assessment, examination, treatment and monitoring of immune-related adverse reactions should be performed during immunotherapy to detect the treatment-related adverse reactions in time, adjust the dose and take corticosteroids for corresponding treatment.

(1) Prevention of high-risk populations: personal or family history of autoimmune diseases; tumor diffuse infiltration, such as cancerous lymphangitis, tumor infiltration with peripheral inflammation; opportunistic infections, chronic infections, etc., which have caused T cell exhaustion and apoptosis; certain drugs that are implicated in autoimmune diseases, such as antiarrhythmic drugs, antihypertensives, antibiotics, anticonvulsants, or antipsychotics, etc.

(2) Examination: Symptoms commonly associated with immunotoxicity include skin, gastrointestinal and endocrine symptoms. In addition, neurological, respiratory, rheumatic, hepatopathy, hematological, nephropathy, cardiovascular and ophthalmic symptoms are included. Abnormal immunotoxicity may occur at any time. Abnormal immunotoxicity may be classified as early (< 2 months) and late (> 2 months) toxicities based on the median time to onset. Early toxicities involve skin (5 weeks), gastrointestinal (7.3 weeks), and liver (7.7 weeks), whereas late toxicities involve lung (8.9 weeks), endocrine (10.4 weeks), and kidney (15.1 weeks). Some abnormal immunotoxicity may occur late or even after 1 year of immunotherapy.

(3) Treatment: The side effects of enhancing the T cell immune response are potential autoimmune inflammations in normal tissues. In most cases, these side effects could be controlled with immunomodulatory drugs. Hormones are the best drug to counteract these inflammatory reactions, especially when they progress to severe stages. Other immunomodulatory drugs, such as the anti-TNF-α antibody infliximab, mycophenolate mofetil, tacrolimus, cyclosporine, etc., may also be selected for patients who are unsatisfied with hormonal therapy. Drugs for inhibiting T cell depletion, such as anti-human thymocyte globulin, were reported to be effective in rare cases.

In case of any immune checkpoint blockade-related adverse reactions, please contact healthcare professionals in a timely manner.

(II) Therapeutic Antibodies

Therapeutic antibodies refer to the antibodies synthesized in the laboratory and designed to destroy tumor cells through various pathways, including ADCC, CDC and apoptosis induced directly via antibodies. Currently, numerous therapeutic antibodies have been approved for treatment of tumors in clinical settings. In 1997, Rituximab (Mabthera), the first chimeric antibody against CD20, was approved for marketing by FDA for the treatment of non-Hodgkin lymphoma. In 1998, Trastuzumab (Herceptin), the first humanized anti-Her2 monoclonal antibody, was marketed for the treatment of breast cancer. In 2006, Panitumumab, the first human antibody against epidermal growth factor, was approved for the treatment of colorectal carcinoma. In 2011, Adcetris, a new-generation antibody-drug conjugate (ADC) drug, was approved by FDA. Adcetris is composed of anti-CD30 chimeric antibody Brentuximab, and Auristain E.

(III) Cancer Vaccines

Cancer vaccine refers to a therapy in which tumor antigens are introduced into patients in various forms, such as tumor cells, tumor-associated proteins or polypeptides, genes expressing tumor antigens, etc., to overcome the immunosuppressive state caused by tumors and activate the patient's own immune system, so as to control or eliminate tumors. Cancer vaccines include prophylactic and therapeutic vaccines. Prophylactic vaccines, such as cervical cancer vaccines, can effectively prevent certain oncogenic HPV-associated cervical diseases. 

The first tumor therapeutic vaccine, Sipuleucel-T vaccine (Provenge), was approved by FDA for the treatment of prostate cancer on 29 April 2010.

(IV) Cell Therapy

In the absence of external intervention, there are few T cells that can recognize tumor cells in the human body, accounting for less than 1/100,000. Cell therapy, also known as adoptive T cell transfer (ACT), is an attempt to allow ordinary T cells become T cells capable of recognizing tumor cells by external modifications, thus triggering immune effects on tumor cells.

ACT includes Lymphokine-Activated Killer cells (LAK), Tumor-Infiltrating Lymphocytes (TIL), Natural Killer cells (NK), Cytokine-Induced Killer cells (CIK), Cytotoxic T Lymphocyte (CTL), and genetically modified T cells (CAR-T, TCR-T) according to the course of its development in turn.

(1) TILs are lymphocytes isolated from tumor sites and produced in vitro by cytokines such as IL-2, with phenotype mainly CD4 T cells and CD8 T cells; TILs have some tumor specificity and MHC restriction. Although TILs demonstrated powerful cell proliferative capacity and killing effect in the treatment of melanoma, TILs did not demonstrate the similar efficacy in other tumors.

