cancer immunotherapy

"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 [ Streptococcus pyogenes ]."{{cite journal | vauthors = Kucerova P, Cervinkova M | title = Spontaneous regression of tumour and the role of microbial infection--possibilities for cancer treatment | journal = Anti-Cancer Drugs | volume = 27 | issue = 4 | pages = 269–77 | date = April 2016 | pmid = 26813865 | pmc = 4777220 | doi = 10.1097/CAD.0000000000000337 }} "Coley [had] 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..."{{cite journal | vauthors = Kienle GS | title = Fever in Cancer Treatment: Coley's Therapy and Epidemiologic Observations | journal = Global Advances in Health and Medicine | volume = 1 | issue = 1 | pages = 92–100 | date = March 2012 | pmid = 24278806 | pmc = 3833486 | doi = 10.7453/gahmj.2012.1.1.016 }} "Coley developed a toxin that contained heat-killed bacteria [ Streptococcus pyogenes and Serratia marcescens ]. Until 1963, this treatment was used for the treatment of sarcoma." "Coley injected more than 1000 cancer patients with bacteria or bacterial products."{{cite journal | vauthors = McCarthy EF | title = The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas | journal = The Iowa Orthopaedic Journal | volume = 26 | pages = 154–8 | date = 2006 | pmid = 16789469 | pmc = 1888599 }} 51.9% of [Coley's] 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.{{Cite book|url=https://books.google.com/books?id=Z5QgAQAAMAAJ|title=Dissertation Abstracts International: Retrospective Index, Volumes I-XXIX.|date=1970|publisher=University Microfilms|language=en}}{{Cite news|title=Commencement speakers praise, advise local graduates . . .|language=en-US|newspaper=Washington Post|url=https://www.washingtonpost.com/archive/local/1977/06/16/commencement-speakers-praise-advise-local-graduates/7c57014b-90c9-4749-a9f0-8cd7dcf5ffd6/|access-date=2021-07-09|issn=0190-8286}}

In the 1980's, researchers at the National Cancer Institute's Center for Cancer Research (CCR) began exploring the then-heretical idea that a patient’s immune system could be harnessed to fight cancer. These researchers included Michael Potter, Ira Pastan, and Steven Rosenberg who developed approaches including monoclonal antibody-based immunotoxins, checkpoint blockade drugs, cytokine-based therapies, and adoptive cell therapy studies.{{cite web |title=Development of Cancer Immunotherapy |url=https://ccr.cancer.gov/news/landmarks/article/development-of-cancer-immunotherapy |publisher=National Cancer Institute |access-date=3 February 2025}}

There are several types of immunotherapy used to treat cancer:{{cite web |title=Immunotherapy to Treat Cancer |url=https://www.cancer.gov/about-cancer/treatment/types/immunotherapy |publisher=National Cancer Institute |access-date=14 October 2023 |date=24 September 2019}}{{Cite web |title=Immunotherapy for Cancer: An Overview |url=https://oncodaily.com/oncolibrary/immune-oncology/67103.html |archive-date= |access-date=29 May 2024 |website=Oncodaily.com|date=29 May 2024 }}

• Immune checkpoint inhibitors: drugs that block immune system checkpoints to allow immune cells to respond more strongly to the cancer.
• T-cell transfer therapy: a treatment that takes T-cells from the tumor and selects or changes them in the lab to better attack cancer cells, then reintroduces them into the patient.
• Monoclonal antibodies: designed to bind to specific targets on cancer cells, marking cancer cells so that they will be better seen and destroyed by the immune system.
• Treatment vaccines: also known as therapeutic cancer vaccines, help the immune system learn to recognize and react to mutant proteins specific to the tumor and destroy cancer cells containing them.
• Immune system modulators: agents that enhance the body’s immune response against cancer.

Immunotherapies can be categorized as active or passive based on their ability to engage the host immune system against cancer.{{cite journal | vauthors = Galluzzi L, Vacchelli E, Bravo-San Pedro JM, Buqué A, Senovilla L, Baracco EE, Bloy N, Castoldi F, Abastado JP, Agostinis P, Apte RN, Aranda F, Ayyoub M, Beckhove P, Blay JY, Bracci L, Caignard A, Castelli C, Cavallo F, Celis E, Cerundolo V, Clayton A, Colombo MP, Coussens L, Dhodapkar MV, Eggermont AM, Fearon DT, Fridman WH, Fučíková J, Gabrilovich DI, Galon J, Garg A, Ghiringhelli F, Giaccone G, Gilboa E, Gnjatic S, Hoos A, Hosmalin A, Jäger D, Kalinski P, Kärre K, Kepp O, Kiessling R, Kirkwood JM, Klein E, Knuth A, Lewis CE, Liblau R, Lotze MT, Lugli E, Mach JP, Mattei F, Mavilio D, Melero I, Melief CJ, Mittendorf EA, Moretta L, Odunsi A, Okada H, Palucka AK, Peter ME, Pienta KJ, Porgador A, Prendergast GC, Rabinovich GA, Restifo NP, Rizvi N, Sautès-Fridman C, Schreiber H, Seliger B, Shiku H, Silva-Santos B, Smyth MJ, Speiser DE, Spisek R, Srivastava PK, Talmadge JE, Tartour E, Van Der Burg SH, Van Den Eynde BJ, Vile R, Wagner H, Weber JS, Whiteside TL, Wolchok JD, Zitvogel L, Zou W, Kroemer G | title = Classification of current anticancer immunotherapies | journal = Oncotarget | volume = 5 | issue = 24 | pages = 12472–12508 | date = December 2014 | pmid = 25537519 | pmc = 4350348 | doi = 10.18632/oncotarget.2998 }}{{cite web |title=Types of Biological Therapy |url=https://training.seer.cancer.gov/treatment/biotherapy/types.html |website=SEER Training Modules |publisher=National Cancer Institute |access-date=14 October 2023}} Active immunotherapy specifically targets tumor cells via the immune system. Examples include therapeutic cancer vaccines (also known as treatment vaccines,{{Cite web|date=2013-09-30|title=What are Cancer Vaccines?|url=https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/what-are-cancer-vaccines|access-date=2021-08-15|website=Cancer.Net|language=en}} which are designed to boost the body's immune system to fight cancer), CAR-T cells, 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.

