Cancer immunotherapy

Definition

Immunotherapy is a type of treatment designed to boost the body’s natural immune system to fight diseases like cancer. It makes use of substances either made naturally by the body or those developed in the laboratory. In the case of cancer, immunotherapy is used in different ways. While some aim to enhance the immune system generally, others train it to directly destroy cancer cells.

Electron microscope of a human T lymphocyte (T-cell). Such cells are the foot soldiers of the immune system which some immunotherapies harness to fight cancer. Credit: NIAID/NIH.

Importance

In 2013 cancer immunotherapy was named the scientific breakthrough of the year by the prestigious American journal Science. This was based on news that patients in clinical trials with cancers that are hard to treat, such as melanoma and lung cancer, responded positively to a new type of immunotherapy, known as immune checkpoint inhibitors. This is designed to block a biological pathway which cancer cells use to bypass the immune system and so prevent their destruction. By 2016, three checkpoint inhibitor drugs had been approved for market by the US FDA: ipilimumab, pembrolizumab and nivolumab. Pembrolizumab is known to have saved the life of Jimmy Carter, the former president of the USA, whose melanoma spread to his liver and brain.

While immune checkpoint immune inhibitiors have become some of the highest profiles of immunotherapies, many other immunotherapies are now on the market. More than a dozen immunotherapeutic agents have been approved todate to treat 10 different cancer types. In addition to those on the market, many immunotherapies are undergoing clinical trial. In 2013 approximately 800 clinical trials of immunotherapy were listed on ClinicalTrials.gov for a variety of cancers. These included breast, colon, head and neck and kidney cancers. Just how important the field has become can be seen from the fact that in 2016 pharmaceutical analysts estimated the global cancer immunotherapy market to be worth USD 61.97 billion and that it would reach 119.39 billion by 2021. At the end of 2016 GBI Research calculated that there were 2,037 products in development. This comprised 37 percent of the entire oncology development pipeline.

Discovery

The idea of using the immune system to fight cancer has a long history. As early as the 1700s a number of clinicians observed that some cancer patients who experienced a fever from an infection experienced a remission. In 1725, for example, the French physician Antoine Diedier noted that syphilitic patients developed very few malignant tumours. Subsequently, in the 1860s two German physicians, W. Busch and Friedrich Fehleisen, separately noticed that tumours shrank in patients who accidentally contracted erysipelas, a skin infection. Based on this observation and the success of the smallpox vaccine, both Busch and Fehleissen both attempted to treat a small number of patients with inoperable cancer between 1868 and 1882 by deliberately infecting them with erysipelas. Fehleissen reported tumour shrinkage in three out of his seven patients.

Both of the German physicians pursued their experiments with no knowledge of the streptococcal organism that causes erysipelas. The first time a cancer patient was deliberately given the organism to induce erysipelas occurred in 1888. This was carried out by another Germany physician P. Bruns. It again shrank the tumour.

Three years later, in 1891, William Coley, a surgeon based at Memorial Hospital in New York, also began injecting the bacterial agent for erysipelas into patients with sarcoma, a rare form of cancer that can develop in the bone and muscles as well as other parts of the body. He did this after finding the case notes of a patient in his hospital who had survived four episodes of recurrent inoperable sarcoma of the neck following a severe erysipelas infection. He had also spotted 38 similar cases in the medical literature. By the time of his death, in 1936, Coley had his colleagues had treated nearly a thousand patients using 13 different vaccine formulations. One of these they reported effected a cure in 60 out of 120 patients. Coley believed the success of the treatment was due to the bacterial origins of the cancer. His approach, however, had been largely abandoned by the 1940s due to the fact that Coley had never systematically tested his method or codified its application. In addition it had unpleasant effects.

Erysipelas was not the only type of bacterial vaccine tested to treat cancer. In 1929 Raymond Pearl, a researcher at Johns Hopkins Hospital in Baltimore, observed from 1,632 patient autopsies that the incidence of cancer was much lower in patients with tuberculosis. Pearl soon persuaded one of his clinical colleagues to conduct a small trial with the BCG vaccine, first developed to prevent tuberculosis in 1921. While only a few patients were treated, the trial results were promising. Confidence in the vaccine was however shattered in 1930 when over seventy children died from a preparation of the vaccine which contained a virulent strain of tuberculosis. It would take many years before the vaccine would again be explored for treating cancer. The vaccine was finally approved in 1990 for the treatment of superficial bladder cancer.

