cancer immunotherapy cancer immunotherapy cancer immunotherapy (sometimes called immuno-oncology) is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. it is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology. cancer immunotherapypeptide epitope of cd20 bound to rituximab's fabspecialtyimmuno-oncology cancer immunotherapy exploits the fact that cancer cells often have tumor antigens, molecules on their surface that can be detected by the antibody proteins of the immune system, binding to them. the tumor antigens are often proteins or other macromolecules (e.g., carbohydrates). normal antibodies bind to external pathogens, but the modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill. clinical success of cancer immunotherapy is highly variable between different forms of cancer; for instance, certain subtypes of gastric cancer react well to the approach whereas immunotherapy is not effective for other subtypes. in 2018, american immunologist james p. allison and japanese immunologist tasuku honjo received the nobel prize in physiology or medicine for their discovery of cancer therapy by inhibition of negative immune regulation. history "during the 17th and 18th centuries, various forms of immunotherapy in cancer became widespread... in the 18th and 19th centuries, septic dressings enclosing ulcerative tumours were used for the treatment of cancer. surgical wounds were left open to facilitate the development of infection, and purulent sores were created deliberately... one of the most well-known effects of microorganisms on ... cancer was reported in 1891, when an american surgeon, william coley, inoculated patients having inoperable tumours with ." "coley thoroughly reviewed the literature available at that time and found 38 reports of cancer patients with accidental or iatrogenic feverish erysipelas. in 12 patients, the sarcoma or carcinoma had completely disappeared; the others had substantially improved. coley decided to attempt the therapeutic use of iatrogenic erysipelas..." "coley developed a toxin that contained heat-killed bacteria . until 1963, this treatment was used for the treatment of sarcoma." "coley injected more than 1000 cancer patients with bacteria or bacterial products." 51.9% of patients with inoperable soft-tissue sarcomas showed complete tumour regression and survived for more than 5 years, and 21.2% of the patients had no clinical evidence of tumour at least 20 years after this treatment..." research continued in the 20th century under maria o'connor hornung at tulane medical school categories immunotherapies can be categorized as active or passive. active immunotherapy specifically targets tumor cells via the immune system. examples include therapeutic cancer vaccines (also known as treatment vaccines, which are designed to boost the body's immune system to fight cancer), car-t cell, and targeted antibody therapies. in contrast, passive immunotherapy does not directly target tumor cells, but enhances the ability of the immune system to attack cancer cells. examples include checkpoint inhibitors and cytokines. active cellular therapies aim to destroy cancer cells by recognition of distinct markers known as antigens. in cancer vaccines, the goal is to generate an immune response to these antigens through a vaccine. currently, only one vaccine (sipuleucel-t for prostate cancer) has been approved. in cell-mediated therapies like car-t cell therapy, immune cells are extracted from the patient, genetically engineered to recognize tumor-specific antigens, and returned to the patient. cell types that can be used in this way are natural killer (nk) cells, lymphokine-activated killer cells, cytotoxic t cells and dendritic cells. finally, specific antibodies can be developed that recognize cancer cells and target them for destruction by the immune system. examples of such antibodies include rituximab (targeting cd-20), trastuzumab (targeting her-2), and cetuximab (targeting egfr). passive antibody therapies aim to increase the activity of the immune system without specifically targeting cancer cells. for example, cytokines directly stimulate the immune system and increase immune activity. checkpoint inhibitors target proteins (immune checkpoints) that normally dampen the immune response. this enhances the ability of the immune system to attack cancer cells. current research is identifying new potential targets to enhance immune function. approved checkpoint inhibitors include antibodies such as ipilimumab, nivolumab, and pembrolizumab. cellular immunotherapy dendritic cell therapy blood cells are removed from the body, incubated with tumour antigen(s) and activated. mature dendritic cells are then returned to the original cancer-bearing donor to induce an immune response. dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. dendritic cells are antigen-presenting cells (apcs) in the mammalian immune system. in cancer treatment they aid cancer antigen targeting. the only approved cellular cancer therapy based on dendritic cells is sipuleucel-t. one method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates or short peptides (small parts of protein that correspond to the protein antigens on cancer cells). these peptides are often given in combination with adjuvants (highly immunogenic substances) to increase the immune and anti-tumor responses. other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte macrophage colony-stimulating factor (gm-csf). the most common source of antigens used for dendritic cell vaccine in glioblastoma (gbm) as an aggressive brain tumor were whole tumor lysate, cmv antigen rna and tumor-associated peptides like egfrviii. dendritic cells can also be activated in vivo by making tumor cells express gm-csf. this can be achieved by either genetically engineering tumor cells to produce gm-csf or by infecting tumor cells with an oncolytic virus that expresses gm-csf. another strategy is to remove dendritic cells from the blood of a patient and activate them outside the body. the dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate (a solution of broken down tumor cells). these cells (with optional adjuvants) are infused and provoke an immune response. dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. dendritic cell receptors such as tlr3, tlr7, tlr8 or cd40 have been used as antibody targets. dendritic cell-nk cell interface also has an important role in immunotherapy. the design of new dendritic cell-based vaccination strategies should also encompass nk cell-stimulating potency. it is critical to systematically incorporate nk cells monitoring as an outcome in antitumor dc-based