File:Dendritic_cell_therapy.png

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.{{cite journal | vauthors = Riddell SR | title = Progress in cancer vaccines by enhanced self-presentation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 16 | pages = 8933–35 | date = July 2001 | pmid = 11481463 | pmc = 55350 | doi = 10.1073/pnas.171326398 | bibcode = 2001PNAS...98.8933R | doi-access = free }} In cancer treatment, they aid cancer antigen targeting.{{cite journal | vauthors = Palucka K, Banchereau J|author-link2=Jacques Banchereau | title = Dendritic-cell-based therapeutic cancer vaccines | journal = Immunity | volume = 39 | issue = 1 | pages = 38–48 | date = July 2013 | pmid = 23890062 | pmc = 3788678 | doi = 10.1016/j.immuni.2013.07.004 }} 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{{cite journal | vauthors = Hirayama M, Nishimura Y | title = The present status and future prospects of peptide-based cancer vaccines | journal = International Immunology | volume = 28 | issue = 7 | pages = 319–28 | date = July 2016 | pmid = 27235694 | doi = 10.1093/intimm/dxw027 | doi-access = free }} or short peptides (small parts of the 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 sources 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.{{cite book | vauthors = Dastmalchi F, Karachi A, Mitchell D |chapter=Dendritic Cell Therapy |title=eLS |pages=1–27 |publisher=American Cancer Society |doi=10.1002/9780470015902.a0024243 |isbn=9780470015902 | date = June 2018 |s2cid=155185753 }}

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.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

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.{{cite journal | vauthors = Gardner TA, Elzey BD, Hahn NM | title = Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer | journal = Human Vaccines & Immunotherapeutics | volume = 8 | issue = 4 | pages = 534–39 | date = April 2012 | pmid = 22832254 | doi = 10.4161/hv.19795 | doi-access = free }}{{cite journal | vauthors = Oudard S | title = Progress in emerging therapies for advanced prostate cancer | journal = Cancer Treatment Reviews | volume = 39 | issue = 3 | pages = 275–89 | date = May 2013 | pmid = 23107383 | doi = 10.1016/j.ctrv.2012.09.005 }}{{cite journal | vauthors = Sims RB | title = Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate-resistant prostate cancer | journal = Vaccine | volume = 30 | issue = 29 | pages = 4394–97 | date = June 2012 | pmid = 22122856 | doi = 10.1016/j.vaccine.2011.11.058 | doi-access = free }}{{cite journal | vauthors = Shore ND, Mantz CA, Dosoretz DE, Fernandez E, Myslicki FA, McCoy C, Finkelstein SE, Fishman MN | title = Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer | journal = Cancer Control | volume = 20 | issue = 1 | pages = 7–16 | date = January 2013 | pmid = 23302902 | doi = 10.1177/107327481302000103 | doi-access = free }}

File:Adoptive_T-cell_therapy.png{{Main|Adoptive cell transfer}}

Adoptive T cell therapy is a form of passive immunization by the transfusion of T-cells. They are found in blood and tissue and typically activate when they find foreign pathogens. Activation occurs when the T-cell's surface receptors encounter cells that display parts of foreign proteins (either on their surface or intracellularly). These can be either infected cells or other antigen-presenting cells (APCs). The latter 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 tumors, the tumor microenvironment is highly immunosuppressive, interfering with immune-mediated tumour death.{{cite journal | vauthors = Restifo NP, Dudley ME, Rosenberg SA | title = Adoptive immunotherapy for cancer: harnessing the T cell response | journal = Nature Reviews. Immunology | volume = 12 | issue = 4 | pages = 269–81 | date = March 2012 | pmid = 22437939 | pmc = 6292222 | doi = 10.1038/nri3191 }}

Multiple ways of producing tumour-destroying T-cells have been developed. Most commonly, T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. The T-cells can optionally be modified in various ways, cultured and infused into patients. T cells can be modified via genetic engineering, producing CAR-T cell or TCR T cells or by exposing the T cells to tumor antigens in a non-immunosuppressive environment, that they recognize as foreign and learn to attack.

Another approach is transfer of haploidentical γδ T cells or natural killer cells from a healthy donor.{{cite journal | vauthors = Barros MS, de Araújo ND, Magalhães-Gama F, Pereira Ribeiro TL, Alves Hanna FS, Tarragô AM, Malheiro A, Costa AG | title = γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends | journal = Frontiers in Immunology | volume = 12 | pages = 729085 | date = 22 September 2021 | pmid = 34630403 | doi = 10.3389/fimmu.2021.729085 | pmc = 8493128 | doi-access = free }} The major advantage of this approach is that these cells do not cause graft-versus-host disease. The disadvantage is that transferred cells frequently have impaired function.{{cite journal | vauthors = Wilhelm M, Smetak M, Schaefer-Eckart K, Kimmel B, Birkmann J, Einsele H, Kunzmann V | title = Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells | journal = Journal of Translational Medicine | volume = 12 | pages = 45 | date = February 2014 | pmid = 24528541 | pmc = 3926263 | doi = 10.1186/1479-5876-12-45 | doi-access = free }}

The simplest example involves removing TILs from a tumor, culturing but not modifying them, and infusing the result back into the tumour. The first therapy of this type, Lifileucel, achieved US Food and Drug Administration (FDA) approval in February 2024.

{{main|Chimeric antigen receptor T cell}}

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.

Tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR-T) therapy, was approved by the FDA in 2017 to treat acute lymphoblastic leukemia (ALL).{{Cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm|title=Press Announcements – FDA approval brings first gene therapy to the United States | author = Office of the Commissioner|website=fda.gov|access-date=13 December 2017}} 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).{{cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm581216.htm|title=FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma|publisher=fda.gov|date=18 October 2017|access-date=8 November 2017}}

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.{{Cite web | vauthors = Irving M |date=2022-03-29 |title=Implantable immunotherapy "factory" fights cancer faster, more effectively |url=https://newatlas.com/medical/cancer-immunotherapy-master-implant-car-t-cells/ |access-date=2022-03-29 |website=New Atlas |language=en-US}}{{cite journal | vauthors = Agarwalla P, Ogunnaike EA, Ahn S, Froehlich KA, Jansson A, Ligler FS, Dotti G, Brudno Y | title = Bioinstructive implantable scaffolds for rapid in vivo manufacture and release of CAR-T cells | journal = Nature Biotechnology | pages = 1250–1258 | date = March 2022 | volume = 40 | issue = 8 | pmid = 35332339 | doi = 10.1038/s41587-022-01245-x | pmc = 9376243 }}