Vaccines were not the only approach attempted against cancer early on. So too was the injection of blood serum. This approach, known as serum therapy, followed the joint discovery in 1891 by Emil von Behring and Kitasato Shibasaburo, respectively German and Japanese physicians at the Institute for Infectious Diseases in Berlin. They found that serum taken from animals suffering from diphtheria and tetanus conferred immunity to other animals not exposed to such diseases. Soon after the German physician Paul Ehrlich, isolated a substance in blood he called ‘antibodies’ which provided immunity against plant poisons. By 1895 Jules Bordet, a Belgian immunologist and microbiologist, had detected another substance in blood, later named ‘complement’, that acted as an accessory to antibodies in destroying bacteria.

The new knowledge paved the way to the successful development of a serum therapy for diphtheria. Developed by Behring and Ehrlich in 1893 this used serum from horses immunised against diphtheria. In 1895 Jules Hericourt and Charles Richet, two French physicians, reported positive results from two cancer patients injected with serum taken from a donkey and two dogs immunised with an extract of a human osteosarcoma tumour. Over the course of the next two years they had managed to treat a further 50 cases with similarly promising results. The use of serum continued to be investigated for treating cancer by other researchers into the early twentieth century, but with varying results.

Despite their potential, both vaccines and serum therapy had been largely discarded by the 1930s. This was in part due to the rise in radiotherapy and chemotherapy. But it also reflected a more general scepticism within the scientific community about the extent to which the immune system could recognise and destroy malignant tumours. Knowledge about the immune system and cancer entered a new phase during the 1950s following the development of new inbred strains of laboratory animals. One study in particular, published in 1957 Richmond Prehn and Joan Main, based at the US Public Health Service Hospital in Seattle, helped transform the field. Critically they demonstrated for the first time that tumours carried specific markers, known as antigens, which the immune system could recognise and attack. Two years later, another study by Lloyd Old and colleagues at the Memorial Sloan Kettering Cancer Center, New York, demonstrated that mice could be immunised against their own tumours by injecting them with the BCG vaccination against tuberculosis. They discovered that the vaccine activated macrophages, a type of immune cell, which inhibited and destroyed tumour cells.

By 1959 a new concept, known as immunological surveillance, had emerged, based on the new animal studies. This was developed by Frank MacFarlane Burnet, an Australian immunologist. He suggested that the immune system regularly screened and protected the body against tumours and that cancer only developed when the immune system acquired a tolerance to the cancer cells which allowed them to escape destruction, and to proliferate. Based on this hypothesis, Burnet argued that one way to combat cancer would be to find a way of increasing the immune system’s sensitivity to minor deviations from the body’s own cells. His theory reinvigorated interest in immunotherapy. The field, however, suffered a temporary setback following a study published in 1975 by Osias Stutman and colleagues at the Memorial Sloan-Kettering Cancer Center which did not find the incidence of cancer to be any greater in mice genetically bred with an inhibited immune system. It was subsequently shown that the immune system of the mice had not been as inactive as once assumed. The field would once again come alive after 1982 when Aline Van Pel and Thiery Boon at Sloan-Kettering demonstrated in mice that the antigens on tumours were often too weak to stimulate an effective immune response, but that it was possible to enhance the immune response of the mice by injecting them with tumour cells genetically modified to increase their antigenicity.

In addition to the new evidence emerging from animal studies, immunotherapy was beginning once again to be tried out at the clinical level using a number of newly identified substances secreted by the immune system. One of the first to be tested was interferon. This substance, also known as a cytokine, had first been identified in 1957 and shown to suppress the growth of tumours in the late 1960s. Yet its therapeutic testing was initially hampered by the fact that it was difficult to produce. This all changed following the development of recombinant DNA and monoclonal antibodies which paved the way to the large production of interferon for the its testing in clinical trials. By 1986 enough data had been collected for the FDA to approve interferon for the treatment of hairy-cell leukaemia. It was the first immunotherapy to receive formal approval for cancer. Four years years later, the FDA approved another cytokine, interleukin 2 (IL-2), for the treatment of advanced kidney and skin cancer.

