reinfused. activation can take place through gene therapy, or by exposing the t cells to tumor antigens. as of 2014, multiple act clinical trials were underway. importantly, one study from 2018 showed that clinical responses can be obtained in patients with metastatic melanoma resistant to multiple previous immunotherapies. the first 2 adoptive t-cell therapies, tisagenlecleucel and axicabtagene ciloleucel, were approved by the fda in 2017. another approach is adoptive transfer of haploidentical γδ t cells or nk cells from a healthy donor. the major advantage of this approach is that these cells do not cause gvhd. the disadvantage is frequently impaired function of the transferred cells. anti-cd47 therapy many tumor cells overexpress cd47 to escape immunosurveilance of host immune system. cd47 binds to its receptor signal-regulatory protein alpha (sirpα) and downregulate phagocytosis of tumor cell. therefore, anti-cd47 therapy aims to restore clearance of tumor cells. additionally, growing evidence supports the employment of tumor antigen-specific t cell response in response to anti-cd47 therapy. a number of therapeutics are being developed, including anti-cd47 antibodies, engineered decoy receptors, anti-sirpα antibodies and bispecific agents. as of 2017, wide range of solid and hematologic malignancies were being clinically tested. anti-gd2 antibodies the gd2 ganglioside carbohydrate antigens on the surface of cells can be used as targets for immunotherapy. gd2 is a ganglioside found on the surface of many types of cancer cell including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, ewing's sarcoma, liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas. it is not usually expressed on the surface of normal tissues, making it a good target for immunotherapy. as of 2014, clinical trials were underway. immune checkpoints main articles: immune checkpoint and immunotherapy immune checkpoints in the tumour microenvironment cancer therapy by inhibition of negative immune regulation (ctla4, pd1) immune checkpoints affect the immune system function. immune checkpoints can be stimulatory or inhibitory. tumors can use these checkpoints to protect themselves from immune system attacks. currently approved checkpoint therapies block inhibitory checkpoint receptors. blockade of negative feedback signaling to immune cells thus results in an enhanced immune response against tumors. immune checkpoint blockade therapies have varied effectiveness. in hodgkin lymphoma and natural killer t-cell lymphoma, response rates are high, at 50–60%. response rates are quite low for breast and prostate cancers, however. one ligand-receptor interaction under investigation is the interaction between the transmembrane programmed cell death 1 protein (pdcd1, pd-1; also known as cd279) and its ligand, pd-1 ligand 1 (pd-l1, cd274). pd-l1 on the cell surface binds to pd1 on an immune cell surface, which inhibits immune cell activity. among pd-l1 functions is a key regulatory role on t cell activities. it appears that (cancer-mediated) upregulation of pd-l1 on the cell surface may inhibit t cells that might otherwise attack. pd-l1 on cancer cells also inhibits fas- and interferon-dependent apoptosis, protecting cells from cytotoxic molecules produced by t cells. antibodies that bind to either pd-1 or pd-l1 and therefore block the interaction may allow the t-cells to attack the tumor. ctla-4 blockade the first checkpoint antibody approved by the fda was ipilimumab, approved in 2011 for the treatment of melanoma. it blocks the immune checkpoint molecule ctla-4. clinical trials have also shown some benefits of anti-ctla-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs. in on-going trials the combination of ctla-4 blockade with pd-1 or pd-l1 inhibitors is tested on different types of cancer. however, patients treated with checkpoint blockade (specifically ctla-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of having immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions. these are most likely due to the breadth of the induced t-cell activation when anti-ctla-4 antibodies are administered by injection in the bloodstream. using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-ctla-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood. at the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-ctla-4 therapy might result in fewer adverse events. pd-1 inhibitors main article: pd-1 and pd-l1 inhibitors initial clinical trial results with igg4 pd1 antibody nivolumab were published in 2010. it was approved in 2014. nivolumab is approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and hodgkin's lymphoma. a 2016 clinical trial for non-small cell lung cancer failed to meet its primary endpoint for treatment in the first line setting, but is fda approved in subsequent lines of therapy. pembrolizumab (keytruda) is another pd1 inhibitor that was approved by the fda in 2014. pembrolizumab is approved to treat melanoma and lung cancer. antibody bgb-a317 is a pd-1 inhibitor (designed to not bind fc gamma receptor i) in early clinical trials. pd-l1 inhibitors main article: pd-1 and pd-l1 inhibitors in may 2016, pd-l1 inhibitor atezolizumab was approved for treating bladder cancer. anti-pd-l1 antibodies currently in development include avelumab and durvalumab, in addition to an inhibitory affimer. cish other modes of enhancing immuno-therapy include targeting so-called intrinsic checkpoint blockades e.g. cish. many cancer patients do not respond to immune checkpoint blockade. response rate may be improved by combining immune checkpoint blockade with additional rationally selected anticancer therapies, including those that stimulate t cell infiltration. for example, targeted therapies such as radiotherapy, vasculature targeting agents, and immunogenic chemotherapy can improve immune checkpoint blockade response in animal models. oncolytic virus an oncolytic virus is a virus that preferentially infects and kills cancer cells. as the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune responses for long-term immunotherapy. the potential of viruses as anti-cancer agents was first realized in the early twentieth century, although coordinated research efforts did not begin until the 1960s. a number of viruses including adenovirus, reovirus, measles, herpes simplex, newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents. t-vec is the first fda-approved oncolytic virus for the treatment of melanoma. a number of other oncolytic viruses are in phase ii-iii development. polysaccharides certain compounds found in mushrooms, primarily polysaccharides, can up-regulate the immune system and may have anti-cancer properties. for example, beta-glucans such as lentinan have been shown in laboratory studies to stimulate macrophage, nk cells, t cells and immune system cytokines and have been investigated in clinical trials as immunologic adjuvants. neoantigens main article: neoantigenmany tumors express mutations. these mutations potentially create new targetable antigens (neoantigens) for use in t-cell immunotherapy. the presence of cd8+ t cells in cancer lesions, as identified using rna sequencing data, is higher in tumors with a high mutational burden. the level of transcripts associated with the cytolytic activity of natural killer cells and t cells positively correlates with mutational load in many human tumors. in non–small cell lung cancer patients treated with lambrolizumab, mutational load shows a strong correlation with clinical response. in melanoma patients treated with ipilimumab, the long-term benefit is also associated with a higher mutational load, although less significantly. the predicted mhc binding neoantigens in patients with a long-term clinical benefit were enriched for a series of tetrapeptide motifs that were not found in tumors of patients with no or minimal clinical benefit. however, human neoantigens identified in other studies do not show the bias toward tetrapeptide signatures.