{{Excerpt|T cell receptor T cell therapy}}

File:Engineered_monoclonal_antibodies.svg

{{excerpt|Monoclonal antibody therapy|paragraphs=1|this=This paragraph is}}

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.{{cite journal | vauthors = Gadd AJ, Greco F, Cobb AJ, Edwards AD | title = Targeted Activation of Toll-Like Receptors: Conjugation of a Toll-Like Receptor 7 Agonist to a Monoclonal Antibody Maintains Antigen Binding and Specificity | language = en | journal = Bioconjugate Chemistry | volume = 26 | issue = 8 | pages = 1743–52 | date = August 2015 | pmid = 26133029 | doi = 10.1021/acs.bioconjchem.5b00302 | s2cid = 26307107 | url = http://centaur.reading.ac.uk/41984/1/TLR7-Ritux%20conjug%20Revised%20FINAL%20CentAUR.pdf | quote = We demonstrate here for the first time the successful conjugation of a small molecule TLR7 agonist to an antitumor mAb (the anti-hCD20 rituximab) without compromising antigen specificity. }}

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.{{cite journal | vauthors = Pincetic A, Bournazos S, DiLillo DJ, Maamary J, Wang TT, Dahan R, Fiebiger BM, Ravetch JV | title = Type I and type II Fc receptors regulate innate and adaptive immunity | journal = Nature Immunology | volume = 15 | issue = 8 | pages = 707–16 | date = August 2014 | pmid = 25045879 | doi = 10.1038/ni.2939 | pmc = 7430760 }} 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.{{cite journal | vauthors = Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M | title = Safety, activity, and immune correlates of anti-PD-1 antibody in cancer | journal = The New England Journal of Medicine | volume = 366 | issue = 26 | pages = 2443–54 | date = June 2012 | pmid = 22658127 | pmc = 3544539 | doi = 10.1056/NEJMoa1200690 }} 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.{{cite journal | vauthors = Dahan R, Sega E, Engelhardt J, Selby M, Korman AJ, Ravetch JV | title = FcγRs Modulate the Anti-tumor Activity of Antibodies Targeting the PD-1/PD-L1 Axis | journal = Cancer Cell | volume = 28 | issue = 4 | pages = 543 | date = October 2015 | pmid = 28854351 | doi = 10.1016/j.ccell.2015.09.011 | doi-access = free }} 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.{{cite journal | vauthors = Arlauckas SP, Garris CS, Kohler RH, Kitaoka M, Cuccarese MF, Yang KS, Miller MA, Carlson JC, Freeman GJ, Anthony RM, Weissleder R, Pittet MJ | title = In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy | journal = Science Translational Medicine | volume = 9 | issue = 389 | pages = eaal3604 | date = May 2017 | pmid = 28490665 | pmc = 5734617 | doi = 10.1126/scitranslmed.aal3604 }} Furthermore, antibodies targeting the co-stimulatory protein CD40 require engagement with selective Fc receptors for optimal therapeutic efficacy.{{cite journal | vauthors = Dahan R, Barnhart BC, Li F, Yamniuk AP, Korman AJ, Ravetch JV | title = Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement | journal = Cancer Cell | volume = 29 | issue = 6 | pages = 820–31 | date = July 2016 | pmid = 27265505 | pmc = 4975533 | doi = 10.1016/j.ccell.2016.05.001 }} Together, these studies underscore the importance of Fc status in antibody-based immune checkpoint targeting strategies.

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 from murine sources. Human antibodies have been produced using unmodified human DNA.{{cite journal | vauthors = Harding FA, Stickler MM, Razo J, DuBridge RB | title = The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions | journal = mAbs | volume = 2 | issue = 3 | pages = 256–65 | date = May–Jun 2010 | pmid = 20400861 | pmc = 2881252 | doi = 10.4161/mabs.2.3.11641 }}

File:Antibody-dependent_cell-mediated_cytotoxicity.png

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.{{cite journal | vauthors = Weiner LM, Surana R, Wang S | title = Monoclonal antibodies: versatile platforms for cancer immunotherapy | journal = Nature Reviews. Immunology | volume = 10 | issue = 5 | pages = 317–27 | date = May 2010 | pmid = 20414205 | pmc = 3508064 | doi = 10.1038/nri2744 }}{{cite journal | vauthors = Seidel UJ, Schlegel P, Lang P | title = Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies | journal = Frontiers in Immunology | volume = 4 | pages = 76 | year = 2013 | pmid = 23543707 | pmc = 3608903 | doi = 10.3389/fimmu.2013.00076 | doi-access = free }}

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.{{cite journal | vauthors = Jaiswal S, Chao MP, Majeti R, Weissman IL | title = Macrophages as mediators of tumor immunosurveillance | journal = Trends in Immunology | volume = 31 | issue = 6 | pages = 212–19 | date = June 2010 | pmid = 20452821 | doi = 10.1016/j.it.2010.04.001 | pmc = 3646798 }} 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.{{cite journal | vauthors = Weiskopf K | title = Cancer immunotherapy targeting the CD47/SIRPα axis | journal = European Journal of Cancer | volume = 76 | pages = 100–09 | date = May 2017 | pmid = 28286286 | doi = 10.1016/j.ejca.2017.02.013 }}{{cite journal | vauthors = Matlung HL, Szilagyi K, Barclay NA, van den Berg TK | title = The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer | journal = Immunological Reviews | volume = 276 | issue = 1 | pages = 145–64 | date = March 2017 | pmid = 28258703 | doi = 10.1111/imr.12527 | s2cid = 6275163 }} 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.{{cite journal | vauthors = Veillette A, Chen J | title = SIRPα-CD47 Immune Checkpoint Blockade in Anticancer Therapy | journal = Trends in Immunology | volume = 39 | issue = 3 | pages = 173–84 | date = March 2018 | pmid = 29336991 | doi = 10.1016/j.it.2017.12.005 }}

File:GD2_ganglioside.png

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.{{cite journal | vauthors = Ahmed M, Cheung NK | title = Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy | journal = FEBS Letters | volume = 588 | issue = 2 | pages = 288–97 | date = January 2014 | pmid = 24295643 | doi = 10.1016/j.febslet.2013.11.030 | doi-access = free | bibcode = 2014FEBSL.588..288A }}

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.{{cite journal | vauthors = Gelderman KA, Tomlinson S, Ross GD, Gorter A | title = Complement function in mAb-mediated cancer immunotherapy | journal = Trends in Immunology | volume = 25 | issue = 3 | pages = 158–64 | date = March 2004 | pmid = 15036044 | doi = 10.1016/j.it.2004.01.008 }}

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.

