from murine sources. human antibodies have been produced using unmodified human dna. antibody-dependent cell-mediated cytotoxicity. when the fc receptors on natural killer (nk) cells interact with fc regions of antibodies bound to cancer cells, the nk cell releases perforin and granzyme, leading to cancer cell apoptosis. antibody-dependent cell-mediated cytotoxicity (adcc) antibody-dependent cell-mediated cytotoxicity (adcc) requires antibodies to bind to target cell surfaces. antibodies are formed of a binding region (fab) and the fc region that can be detected by immune system cells via their fc surface receptors. fc receptors are found on many immune system cells, including nk cells. when nk cells encounter antibody-coated cells, the latter's fc regions interact with their fc receptors, releasing perforin and granzyme b to kill the tumor cell. examples include rituximab, ofatumumab, elotuzumab, and alemtuzumab. antibodies under development have altered fc regions that have higher affinity for a specific type of fc receptor, fcγriiia, which can dramatically increase effectiveness. complement activation the complement system includes blood proteins that can cause cell death after an antibody binds to the cell surface (the classical complement pathway, among the ways of complement activation). generally, the system deals with foreign pathogens but can be activated with therapeutic antibodies in cancer. the system can be triggered if the antibody is chimeric, humanized, or human; as long as it contains the igg1 fc region. complement can lead to cell death by activation of the membrane attack complex, known as complement-dependent cytotoxicity; enhancement of antibody-dependent cell-mediated cytotoxicity; and cr3-dependent cellular cytotoxicity. complement-dependent cytotoxicity occurs when antibodies bind to the cancer cell surface, the c1 complex binds to these antibodies and subsequently, protein pores are formed in cancer cell membrane. blocking antibody therapies can also function by binding to proteins and physically blocking them from interacting with other proteins. checkpoint inhibitors (ctla-4, pd-1, and pd-l1) operate by this mechanism. briefly, checkpoint inhibitors are proteins that normally help to slow immune responses and prevent the immune system from attacking normal cells. checkpoint inhibitors bind these proteins and prevent them from functioning normally, which increases the activity of the immune system. examples include durvalumab, ipilimumab, nivolumab, and pembrolizumab. fda-approved antibodies cancer immunotherapy:monoclonal antibodies antibody brand name type target approval date approved treatment(s) alemtuzumab campath humanized cd522001b-cell chronic lymphocytic leukemia (cll) atezolizumab tecentriq humanized pd-l1 2016 bladder cancer avelumab bavencio human pd-l1 2017 metastatic merkel cell carcinoma ipilimumab yervoy human ctla4 2011 metastatic melanoma elotuzumab empliciti humanized slamf72015multiple myeloma ofatumumab arzerra human cd20 2009 refractory cll nivolumab opdivo human pd-1 2014 unresectable or metastatic melanoma, squamous non-small cell lung cancer, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, classical hodgkin lymphoma pembrolizumab keytruda humanized pd-1 2014 unresectable or metastatic melanoma, squamous non-small cell lung cancer (nsclc), hodgkin's lymphoma, merkel-cell carcinoma (mcc), primary mediastinal b-cell lymphoma (pmbcl), stomach cancer, cervical cancer rituximab rituxan, mabthera chimeric cd20 1997 non-hodgkin lymphoma durvalumab imfinzi human pd-l1 2017 bladder cancer non-small cell lung cancer alemtuzumab alemtuzumab (campath-1h) is an anti-cd52 humanized igg1 monoclonal antibody indicated for the treatment of fludarabine-refractory chronic lymphocytic leukemia (cll), cutaneous t-cell lymphoma, peripheral t-cell lymphoma and t-cell prolymphocytic leukemia. cd52 is found on >95% of peripheral blood lymphocytes (both t-cells and b-cells) and monocytes, but its function in lymphocytes is unknown. it binds to cd52 and initiates its cytotoxic effect by complement fixation and adcc mechanisms. due to the antibody target (cells of the immune system), common complications of alemtuzumab therapy are infection, toxicity and myelosuppression. durvalumab main article: durvalumab durvalumab (imfinzi) is a human immunoglobulin g1 kappa (igg1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (pd-l1) with the pd-1 and cd80 (b7.1) molecules. durvalumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: have disease progression during or following platinum-containing chemotherapy. have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. on 16 february 2018, the food and drug