By the 1990s a new class of drugs had begun to emerge for immunotherapy using antibodies, a type of protein that the immune system uses to neutralise harmful agents. Antibodies had first been demonstrated to a powerful weapon for treating lymphoma in 1980, but it was difficult to produce standardised antibodies that could bind to a particular target. This all changed as a result of a new a technique, published in 1975 by Cesar Milstein and Georges Kohler, which facilitated the large-scale production of standardised and highly specific antibodies called monoclonal antibodies (Mabs). One of the first immunotherapy drugs using Mabs to be approved was rituximab. This was licensed by the FDA, for non-Hodgkin’s lymphoma in 1997. The drug is designed to lock on to CD20, a particular marker found on the surface of B lymphocytes involved in the cancer. Once the antibodies bind the B cells, other immune cells will move in to destroy them.

Since the approval of rituximab, many other immunotherapy drugs have been developed using Mabs. One of the reasons Mabs have proven so important to immunotherapy is because they are so versatile. Not only can Mabs bind to tumour cells and thereby signal various immune cells to attack them, they can also be used to prevent a tumour cell getting access to growth factors or inhibit the formation of new blood cells that tumours need to grow. They can also be used to block the mechanism tumour cells use to inhibit an immune response. This last mechanism is addressed by a new class of drugs, known as immune checkpoint inhibitors which are now a promising new field in the treatment of cancer. The first immune checkpoint inhibitor drug was approved for the treatment of metastatic melanoma by the FDA in 2011.

Another type of immunotherapy currently under development today is adoptive cell therapy (ACT). This technique was born out of the observation in the 1960s that certain white blood cells, known as cytotoxic lymphocytes, destroyed cancer cells in test tubes. A key pioneer of the technique was Steven Rosenberg at the National Institute of Health who in 1985 reported the successful treatment of melanoma patients with repeated infusions of a sub-population of cytotoxic lymphocytes directed against tumours isolated from human blood that had been incubated with IL-2. While shown to be promising, the steps involved in the development of the treatment proved time-consuming and expensive limiting its adoption. New improvements, however, have been made to the technique in recent years. One of the key breakthroughs was the development of chimeric antigen receptor, or CAR, T therapy. Such treatment involves extracting T cells from a patient’s blood and then genetically modifying them to increase their capacity to bind to specific markers on tumour cells so that the immune system will direct an attack against the tumour cells. As of March 2017 there were nearly 300 clinical trials with CAR-T therapy and two were on track to be approved later in the year. In July 2017 the FDA Oncologic Drugs Advisory Committee recommended the approval of CAR-T therapy (CTL019, tisagenlecleucel) for the treatment of children who have not responded to traditional treatments for B-cell acute lymphoblastic leukemia. This was based on the results of a clinical trial with 63 patients between April 2015 and August 2016. More than 82 per cent of the patients went into remission. While promising, the treatment carries the risk of potentially fatal side effects such as cytokine-release syndome. In addition the treatment is expensive because each batch of the drug has to be tailored to each individual patient, a process that can take several weeks to complete.

Application

By 2015 more than 25 cancer immunotherapies had gained regulatory approval. The majority have been approved in the last decade. Many different types of agent are used in these therapies. Each use different mechanisms to boost or restore the immune system's fight against cancer. Those that are designed to enhance pre-existing immune responses, known as passive immunotherapy, tend to use agents like monoclonal antibodies and cytokines. Such drugs tend to have a short-life. By contrast active immunotherapy, which is designed to stimulate a patient's immune response against tumour cells, have a more durable effect. The treatment is often called a cancer vaccine. Cancer vaccines difer from traditional vaccines used to prevent infectious diseases. Their intended goal is not to prevent disease, but rather to stimulate an active immune response against the cancer. CAR T therapy is an example of such treatment.