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.{{cite journal | vauthors = Byrd JC, Stilgenbauer S, Flinn IW | title = Chronic lymphocytic leukemia | journal = Hematology. American Society of Hematology. Education Program | volume = 2004 | issue = 1 | pages = 163–83 | date = 1 January 2004 | pmid = 15561682 | doi = 10.1182/asheducation-2004.1.163 | doi-access = free }}{{cite journal | vauthors = Domagała A, Kurpisz M | title = CD52 antigen--a review | journal = Medical Science Monitor | volume = 7 | issue = 2 | pages = 325–31 | date = 2001 | pmid = 11257744 | url = https://www.medscimonit.com/download/index/idArt/421140 }}{{cite journal | vauthors = Dearden C | title = How I treat prolymphocytic leukemia | journal = Blood | volume = 120 | issue = 3 | pages = 538–51 | date = July 2012 | pmid = 22649104 | doi = 10.1182/blood-2012-01-380139 | doi-access = free }}

{{Excerpt|Atezolizumab}}

{{Excerpt|Atezolizumab/hyaluronidase}}

{{Excerpt|Avelumab}}

{{Main|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.{{Cite journal | url=https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm597248.htm | title=FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC| journal=FDA| date=9 February 2019}}

{{Excerpt|Elotuzumab}}

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.{{cite journal | vauthors = Sondak VK, Smalley KS, Kudchadkar R, Grippon S, Kirkpatrick P | title = Ipilimumab | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 6 | pages = 411–12 | date = June 2011 | pmid = 21629286 | doi = 10.1038/nrd3463 }}{{cite journal | vauthors = Lipson EJ, Drake CG | title = Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma | journal = Clinical Cancer Research | volume = 17 | issue = 22 | pages = 6958–62 | date = November 2011 | pmid = 21900389 | pmc = 3575079 | doi = 10.1158/1078-0432.CCR-11-1595 }}{{cite journal | vauthors = Thumar JR, Kluger HM | title = Ipilimumab: a promising immunotherapy for melanoma | journal = Oncology | volume = 24 | issue = 14 | pages = 1280–88 | date = December 2010 | pmid = 21294471 }}{{cite journal | vauthors = Chambers CA, Kuhns MS, Egen JG, Allison JP | title = CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy | journal = Annual Review of Immunology | volume = 19 | pages = 565–94 | year = 2001 | pmid = 11244047 | doi = 10.1146/annurev.immunol.19.1.565 | doi-access = free }}

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.

{{Main|Nivolumab}}Nivolumab 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.{{cite journal | vauthors = Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB | title = Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy | journal = Frontiers in Pharmacology | volume = 8 | pages = 49 | date = 2017 | pmid = 28228726 | pmc = 5296331 | doi = 10.3389/fphar.2017.00049 | doi-access = free }}

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.{{cite journal | vauthors = Castillo J, Perez K | title = The role of ofatumumab in the treatment of chronic lymphocytic leukemia resistant to previous therapies | journal = Journal of Blood Medicine | volume = 1 | pages = 1–8 | year = 2010 | pmid = 22282677 | pmc = 3262337 | doi = 10.2147/jbm.s7284 | doi-access = free }}{{cite journal | vauthors = Zhang B | title = Ofatumumab | journal = mAbs | volume = 1 | issue = 4 | pages = 326–31 | date = Jul–Aug 2009 | pmid = 20068404 | pmc = 2726602 | doi = 10.4161/mabs.1.4.8895 }}

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).{{cite web|title=Pembrolizumab label |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s014lbl.pdf|publisher=FDA|date=May 2017}} linked from [http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=125514 Index page at FDA website] November 2016{{cite web|title=Pembrolizumab label at eMC|url=https://www.medicines.org.uk/emc/medicine/30602|publisher=UK Electronic Medicines Compendium|date=27 January 2017|access-date=4 October 2018|archive-date=13 December 2017|archive-url=https://web.archive.org/web/20171213010050/https://www.medicines.org.uk/emc/medicine/30602|url-status=dead}} It is also indicated for certain patients with urothelial carcinoma, stomach cancer and cervical cancer.{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s034lbl.pdf|title=HIGHLIGHTS OF PRESCRIBING INFORMATION - KEYTRUDA (Pembrolizumab)|date=June 2018|website=fda.gov|access-date=27 February 2019}}

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{{Clarify|reason=Vague|date=April 2016}} and cellular growth arrest. Rituximab also increases the sensitivity of cancerous B-cells to chemotherapy.{{cite journal | vauthors = Keating GM | title = Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma | journal = Drugs | volume = 70 | issue = 11 | pages = 1445–76 | date = July 2010 | pmid = 20614951 | doi = 10.2165/11201110-000000000-00000 }}{{cite journal | vauthors = Plosker GL, Figgitt DP | title = Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia | journal = Drugs | volume = 63 | issue = 8 | pages = 803–43 | year = 2003 | pmid = 12662126 | doi = 10.2165/00003495-200363080-00005 }}{{cite journal | vauthors = Cerny T, Borisch B, Introna M, Johnson P, Rose AL | title = Mechanism of action of rituximab | journal = Anti-Cancer Drugs | volume = 13 | issue = Suppl 2 | pages = S3–10 | date = November 2002 | pmid = 12710585 | doi = 10.1097/00001813-200211002-00002 | s2cid = 25061294 }}{{cite book | vauthors = Janeway C, Travers P, Walport M, Shlomchik M |author-link1 = Charles Janeway |title=Immunobiology | edition = Fifth |publisher=Garland Science |year=2001 |location=New York and London |url=https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=10 |isbn=978-0-8153-4101-7}}{{page needed|date=February 2018}}{{cite journal | vauthors = Weiner GJ | title = Rituximab: mechanism of action | journal = Seminars in Hematology | volume = 47 | issue = 2 | pages = 115–23 | date = April 2010 | pmid = 20350658 | pmc = 2848172 | doi = 10.1053/j.seminhematol.2010.01.011 }}

{{Excerpt|Trastuzumab}}

== {{anchor|Immune checkpoint blockade}} Immune checkpoint antibody therapy or immune checkpoint blockade ==