administration approved durvalumab for patients with unresectable stage iii non-small cell lung cancer (nsclc) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. ipilimumab ipilimumab (yervoy) is a human igg1 antibody that binds the surface protein ctla4. in normal physiology t-cells are activated by two signals: the t-cell receptor binding to an antigen-mhc complex and t-cell surface receptor cd28 binding to cd80 or cd86 proteins. ctla4 binds to cd80 or cd86, preventing the binding of cd28 to these surface proteins and therefore negatively regulates the activation of t-cells. active cytotoxic t-cells are required for the immune system to attack melanoma cells. normally inhibited active melanoma-specific cytotoxic t-cells can produce an effective anti-tumor response. ipilimumab can cause a shift in the ratio of regulatory t-cells to cytotoxic t-cells to increase the anti-tumor response. regulatory t-cells inhibit other t-cells, which may benefit the tumor. nivolumab main article: nivolumabnivolumab is a human igg4 antibody that prevents t-cell inactivation by blocking the binding of programmed cell death 1 ligand 1 or programmed cell death 1 ligand 2 (pd-l1 or pd-l2), a protein expressed by cancer cells, with pd-1, a protein found on the surface of activated t-cells. nivolumab is used in advanced melanoma, metastatic renal cell carcinoma, advanced lung cancer, advanced head and neck cancer, and hodgkin's lymphoma. ofatumumab ofatumumab is a second generation human igg1 antibody that binds to cd20. it is used in the treatment of chronic lymphocytic leukemia (cll) because the cancerous cells of cll are usually cd20-expressing b-cells. unlike rituximab, which binds to a large loop of the cd20 protein, ofatumumab binds to a separate, small loop. this may explain their different characteristics. compared to rituximab, ofatumumab induces complement-dependent cytotoxicity at a lower dose with less immunogenicity. pembrolizumab as of 2019, pembrolizumab, which blocks pd-1, programmed cell death protein 1, has been used via intravenous infusion to treat inoperable or metastatic melanoma, metastatic non-small cell lung cancer (nsclc) in certain situations, as a second-line treatment for head and neck squamous cell carcinoma (hnscc), after platinum-based chemotherapy, and for the treatment of adult and pediatric patients with refractory classic hodgkin's lymphoma (chl). it is also indicated for certain patients with urothelial carcinoma, stomach cancer and cervical cancer. rituximab rituximab is a chimeric monoclonal igg1 antibody specific for cd20, developed from its parent antibody ibritumomab. as with ibritumomab, rituximab targets cd20, making it effective in treating certain b-cell malignancies. these include aggressive and indolent lymphomas such as diffuse large b-cell lymphoma and follicular lymphoma and leukemias such as b-cell chronic lymphocytic leukemia. although the function of cd20 is relatively unknown, cd20 may be a calcium channel involved in b-cell activation. the antibody's mode of action is primarily through the induction of adcc and complement-mediated cytotoxicity. other mechanisms include apoptosis and cellular growth arrest. rituximab also increases the sensitivity of cancerous b-cells to chemotherapy. cytokine therapy cytokines are proteins produced by many types of cells present within a tumor. they can modulate immune responses. the tumor often employs them to allow it to grow and reduce the immune response. these immune-modulating effects allow them to be used as drugs to provoke an immune response. two commonly used cytokines are interferons and interleukins. interleukin-2 and interferon-α are cytokines, proteins that regulate and coordinate the behavior of the immune system. they have the ability to enhance anti-tumor activity and thus can be used as passive cancer treatments. interferon-α is used in the treatment of hairy-cell leukaemia, aids-related kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and malignant melanoma. interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. interferon interferons are produced by the immune system. they are usually involved in anti-viral response, but also have use for cancer. they fall in three groups: type i (ifnα and ifnβ), type ii (ifnγ) and type iii (ifnλ). ifnα has been approved for use in hairy-cell leukaemia, aids-related kaposi's sarcoma, follicular lymphoma, chronic myeloid leukaemia and melanoma. type i and ii ifns have been researched extensively and although both types promote anti-tumor immune system effects, only type i ifns have been shown to be clinically effective. ifnλ shows promise for its anti-tumor effects in animal models. unlike type i