Issues

While immunotherapy for cancer has travelled a long way since its early beginning, advances in the field have not been straightforward and major issues still need to be resolved. Scientists are still a long way from understanding why some patients benefit more than others from the treatments and overcoming their potentially serious side effects, some of which can be fatal. It has also only so far proven of use for certain types of cancer. Only about a third of all cancers are amenable to treatment by the immunotherapies so far appoved by the FDA. In addition the treatments remain highly expensive, which poses questions about how far society will be willing to pay for them.

This section draws extensively from Lara Marks, 'The changing fortune of immunotherapy', in L. Marks, ed. Engineering Health: Biotechnology and Medicine, Royal Society of Chemistry, forthcoming, Sept 2017.

Cancer immunotherapy: timeline of key events

Based on the observation that some tumours shrink in patients with a bacterial skin infection, the surgeon William Coley treated a 21 year old man with inoperable sarcoma with mixture containing heat-treated bacteria. The man went into complete remision. W. Coley, 'The Treatment of Malignant Tumors By Repeated Inoculations of Erysipelas: With A Report of Ten Original Cases', The American Journal of Medical Sciences, 105 (1893): 487-511. 1893-05-01T00:00:00+0000Antiserum preparted against human oesteogenic sarcoma in an ass and 2 dogs. Reported successful in treating 50 patients suffering from cancer of the stomach and chest wall. J Hericourt, C Richet, 'Traitement d'un cas de sarcome par la sarcome par la serotherapie', Seances Acad Sci, 120 (1895), 948-50.1895-01-01T00:00:00+0000The vaccine was developed by William Coley, a New York surgeon, together with the pharmaceutical company Parke, Davis & Co. The vaccine contained a combination of heat-killed bacteria. 1899-01-01T00:00:00+0000The work was carried out independently by Leo Loeb, in Canada and the US, and by Carl Jensen in Copenhagen. Results from the experiments showed some animals were more susceptible to transplanted tumour tissue than others. This ignited a debate 1901-01-01T00:00:00+0000Patients reported an alleviation of their symptoms. E von Leyden, F Blumenthal, 'Vorlaufige Mittheilungen uber einige Ergebnisse der Krebsforschung aug der I. medizinischen Klinik', Deutsche Med Wschr, 28 (1902), 637-8.1902-01-01T00:00:00+0000P Ehrlich, 'About the current state of carcinoma research', Lecture given to students at Amsterdam University, Association of Scientific work, 19081908-01-01T00:00:00+0000E. Freund, G. Kaminer, 'Ueber die Beziehungen zwischen Tumorzellen und Blutserum', Biochem. Ztschr, 26 (1910) 26, 312-24.1910-01-01T00:00:00+0000 JB Murphy, 'Studies on tissue specificity', Journal of Experimental Medicine, 19 (1914), 181-86.1914-01-01T00:00:00+0000The experiments involved increasing the number of lymphocytes in the blood of mice by treating them with low doses of X-rays. JB Murphy, JJ Morton, 'The effects of X-rays on the resistance to cancer in mice', Science, 42 (1915), 842. 1915-01-01T00:00:00+0000The trials were carried out by James B Murphy and colleagues at the Rockefeller Institute. 1916-01-01T00:00:00+0000E. Freund, G. Kaminer, Wiener Klinische Wochenschrift, Jan 19241924-01-01T00:00:00+0000E Witebsky, 'Disponibilitiit und Spezifitat alkoholloslicher Strukturen von Organen und bosartigen Geschwulsten', Zeitschrift fur Imrnunitaetsforschung, Allergie und Klinische Immunologie' 62 (1929), 35-73. 1929-01-01T00:00:00+0000R Pearl, 'Cancer and tuberculosis', American Journal of Hygiene, 9 (1929), 97-149. 1929-04-01T00:00:00+0000Lewis Thomas and Frank MacFarlane Burnet develop a theory that the immune system regularly screens and protects the body against cancer, and that cancer only develops when this mechanism fails. 