{{Main|Immune checkpoint|Immunotherapy}}

File:Immune checkpoints in the tumour microenvironment.svg

File:11 Hegasy CTLA4 PD1 Immunotherapy.png

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. Checkpoint therapies approved as of 2012 block inhibitory checkpoint receptors. Blockade of negative feedback signaling to immune cells thus results in an enhanced immune response against tumors.{{cite journal | vauthors = Pardoll DM | title = The blockade of immune checkpoints in cancer immunotherapy | journal = Nature Reviews. Cancer | volume = 12 | issue = 4 | pages = 252–64 | date = March 2012 | pmid = 22437870 | pmc = 4856023 | doi = 10.1038/nrc3239 }} As of 2020, 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.{{Cite journal| vauthors = Ganesan S, Mehnert J |date=2020-03-09|title=Biomarkers for Response to Immune Checkpoint Blockade |journal=Annual Review of Cancer Biology |volume=4|issue=1|pages=331–351|doi=10.1146/annurev-cancerbio-030419-033604 |doi-access=free}} A major challenge are the large variations in responses to immunocheckpoint inhibitors, some patients showing spectacular clinical responses while no positive effects are seen in others. A plethora of possible reasons for the absence of efficacy in many patients have been proposed, but the biomedical community has still to begin to find consensus in this respect. For instance, a recent paper documented that infection with Helicobacter pylori would negatively influence the effects of immunocheckpoint inhibitors in gastric cancer.,{{cite journal | vauthors = Magahis PT, Maron SB, Cowzer D, King S, Schattner M, Janjigian Y, Faleck D, Laszkowska M | title = Impact of Helicobacter pylori infection status on outcomes among patients with advanced gastric cancer treated with immune checkpoint inhibitors. | journal = J Immunother Cancer | date = October 2023 | volume = 11 | issue = 10 | pages = e007699 | pmid = 37899129| pmc = 10619027 | doi = 10.1136/jitc-2023-007699 | doi-access = free }} but this notion was quickly challenged by others.{{cite journal | vauthors = Yu B, Peppelenbosch M, Fuhler G| title = Impact of Helicobacter pylori infection status on outcomes among patients with advanced gastric cancer treated with immune checkpoint inhibitors.| journal = J Immunother Cancer | date = January 2024 | volume = 12| issue = 1| pages = e008422| pmid = 38242721| pmc = 10806497 | doi = 10.1136/jitc-2023-008422 | doi-access = free }}

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.{{cite journal | vauthors = Granier C, De Guillebon E, Blanc C, Roussel H, Badoual C, Colin E, Saldmann A, Gey A, Oudard S, Tartour E | title = Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer | journal = ESMO Open | volume = 2 | issue = 2 | pages = e000213 |year = 2017 | pmid = 28761757 | pmc = 5518304 | doi = 10.1136/esmoopen-2017-000213 }}

The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 to treat melanoma.{{cite journal | vauthors = Cameron F, Whiteside G, Perry C | title = Ipilimumab: first global approval | journal = Drugs | volume = 71 | issue = 8 | pages = 1093–104 | date = May 2011 | pmid = 21668044 | doi = 10.2165/11594010-000000000-00000 }} It blocks the immune checkpoint molecule CTLA-4. As of 2012, clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs.{{cite journal |last1=Farhangnia |first1=Pooya |title=Current and future immunotherapeutic approaches in pancreatic cancer treatment |journal=Journal of Hematology & Oncology |date=June 4, 2024 |volume=17 |issue=1 |page=40 |doi=10.1186/s13045-024-01561-6 |pmid=38835055 |doi-access=free|pmc=11151541 }}{{cite journal | vauthors = Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M | title = Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study | journal = Journal of Clinical Oncology | volume = 30 | issue = 17 | pages = 2046–54 | date = June 2012 | pmid = 22547592 | doi = 10.1200/JCO.2011.38.4032 | doi-access = free }}{{cite journal | vauthors = Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA, Donehower RC, Jaffee EM, Laheru DA | title = Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer | journal = Journal of Immunotherapy | volume = 36 | issue = 7 | pages = 382–89 | date = September 2013 | pmid = 23924790 | pmc = 3779664 | doi = 10.1097/CJI.0b013e31829fb7a2 }} In on-going trials the combination of CTLA-4 blockade with PD-1 or PD-L1 inhibitors is tested on different types of cancer.{{ClinicalTrialsGov|NCT01928394|A Study of Nivolumab by Itself or Nivolumab Combined With Ipilimumab in Patients With Advanced or Metastatic Solid Tumors}}

However, as of 2015 it is known that 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.{{cite journal | vauthors = Postow MA, Callahan MK, Wolchok JD | title = Immune Checkpoint Blockade in Cancer Therapy | journal = Journal of Clinical Oncology | volume = 33 | issue = 17 | pages = 1974–82 | date = June 2015 | pmid = 25605845 | pmc = 4980573 | doi = 10.1200/JCO.2014.59.4358 }} 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.

A 2024 cohort study of ICI use during pregnancy showed no overreporting of specific adverse effects on pregnancy, fetal, and/or newborn outcomes, interestingly.{{cite journal | vauthors = Gougis P, Hamy AS, Jochum F, Bihan K, Carbonnel M, Salem JE, Dumas E, Kabirian R, Grandal B, Barraud S, Coussy F, Hotton J, Savarino R, Marabelle A, Cadranel J, Spano JP, Laas E, Reyal F, Abbar B | title = Immune Checkpoint Inhibitor Use During Pregnancy and Outcomes in Pregnant Individuals and Newborns | journal = JAMA Network Open | volume = 7 | issue = 4 | pages = e245625 | date = April 2024 | pmid = 38630478 | pmc = 11024778 | doi = 10.1001/jamanetworkopen.2024.5625 }}

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.{{cite journal | vauthors = van Hooren L, Sandin LC, Moskalev I, Ellmark P, Dimberg A, Black P, Tötterman TH, Mangsbo SM | title = Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer | journal = European Journal of Immunology | volume = 47 | issue = 2 | pages = 385–93 | date = February 2017 | pmid = 27873300 | doi = 10.1002/eji.201646583 | s2cid = 2463514 | doi-access = free }} 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.