ifns, interferon gamma is not approved yet for the treatment of any cancer. however, improved survival was observed when interferon gamma was administrated to patients with bladder carcinoma and melanoma cancers. the most promising result was achieved in patients with stage 2 and 3 of ovarian carcinoma. the in vitro study of ifn-gamma in cancer cells is more extensive and results indicate anti-proliferative activity of ifn-gamma leading to the growth inhibition or cell death, generally induced by apoptosis but sometimes by autophagy. interleukin interleukins have an array of immune system effects. interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. in normal physiology it promotes both effector t cells and t-regulatory cells, but its exact mechanism of action is unknown. combination immunotherapy combining various immunotherapies such as pd1 and ctla4 inhibitors can enhance anti-tumor response leading to durable responses. combining ablation therapy of tumors with immunotherapy enhances the immunostimulating response and has synergistic effects for curative metastatic cancer treatment. combining checkpoint immunotherapies with pharmaceutical agents has the potential to improve response, and such combination therapies are a highly investigated area of clinical investigation. immunostimulatory drugs such as csf-1r inhibitors and tlr agonists have been particularly effective in this setting. polysaccharide-k japan's ministry of health, labour and welfare approved the use of polysaccharide-k extracted from the mushroom, coriolus versicolor, in the 1980s, to stimulate the immune systems of patients undergoing chemotherapy. it is a dietary supplement in the us and other jurisdictions. genetic pre-testing for therapeutic significance because of the high cost of many of immunotherapy medications and the reluctance of medical insurance companies to prepay for their prescriptions various test methods have been proposed, to attempt to forecast the effectiveness of these medications. the detection of pd-l1 protein seemed to be an indication of cancer susceptible to several immunotherapy medications, but research found that both the lack of this protein or its inclusion in the cancerous tissue was inconclusive, due to the little-understood varying quantities of the protein during different times and locations within the infected cells and tissue. in 2018 some genetic indications such as tumor mutational burden (tmb, the number of mutations within a targeted genetic region in the cancerous cell's dna), and microsatellite instability (msi, the quantity of impaired dna mismatch leading to probable mutations), have been approved by the fda as good indicators for the probability of effective treatment of immunotherapy medication for certain cancers, but research is still in progress. the patient prioritization for immunotherapy based on tmb is still highly controversial. in some cases the fda has approved genetic tests for medication that is specific to certain genetic markers. for example, the fda approved braf associated medication for metastatic melanoma, to be administered to patients after testing for the braf genetic mutation. tests of this sort are being widely advertised for general cancer treatment and are expensive. in the past, some genetic testing for cancer treatment has been involved in scams such as the duke university cancer fraud scandal, or claimed to be hoaxes. research adoptive t-cell therapy cancer specific t-cells can be obtained by fragmentation and isolation of tumour infiltrating lymphocytes, or by genetically engineering cells from peripheral blood. the cells are activated and grown prior to transfusion into the recipient (tumor bearer). adoptive t cell therapy is a form of passive immunization by the transfusion of t-cells (adoptive cell transfer). they are found in blood and tissue and usually activate when they find foreign pathogens. specifically they activate when the t-cell's surface receptors encounter cells that display parts of foreign proteins on their surface antigens. these can be either infected cells, or antigen-presenting cells (apcs). they are found in normal tissue and in tumor tissue, where they are known as tumor infiltrating lymphocytes (tils). they are activated by the presence of apcs such as dendritic cells that present tumor antigens. although these cells can attack the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumour death. multiple ways of producing and obtaining tumour targeted t-cells have been developed. t-cells specific to a tumor antigen can be removed from a tumor sample (tils) or filtered from blood. subsequent activation and culturing is performed ex vivo, with the results