1957-01-01T00:00:00+0000LJ Old, DA Clarke, B Benacerraf, 'Effect of bacillus calmette-guerin infection on transplanted tumours in the mouse', Nature, 184 (1959), 291-92.1959-07-25T00:00:00+0000LJ Old, EA Boyse, E Oettgen, ED Harven, ED Geering, B Williamson, P Clifford, 'Precipitating antibody in human serum to an antigen present in cultured Burkitt's lymphoma cells', Proc Natl Acad Sci USA, 56 (1966), 1699–1704.1966-12-01T00:00:00+0000I. Hellstrom, K. E. Hellstrom, C. A. Evans, G. Heppaer, G. E. Piece, I. P. S. Yang, 'Serum-mediated protection of neoplastic cells from inhibition by lymphocytes immune to their tumor-specific antigens', PNAS USA, 1969, 62, 362-9.1969-02-01T00:00:00+0000H. O. Sjogren, I. Hellstrom, S. C. Bansal, K. E. Hellstom, 'Suggestive evidence that the blocking antibodies of tumor-bearing individuals may be antigen--antibody complexes', PNAS, USA, 1971, 68/6, 1372-5. 1971-06-01T00:00:00+00001972-01-01T00:00:00+0000The transplant was carried out by Richard O'Reilly and Robert Good. This lays the foundation for the routine use of bone marrow transplants for treating some blood cancers. Such transplants are classed as immunotherapy because immune cells from the donor kill cancer cells in the recipient. 1973-01-01T00:00:00+0000O Stutman, 'Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice', Science, 183 (1974), 534-6.1974-02-08T00:00:00+0000R Kiessling, E Klein, H Pross, H Wigzell, 'Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. 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It marks the first time a monoclonal antibody successfully treats cancer in a patient.1981-01-01T00:00:00+0000EA Grimm, A Mazumder, HZ Zhang, SA Rosenberg, 'Lymphokine-activated killer cell phenomenon', Journal Experimental Medicine, 155 (1982), 1823-41.1982-06-01T00:00:00+0000JP Allison, BW McIntyre, D Bloch, 'Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody', Journal Immunology, 129 (1982), 2293.1982-11-01T00:00:00+0000A N Houghton, M Eisinger, A P Albino, J G Cairncross, L J Old, 'Surface antigens of melanocytes and melanomas. 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M Hein et al, 'Production of stable cytolytic T-cell clones directed against autologous human melanoma', International Journal of Cancer, 39 (1987), 390-96. 1987-03-15T00:00:00+0000Z Dembi et al, 'Transfection of the CD8 gene enhances T-cell recognition', Nature, 326 (1987), 510-11.1987-04-02T00:00:00+0000SA Rosenberg et al, 'A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone', New England Journal of Medicine, 9/316 (1987), 889-97. 1987-04-09T00:00:00+0000JF Brunet et al, 'A new member of the immunoglobulin superfamily--CTLA-4', Nature 328 (1987), 267-70. 1987-07-16T00:00:00+0000C Doyle, JL Strominger, 'Interaction between CD4 and class II MHC molecules mediates cell adhesion', Nature, 330 (1987), 256-9.1987-11-19T00:00:00+0000G Degiovanni et al, European Journal Immunology, 18 (1988+), 671-6; Knuth et al, Proc Natl Acad Sci USA, 86 (1989), 2804-08; Van den Eynde et al, International Journal of Cancer, 15 /44 (1989), 634-40. 1988-05-01T00:00:00+0000CE Rudd, JM Trevillyan, JD Dasgupta, LL Wong, SF Schlossman, 'The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (Pp58) from human T lymphocytes', Proc Natl Acad Sci USA, 85 (1988), 5190-94.1988-07-01T00:00:00+00001988-07-14T00:00:00+0000P Dariavach, MG Mattei, P Golstein, MP Lefranc, 'Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains', European Journal Immunology, 18 (1988), 1901-05.1988-12-01T00:00:00+0000SA Rosenberg et al, 'Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report', New England Journal of Medicine, 319 (1988), 1676-80.1988-12-22T00:00:00+0000CV Thompson, T Lindsten, JA Ledbetter, SL Kunkel, SA Young, SG Emerson, JM Leiden, CL June, 'CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines', Proc Natl Acad Sci U S A , 86 (1989),1333-7.1989-02-01T00:00:00+0000Study conducted by French Anderson in collaboration with Steven Rosenberg in 52 year old cancer patient as preliminary experiment to test gene therapy in children with severe combined immunodeficiency disorder. 