{{main|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.{{Cite news|url=https://www.nytimes.com/2016/05/19/business/food-and-drug-administration-immunotherapy-bladder-cancer.html|title=F.D.A. Approves an Immunotherapy Drug for Bladder Cancer|access-date=21 May 2016| vauthors = Pollack A |date=18 May 2016|newspaper=The New York Times|issn=0362-4331}} 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.{{Cite news|url=https://www.wsj.com/articles/bristol-myers-opdivo-failed-to-meet-endpoint-in-key-lung-cancer-study-1470400926|title=Bristol Myers: Opdivo Failed to Meet Endpoint in Key Lung-Cancer Study| vauthors = Steele A |date=5 August 2016|newspaper=The Wall Street Journal|issn=0099-9660|access-date=5 August 2016}}

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.{{cite press release|url=https://globenewswire.com/news-release/2016/06/05/846118/0/en/BeiGene-Presents-Initial-Clinical-Data-on-PD-1-Antibody-BGB-A317-at-the-2016-American-Society-of-Clinical-Oncology-Annual-Meeting.html|title=BeiGene Presents Initial Clinical Data on PD-1 Antibody BGB-A317 at the 2016 American Society of Clinical Oncology Annual Meeting|author=BeiGene, Ltd.|year=2016|publisher=Globe Newswire}}

{{main|PD-1 and PD-L1 inhibitors}}

In May 2016, PD-L1 inhibitor atezolizumab{{cite web|url=http://www.roche.com/investors/updates/inv-update-2016-04-11.htm|title=FDA grants priority review for Roche's cancer immunotherapy atezolizumab in specific type of lung cancer|last1=Roche}} was approved for treating bladder cancer.

Anti-PD-L1 antibodies currently in development include avelumab{{cite web|last1=Merck Group|title=Immuno-oncology Avelumab|url=http://www.merckgroup.com/en/innovation/research_activities/immuno_oncology/immuno_oncology.html}} and durvalumab,{{cite web|last1=Cure today|title=Durvalumab continues to progress in treatment of advanced bladder cancer.|date=April 2016 |url=http://www.curetoday.com/articles/durvalumab-continues-to-progress-in-treatment-of-advanced-bladder-cancer}} in addition to an inhibitory affimer.{{cite web|last1=Avacta Life Sciences|title=Affimer biotherapeutics target cancer's off-switch with PD-L1 inhibitor|url=https://www.avactalifesciences.com/blogs/affimer-biotherapeutics-target-cancer-s-switch-pd-l1-inhibitor|access-date=16 May 2016|archive-url=https://web.archive.org/web/20160806162015/https://www.avactalifesciences.com/blogs/affimer-biotherapeutics-target-cancer-s-switch-pd-l1-inhibitor|archive-date=6 August 2016|url-status=dead}}

{{Excerpt|Adoptive cell transfer#Intrinsic (Intracellular) checkpoint blockade}}

Many cancer patients do not respond to immune checkpoint blockade. Response rate may be improved by combining that with additional therapies, including those that stimulate T cell infiltration. For example, targeted therapies such as radiotherapy, vasculature targeting agents, and immunogenic chemotherapy{{cite journal |vauthors=Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, Yamazaki T, Poirier-Colame V, Newton A, Redouane Y, Lin YJ, Wojtkiewicz G, Iwamoto Y, Mino-Kenudson M, Huynh TG, Hynes RO, Freeman GJ, Kroemer G, Zitvogel L, Weissleder R, Pittet MJ |date=February 2016 |title=Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy |journal=Immunity |volume=44 |issue=2 |pages=343–54 |doi=10.1016/j.immuni.2015.11.024 |pmc=4758865 |pmid=26872698}} can improve immune checkpoint blockade response in animal models.

Combining immunotherapies such as PD1 and CTLA4 inhibitors can create to durable responses.{{cite journal | vauthors = Ott PA, Hodi FS, Kaufman HL, Wigginton JM, Wolchok JD | title = Combination immunotherapy: a road map | journal = Journal for Immunotherapy of Cancer | volume = 5 | pages = 16 | year = 2017 | pmid = 28239469 | pmc = 5319100 | doi = 10.1186/s40425-017-0218-5 | doi-access = free }}{{cite journal | vauthors = Mahoney KM, Rennert PD, Freeman GJ | title = Combination cancer immunotherapy and new immunomodulatory targets | journal = Nature Reviews. Drug Discovery | volume = 14 | issue = 8 | pages = 561–84 | date = August 2015 | pmid = 26228759 | doi = 10.1038/nrd4591 | s2cid = 2220735 }}

Combinatorial ablation and immunotherapy enhances the immunostimulating response and has synergistic effects for metastatic cancer treatment.{{cite journal | vauthors = Mehta A, Oklu R, Sheth RA | title = Thermal Ablative Therapies and Immune Checkpoint Modulation: Can Locoregional Approaches Effect a Systemic Response? | journal = Gastroenterology Research and Practice | volume = 2016 | pages = 9251375 | year = 2015 | pmid = 27051417 | pmc = 4802022 | doi = 10.1155/2016/9251375 | doi-access = free }}

Combining checkpoint immunotherapies with pharmaceutical agents has the potential to improve response, and as of 2018 were a target of clinical investigation.{{cite journal | vauthors = Tang J, Shalabi A, Hubbard-Lucey VM | title = Comprehensive analysis of the clinical immuno-oncology landscape | journal = Annals of Oncology | volume = 29 | issue = 1 | pages = 84–91 | date = January 2018 | pmid = 29228097 | doi = 10.1093/annonc/mdx755 | doi-access = free }} Immunostimulatory drugs such as CSF-1R inhibitors and TLR agonists have been effective.{{cite journal | vauthors = Perry CJ, Muñoz-Rojas AR, Meeth KM, Kellman LN, Amezquita RA, Thakral D, Du VY, Wang JX, Damsky W, Kuhlmann AL, Sher JW, Bosenberg M, Miller-Jensen K, Kaech SM | title = Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity | journal = The Journal of Experimental Medicine | volume = 215 | issue = 3 | pages = 877–93 | date = March 2018 | pmid = 29436395 | pmc = 5839759 | doi = 10.1084/jem.20171435 }}{{cite journal| vauthors = Rodell CB, Arlauckas SP, Cuccarese MF, Garris CS, Li R, Ahmed MS, Kohler RH, Pittet MJ, Weissleder R |date=21 May 2018|title=TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy |journal=Nature Biomedical Engineering |volume=2|issue=8|pages=578–588|doi=10.1038/s41551-018-0236-8 |pmid=31015631|pmc=6192054|doi-access=free}}