(2) Immunotherapy-related antibodies of NK cells have been used in the treatment of melanoma, lung cancer and renal cancer. NK cells belong to the innate immune system and, unlike T cells, do not require tumor-specific recognition or clonal amplification before exerting anti-tumor effects. The anti-tumor benefit of NK cells is controlled by a large number of receptors on the cell surface.

(3) CIK cells are NK T cells derived from peripheral blood mononuclear cells induced by anti-CD3 monoclonal antibody and cytokines such as IL-2, IFN-y, and IL-1α in vitro, showing CD3 and CD56 phenotypes, which have both non-MHC restriction and anti-tumor activity of T lymphocytes.

(4) CTL cells are the primary effector cells of specific anti-tumor immunity, and are prepared in the following procedures of isolating tumor cells; modulating tumor cells: introducing B7 genes into tumor cells by direct introduction or reverse transcriptase-mediated transfer, and testing the expression of B7 molecules in tumor cells; inducing CTLs: inducing highly active CTLs by co-culture of modulated tumor cells with effector cells; isolating CTL cells are for clinical treatment.

(5) Latest CAR-T therapy: immunologists collect T cells from the patient's blood, and then genetically engineer the collected T cells to allow specific receptors, called chimeric antigen receptors (CARs), capable of recognizing specific tumor antigens expressed on the T cells; immunologists also couple signaling regions leading to T cell activation in the intracellular domains of the receptors. CAR is a protein receptor that allows T cells to recognize specific proteins (antigens) on the tumor cells, and CAR-expressing T cells recognize and bind tumor antigens, thereby attacking tumor cells. This CAR-expressing T cell is referred to as CAR-T. The designed CAR-T can be cultured and grown in the laboratory. Once there are billions of CAR-T cells, the amplified CAR-T cells will be injected into a patient, and the injected T cells will also proliferate in the patient and kill tumor cells with corresponding specific antigens. CAR-T cell therapy has demonstrated good targeting, killing and durability in clinical trials, providing a new solution for immune cell therapy, and exhibiting tremendous development potential and application prospects. CAR-T drugs that have been approved by FDA include: Kymriah (Tisagenlecleucel, CTL-019) for the treatment of acute lymphoblastic leukemia (ALL) in children and young adults (2 to 25 years of age), and Yescarta (Axicabtagene Ciloleucel, KTE-C10) for the treatment of adult patients with specific types of large B-cell lymphoma who have failed to respond to other therapies or have relapsed after at least 2 prior regimens. So far such therapy has been limited to small-scale clinical trials in which designed immune cells have yielded some significant efficacy in patients with advanced hematologic tumors and are being attempted for solid tumors. Although these preliminary results are encouraging, CAR-T cell therapy remain to be studied in many aspects, such as unique side effects, cytokine release syndrome, etc.

(6) TCR-T cell therapy, like CAR-T therapy, also improves the recognition and attack ability of T cell receptors to specific cancer cell antigens by means of genetic modification. TCR-T is based on the principle of extracting T cells that can kill tumors by restricted antigen recognition from the patient's TILs, obtaining the sequence of T cell receptor (TCR) by gene cloning technique, and then transfecting this gene into more T cells by a vector, so that T cells recognizing the antigen increased thousands times. TCR-T is derived from TCR and therefore recognizes antigens derived from the cell nucleuses, cytoplasms, and membranes. At present, many relevant studies are ongoing, and some of these studies have good prospects.

(V) Small Molecule Inhibitors

Many immunosuppressive molecules exist in the tumor microenvironment, and the immunotherapeutic strategy to improve the tumor immune microenvironment by modulating the functions of these inhibitory molecules has also received attention. Indoleamine- (2,3) -dioxygenase (IDO), which is expressed in tumors, mediates tumor immune escape. IDO on antigen presenting cells such as macrophages and dendritic cells can induce T cell immune tolerance to tumor antigens by inhibiting T cell proliferation. Therefore, IDO inhibitors can regulate the tryptophan content of the tumor microenvironment to avoid inhibition of T cell proliferation in the tumor microenvironment, and become a potential immunotherapeutic target. Many Phase I/II clinical studies have demonstrated that IDO inhibitors could improve the efficacy of PD-1/PD-L1 inhibitors.

(VI) Immune System Modulators

Immune system modulators are one of the earliest methods used in tumor immunotherapy. The immune system modulators are often referred to as active nonspecific immunotherapy, and it could be traced back to the treatment of sarcomas by William Coley using streptococcal cultures as early as in 1892. Immune system modulators include subsequently developed cytokine therapy (IL-2, INF), synthetic molecules, immune adjuvants (BCG), and short peptides (thymofasin). Recently, some scholars have used malaria to treat tumors, which, in fact, took the use of plasmodium-activated inflammatory response, and nonspecific immune effects. However, immune system modulators have a response rate of only 10% as a single agent and are mainly used in some solid tumors, including metastatic renal cancer and malignant melanoma. In the future, investigations may focus on the combination of nonspecific and specific immunotherapies, or the combination of different immune system modulators.