1989-05-01T00:00:00+0000M Kobayashi, L Fitz, M Ryan, RM Hewick, SC Clark, S Chan, R Loudon, F Sherman, B Perussia, G Trinchieri, ' Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes', Journal Expermental Medicine', 170 (1989), 827-45.1989-09-01T00:00:00+0000G Gross, T Waks, Z Eshhar, 'Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity (chimeric genes/antibody variable region)', Proc Natl Acad Sci USA, 86 (1989), 10024-8.1989-12-01T00:00:00+0000The approval was given based on results from a clinical trial carried out by Harry Herr and Herbert Oettgen. The BCG vaccine stimulates an immune response that targets both the tuberculosis bacteria and bladder cancer cells. 1990-01-01T00:00:00+0000G Dranoff, E Jaffee, A Lazenby, P Golumbek, H Levitsky, K Brose, V Jackson, H Hamada, D Pardoll, RC Mulligan, 'Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity', Proc Natl Acad Sci USA, 90 (1993), 3539–43.1993-04-15T00:00:00+0000A Bendelac et al, Science, 263 (1994), 1774-78; A Bendelac et al, Science, 268 (1995), 863-5. 1994-03-25T00:00:00+0000DR Leach, MF Krummel, JP Allison, 'Enchancement of antitumor immunity by CTLA-4 blockade', Science, 271/5256 (1996), 1734-36.1996-03-22T00:00:00+0000Research showed that tumour growth can be stopped in mice using a monoclonal antibody that blocks CTLA-4. 1996-03-22T00:00:00+0000B Bogen, 'Peripheral T cell tolerance as a tumor escape mechanism', European Journal Immunology, 26 (1996), 2671-79.1996-11-01T00:00:00+0000Ritxuan (rituiximab) is approved for the treatment of non-Hodgkin Lymphoma. The drug arose out of Ronald Levy's research for three decades to find a way of harnessing the power of the body's own immune system to fight cancer. 1997-01-01T00:00:00+0000Launched by the biotechnology company Medarex in collaboration with Jim Allison. 2000-01-01T00:00:00+0000Research led by Rajasekharan Somasundaram and Dorothee Herlyn published in Cancer Research.2002-09-14T00:00:00+0000Y. Iwai, M. Ishida, Y. Tanaka, T. Okazaki, T. Honjo, N. Minato, 'Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade', PNAS USA, 99/19 (2002), 12293-7.2002-09-17T00:00:00+0000JD Fontenot, MA Gavin, AY Rudensky, 'Foxp3 programs the development and function of CD4+CD25+ regulatory T cells', Nature Immunology, 4 (2003), 330-36.2003-03-03T00:00:00+0000The two companies agreed to share the costs and responsibilities of research and product development up to the completion of a Phase 2 clinical study in each party's territory.2005-05-01T00:00:00+0000Drug, MSX-1106, to be assessed for malignant melanoma, renal cell cancer, castrate-resistant prostate cancer and non-small cell lung carcinoma2008-11-24T00:00:00+0000The drug was approved for the treatment of unresectable or metastatic melanoma. The drug uses a monoclonal that blocks CTLA-4 so as to activate an immune response against the cancer.2011-03-25T00:00:00+0000Emily Whitehead, aged 6, was the first child ever to be given the genetically altered T cells. She experienced severe side effects, including raging fever, dramatic drop in blood pressure, lung congestion, but emerged cancer free. Treatment was led by Carl June. Engineering the T cells was estimated to cost $20,000 per patient. 2012-04-01T00:00:00+0000The drug, a monoclonal antibody, was approved by the FDA for the treatment of patients with melanoma. 2014-12-22T00:00:00+0000More than 82 per cent of the patients went into remission. 2015-04-01T00:00:00+0000Results presented to American Society for Clinical Conference from trials involving monoclonal antibody drugs for lung and skin cancer. The drugs block a protein known as PD-1, which functions as an immune checkpoint, being responsible for preventing the activation of T-cells.2015-06-05T00:00:00+0000K.B. Chiappinelli, P.L. Strissel, A. Desrichard, et al, 'Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses', Cell, 162 (2015), 974-86.2015-08-27T00:00:00+0000Based on the analysis of data from hundreds of patients, scientists found markers on tumour cells flagging up very early mutations of the disease. The advantage is these appear on all tumour cells, thereby providing a good target for treatment. N. McGranahan, et al, 'Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade', Science, 351/6280 (2016), 1463-69. 