Two independent 2024 clinical trials reported that combinations of JAK inhibitors with anti–PD-1 immunotherapy could improve efficacy. A phase 2 trial investigated the combination as a first-line therapy for metastatic non-small-cell lung cancer. Administration of itacitinib after treatment with pembrolizumab improved therapeutic response. A separate phase 1/2 trial with patients with relapsed/refractory Hodgkin’s lymphoma combined ruxolitinib and nivolumab, yielding improved clinical efficacy in patients who had previously failed checkpoint blockade immunotherapy.{{cite journal | vauthors = Zak J, Pratumchai I, Marro BS, Marquardt KL, Zavareh RB, Lairson LL, Oldstone MB, Varner JA, Hegerova L, Cao Q, Farooq U, Kenkre VP, Bachanova V, Teijaro JR | title = JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma | journal = Science | volume = 384 | issue = 6702 | pages = eade8520 | date = June 2024 | pmid = 38900864 | doi = 10.1126/science.ade8520 | pmc = 11283877 | bibcode = 2024Sci...384e8520Z }}

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.{{cite journal | vauthors = Dranoff G | title = Cytokines in cancer pathogenesis and cancer therapy | journal = Nature Reviews. Cancer | volume = 4 | issue = 1 | pages = 11–22 | date = January 2004 | pmid = 14708024 | doi = 10.1038/nrc1252 | s2cid = 42092046 }}

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.{{Cite web | url=https://ibiotherapy.com/immunotherapy/| title=Immunotherapy For Cancer | accessdate=2023-05-12}}

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.{{cite journal | vauthors = Dunn GP, Koebel CM, Schreiber RD | title = Interferons, immunity and cancer immunoediting | journal = Nature Reviews. Immunology | volume = 6 | issue = 11 | pages = 836–48 | date = November 2006 | pmid = 17063185 | doi = 10.1038/nri1961 | s2cid = 223082 }}{{cite journal | vauthors = Lasfar A, Abushahba W, Balan M, Cohen-Solal KA | title = Interferon lambda: a new sword in cancer immunotherapy | journal = Clinical & Developmental Immunology | volume = 2011 | pages = 349575 | year = 2011 | pmid = 22190970 | pmc = 3235441 | doi = 10.1155/2011/349575 | doi-access = free }}

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 administered 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.{{cite journal | vauthors = Razaghi A, Owens L, Heimann K | title = Review of the recombinant human interferon gamma as an immunotherapeutic: Impacts of production platforms and glycosylation | journal = Journal of Biotechnology | volume = 240 | pages = 48–60 | date = December 2016 | pmid = 27794496 | doi = 10.1016/j.jbiotec.2016.10.022 }}

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.{{cite journal | vauthors = Coventry BJ, Ashdown ML | title = The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses | journal = Cancer Management and Research | volume = 4 | pages = 215–21 | year = 2012 | pmid = 22904643 | pmc = 3421468 | doi = 10.2147/cmar.s33979 | doi-access = free }}

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. In some cases the FDA has approved genetic tests for medication 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.{{cite web | url = https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm611981.htm | title = FDA approves Encorafenib and Binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations | date = 27 June 2018 | publisher = U.S. Food and Drug Administration }}

As of 2018, 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.{{cite web|url=http://www.cancergenetics.com/cancer-genetics-offers-the-fda-approved-dako-pd-l1-ihc-22c3-pharmdx-companion-diagnostic-test-for-keytruda/|title=Cancer Genetics offers the FDA-approved DAKO PD-L1 IHC 22C3 pharmDx companion diagnostic test for KEYTRUDA®|work=Cancer Genetics Inc. |date=3 February 2016}}{{cite journal | vauthors = Udall M, Rizzo M, Kenny J, Doherty J, Dahm S, Robbins P, Faulkner E | title = PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validation metrics | journal = Diagnostic Pathology | volume = 13 | issue = 1 | pages = 12 | date = February 2018 | pmid = 29426340 | pmc = 5807740 | doi = 10.1186/s13000-018-0689-9 | doi-access = free }}{{cite journal | vauthors = Dacic S | title = Time is up for PD-L1 testing standardization in lung cancer | journal = Annals of Oncology | volume = 29 | issue = 4 | pages = 791–792 | date = April 2018 | pmid = 29688334 | doi = 10.1093/annonc/mdy069 | doi-access = free }}

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.{{cite journal | vauthors = Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, Stephens PJ, Daniels GA, Kurzrock R | title = Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers | journal = Molecular Cancer Therapeutics | volume = 16 | issue = 11 | pages = 2598–2608 | date = November 2017 | pmid = 28835386 | pmc = 5670009 | doi = 10.1158/1535-7163.MCT-17-0386 }}{{cite web | url = http://www.ascopost.com/News/59015 | title = FDA Accepts sBLA for First-Line Nivolumab Plus Low-Dose Ipilimumab in NSCLC With Tumor Mutational Burden ≥ 10 mut/mb | date = 7 February 2018 | publisher = American Society of Clinical Oncology | work = ASCO Post }} As of 2020, the patient prioritization for immunotherapy based on TMB was still highly controversial.{{cite journal | vauthors = Liu D, Schilling B, Liu D, Sucker A, Livingstone E, Jerby-Arnon L, Zimmer L, Gutzmer R, Satzger I, Loquai C, Grabbe S, Vokes N, Margolis CA, Conway J, He MX, Elmarakeby H, Dietlein F, Miao D, Tracy A, Gogas H, Goldinger SM, Utikal J, Blank CU, Rauschenberg R, von Bubnoff D, Krackhardt A, Weide B, Haferkamp S, Kiecker F, Izar B, Garraway L, Regev A, Flaherty K, Paschen A, Van Allen EM, Schadendorf D | title = Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma | journal = Nature Medicine | volume = 25 | issue = 12 | pages = 1916–1927 | date = December 2019 | pmid = 31792460 | pmc = 6898788 | doi = 10.1038/s41591-019-0654-5 }}{{cite journal | vauthors = Motzer RJ, Robbins PB, Powles T, Albiges L, Haanen JB, Larkin J, Mu XJ, Ching KA, Uemura M, Pal SK, Alekseev B, Gravis G, Campbell MT, Penkov K, Lee JL, Hariharan S, Wang X, Zhang W, Wang J, Chudnovsky A, di Pietro A, Donahue AC, Choueiri TK | title = Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial | journal = Nature Medicine | pages = 1733–1741 | date = September 2020 | volume = 26 | issue = 11 | pmid = 32895571 | doi = 10.1038/s41591-020-1044-8 | pmc = 8493486 | doi-access = free }}

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.{{Cite news | vauthors = Flam F |date=2015-01-22 |title=Duke U Cancer Fraud Scandal: A Cautionary Tale For Obama's Precision Medicine Push |url=https://www.forbes.com/sites/fayeflam/2015/01/22/investigator-offers-lessons-from-precision-medicines-cancer-scandal/ |access-date=2024-04-21 |work=Forbes |language=en}}[https://sciencebasedmedicine.org/liquid-biopsies-for-cancer-life-saving-tests-or-overdiagnosis-and-overtreatment-taken-to-a-new-level/ "Liquid biopsies" for cancer screening: Life-saving tests, or overdiagnosis and overtreatment taken to a new level?] David Gorski, 28 September 2015, Science-Based Medicine website[https://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/insurance-wont-pay-braf-test A public discussion by cancer patients] from 2011 on the melanoma.org website shows costs and claims.