clinical trials. drugs sipuleucel-t (provenge) was approved for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer in 2010. the treatment consists of removal of antigen-presenting cells from blood by leukapheresis and growing them with the fusion protein pa2024 made from gm-csf and prostate-specific prostatic acid phosphatase (pap) and reinfused. this process is repeated three times. car-t cell therapy main article: chimeric antigen receptor the premise of car-t immunotherapy is to modify t cells to recognize cancer cells in order to target and destroy them. scientists harvest t cells from people, genetically alter them to add a chimeric antigen receptor (car) that specifically recognizes cancer cells, then infuse the resulting car-t cells into patients to attack their tumors. approved drugs tisagenlecleucel (kymriah), a chimeric antigen receptor (car-t) therapy, was approved by fda in 2017 to treat acute lymphoblastic leukemia (all). this treatment removes cd19 positive cells (b-cells) from the body (including the diseased cells, but also normal antibody-producing cells). axicabtagene ciloleucel (yescarta) is another car-t therapeutic, approved in 2017 for treatment of diffuse large b-cell lymphoma (dlbcl). t cell receptor t cell therapy main article: t cell receptor t cell therapy tcr-t therapies use heterodimers made of alpha and beta peptide chains to recognize mhc-presented polypeptide fragments molecules. unlike car-t's cell surface antigens, tcr-t can recognize that larger set of intracellular antigen fragments. however, tcr-t cell therapy depends on mhc molecules, limiting its usefulness. multifunctional alginate scaffolds for t cell engineering and release multifunctional alginate scaffolds for t cell engineering and release (master) is a technique for in situ engineering, replication and release of genetically engineered t cells. it is an evolution of car t cell therapy. t cells are extracted from the patient and mixed with a genetically engineered virus that contains a cancer targeting gene (as with car t). the mixture is then added to a master (scaffold), which absorbs them. the master contains antibodies that activate the t cells and interleukins that trigger cell proliferation. the master is then implanted into the patient. the activated t cells interact with the viruses to become car t cells. the interleukins stimulate these car t cells to proliferate, and the car t cells exit the master to attack the cancer. the technique takes hours instead of weeks. and because the cells are younger, they last longer in the body, show stronger potency against cancer, and display fewer markers of exhaustion. these features were demonstrated in mouse models. the treatment was more effective and longer lasting against lymphoma. antibody therapy many forms of antibodies can be engineered. main article: monoclonal antibody therapy antibodies are a key component of the adaptive immune response, playing a central role in both recognizing foreign antigens and stimulating an immune response. antibodies are y-shaped proteins produced by some b cells and are composed of two regions: an antigen-binding fragment (fab), which binds to antigens, and a fragment crystallizable (fc) region, which interacts with so-called fc receptors that are expressed on the surface of different immune cell types including macrophages, neutrophils and nk cells. many immunotherapeutic regimens involve antibodies. monoclonal antibody technology engineers and generates antibodies against specific antigens, such as those present on tumor surfaces. these antibodies which are specific to the antigens of the tumor can then be injected into a tumor. conjugation two types are used in cancer treatments: naked monoclonal antibodies are antibodies without added elements. most antibody therapies use this antibody type. conjugated monoclonal antibodies are joined to another molecule, which is either cytotoxic or radioactive. the toxic chemicals are those typically used as chemotherapy drugs, but other toxins can be used. the antibody binds to specific antigens on cancer cell surfaces, directing the therapy to the tumor. radioactive compound-linked antibodies are referred to as radiolabelled. chemolabelled or immunotoxins antibodies are tagged with chemotherapeutic molecules or toxins, respectively. research has also demonstrated conjugation of a tlr agonist to an anti-tumor monoclonal antibody. fc regions fc's ability to bind fc receptors is important because it allows antibodies to activate the immune system. fc regions are varied: they exist in numerous subtypes and can be further modified, for example with the addition of sugars in a process called glycosylation. changes in the fc region can alter an antibody's ability to engage fc receptors and, by extension, will determine the type of immune response that the antibody triggers. for example, immune checkpoint blockers targeting pd-1 are antibodies designed to bind pd-1 expressed by t cells and reactivate these cells to eliminate tumors. anti-pd-1 drugs contain not only a fab region that binds pd-1 but also an fc region. experimental work indicates that the fc portion of cancer immunotherapy drugs can affect the outcome of treatment. for example, anti-pd-1 drugs with fc regions that bind inhibitory fc receptors can have decreased therapeutic efficacy. imaging studies have further shown that the fc region of anti-pd-1 drugs can bind fc receptors expressed by tumor-associated macrophages. this process removes the drugs from their intended targets (i.e. pd-1 molecules expressed on the surface of t cells) and limits therapeutic efficacy. furthermore, antibodies targeting the co-stimulatory protein cd40 require engagement with selective fc receptors for optimal therapeutic efficacy. together, these studies underscore the importance of fc status in antibody-based immune checkpoint targeting strategies. human/non-human antibodies antibodies can come from a variety of sources, including human cells, mice, and a combination of the two (chimeric antibodies). different sources of antibodies can provoke different kinds of immune responses. for example, the human immune system can recognize mouse antibodies (also known as murine antibodies) and trigger an immune response against them. this could reduce the effectiveness of the antibodies as a treatment and cause an immune reaction. chimeric antibodies attempt to reduce murine antibodies' immunogenicity by replacing part of the antibody with the corresponding human counterpart. humanized antibodies are almost completely human; only the complementarity determining regions of the variable regions are derived