{{Further|topic=the Autologous Lymphoid Effector Cells Specific Against Tumor cells technology|ALECSAT}}

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.{{cite journal | vauthors = Fukuhara H, Ino Y, Todo T | title = Oncolytic virus therapy: A new era of cancer treatment at dawn | journal = Cancer Science | volume = 107 | issue = 10 | pages = 1373–79 | date = October 2016 | pmid = 27486853 | pmc = 5084676 | doi = 10.1111/cas.13027 }}{{cite journal | vauthors = Haddad D | title = Genetically Engineered Vaccinia Viruses As Agents for Cancer Treatment, Imaging, and Transgene Delivery | journal = Frontiers in Oncology | volume = 7 | pages = 96 | year = 2017 | pmid = 28589082 | pmc = 5440573 | doi = 10.3389/fonc.2017.00096 | doi-access = free }}{{cite journal | vauthors = Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y | title = Cancer immunotherapy beyond immune checkpoint inhibitors | journal = Journal of Hematology & Oncology | volume = 11 | issue = 1 | pages = 8 | date = January 2018 | pmid = 29329556 | pmc = 5767051 | doi = 10.1186/s13045-017-0552-6 | doi-access = free }}

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.{{cite journal | vauthors = Lawler SE, Speranza MC, Cho CF, Chiocca EA | title = Oncolytic Viruses in Cancer Treatment: A Review | journal = JAMA Oncology | volume = 3 | issue = 6 | pages = 841–849 | date = June 2017 | pmid = 27441411 | doi = 10.1001/jamaoncol.2016.2064 | s2cid = 39321536 | doi-access = free }}

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.{{cite journal | vauthors = Aleem E | title = β-Glucans and their applications in cancer therapy: focus on human studies | journal = Anti-Cancer Agents in Medicinal Chemistry | volume = 13 | issue = 5 | pages = 709–19 | date = June 2013 | pmid = 23293888 | doi = 10.2174/1871520611313050007 }}

{{Main|Neoantigen}}Many 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.{{cite journal | vauthors = Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, Hollmann TJ, Bruggeman C, Kannan K, Li Y, Elipenahli C, Liu C, Harbison CT, Wang L, Ribas A, Wolchok JD, Chan TA | title = Genetic basis for clinical response to CTLA-4 blockade in melanoma | journal = The New England Journal of Medicine | volume = 371 | issue = 23 | pages = 2189–99 | date = December 2014 | pmid = 25409260 | pmc = 4315319 | doi = 10.1056/NEJMoa1406498 }} However, human neoantigens identified in other studies do not show the bias toward tetrapeptide signatures.{{cite journal | vauthors = Schumacher TN, Schreiber RD | title = Neoantigens in cancer immunotherapy | journal = Science | volume = 348 | issue = 6230 | pages = 69–74 | date = April 2015 | pmid = 25838375 | doi = 10.1126/science.aaa4971 | bibcode = 2015Sci...348...69S | doi-access = free }}

In the 1980s, Japan's Ministry of Health, Labour and Welfare approved polysaccharide-K extracted from the mushroom, Coriolus versicolor, to stimulate the immune systems of patients undergoing chemotherapy. It is a dietary supplement in the US and other jurisdictions.{{cite web |archive-url=https://web.archive.org/web/20060215064239/http://www.cancer.org/docroot/ETO/content/ETO_5_3X_Coriolous_Versicolor.asp|url=http://www.cancer.org/docroot/ETO/content/ETO_5_3X_Coriolous_Versicolor.asp|archive-date=15 February 2006|url-status=dead|title=Coriolus Versicolor|publisher=American Cancer Society}}

• Cancer vaccine
• Antigen 5T4
• Coley's toxins
• Combinatorial ablation and immunotherapy
• Cryoimmunotherapy
• Photoimmunotherapy
• Radioimmunotherapy

{{Reflist}}

• [https://www.cancer.gov/about-cancer/treatment/types/immunotherapy A primer on "Immunotherapy to Treat Cancer"], NIH
• [https://www.cancer.gov/research/areas/treatment/immunotherapy-using-immune-system Immunotherapy – Using the Immune System to Treat Cancer] {{Webarchive|url=https://web.archive.org/web/20170404222913/https://www.cancer.gov/research/areas/treatment/immunotherapy-using-immune-system |date=4 April 2017 }}
• [http://www.cancerresearch.org/cancer-immunotherapy Cancer Research Institute – What is Cancer Immunotherapy]
• [https://web.archive.org/web/20190901011219/http://www.c-imt.org/ Association for Immunotherapy of Cancer]
• [http://www.sitcancer.org Society for Immunotherapy of Cancer]
• {{cite news |url=https://www.economist.com/news/science-and-technology/21653602-doctors-are-tryingwith-some-successto-recruit-immune-system-help|title=And Then There Were Five|work=Economist}}
• {{cite web|url=http://www.immunooncology.com/home.aspx|title=Discover the Science of Immuno-Oncology|publisher=Bristol-Myers Squibb|access-date=13 March 2014|archive-url=https://web.archive.org/web/20141010230254/http://www.immunooncology.com/home.aspx|archive-date=10 October 2014|url-status=dead}}
• {{cite journal | vauthors = Eggermont A, Finn O | title = Advances in immuno-oncology. Foreword | journal = Annals of Oncology | volume = 23 | issue = Suppl 8 | pages = viii5 | date = September 2012 | pmid = 22918929 | doi = 10.1093/annonc/mds255 | doi-access = free }}
• [https://www.shalby.org/specialities/oncology/ "Cancer Immunotherapy in Gujarat"]

{{Tumors}}

{{Chemotherapeutic agents}}

{{Breakthrough of the Year}}

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Category:Branches of immunology