2016-03-25T00:00:00+0000UK scientists show how the TALENs gene editing tool can be used to switch on the immune system to stop cancer. L. Menger, et al, 'TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors', Cancer Research, 2016, doi: 10.1158/0008-5472.CAN-15-3352. 2016-04-15T00:00:00+0000Work led by Carl June at University of Pennsylvannia to treat patients with multiple myeloma, melanoma and sarcoma.2016-06-21T00:00:00+0000Research carried out by a team led by Dimitry I Gabriolvich. 2016-08-05T00:00:00+0000R.L. Ferris, 'Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck', NEJM (9 Oct 2016), DOI: 10.1056/NEJMoa1602252.2016-10-09T00:00:00+0000It was the first time tyhe FDA approved an immune checkpoint inhibitor for the treatment of lung cancer. The drug was developed by Merck & Co.2016-10-24T00:00:00+0000Developed by EMD Serono avelumab is a PD-L1 blocking monoclonal antibody. It was the first FDA approved product to treat metastatic Merckel cell carcinoma.2017-03-23T00:00:00+0000The drug CTL019 (tisagenlecleucel) was developed by Novartis. Treatment involves removing T cells from the patient and genetically modifying them to increase their capacity to bind to tumour cells in order to get the immune sytem to attack the tumours. It is targeted at children and young adults from three to 25 years old who have not responded to traditional treatments.2017-07-12T00:00:00+0000The drug Kymriah (tisagenlecleucel) is the first gene therapy to become available in the US. 2017-08-30T00:00:00+0000The drug, a form of immunotherapy, is a PDL1 checkpoint inhibitor.2017-09-20T00:00:00+0000
Date Event People Places
May 1893First successful treatment of cancer patient with immunotherapyColeyMemorial Sloan Kettering Cancer Center
1895Humans treated with antiserum prepared against human cancer. This established the principle of using serotherapy to fight cancerHericourt, RichetCollege de France
1899First commercial vaccine developed for treatment of sarcomaColeyMemorial Sloan Kettering Cancer Center, Parke Davis & Co
1901 - 1903First successful transplants of tumours in animals reported, providing a new experimental system for studying the role of the immune system in cancerLeob, JensenUniversity of Pennsylvania, Agriculture and Veterinary Institute
1902First attempt to vaccinate against cancer with a patient's own tumour tissuevon Leyden, Blumenthal 
1908Paul Ehrlich reports that spontaneously developed tumours can be suppressed by the immune system EhrlichGoettingen University
1910Austrian physicians Ernest Freund and Gisa Kaminer observed that something in blood serum from cancer patients pervents the destruction of cancer cellsFreund, KaminerRudolf-Stiftung Hospital
1914Experiments by James B Murphy demonstrate that lymphocytes help animals reject grafted tumoursMurphyRockefeller Intitute
1915 James B Murphy puts forward hypothesis that the nonspecific stimulation of lymphocytes could provide a cure for cancer based on experiments he and John J Morton carried out on miceMurphy, MortonRockefeller Institute
1916 - 1922Disappointing results reported from clinical trials treating breast cancer patients with low doses of X-ray radiation following tumour removal, discrediting the theory that stimulation of lymphocytes could help cure cancer. MurphyRockefeller Institute
1924Austrian physicians Ernest Freund and Gisa Kaminer discover a substance in intestines of cancer patients that reduce ability of normal serum to dissolve cancer cells. Freund, KaminerRudolf-Stiftung Hospital
1929First molecular marker, antigen, identified on a tumour, laying foundation for use of antibodies to diagnose and treat cancerWitebsky University of Heidelberg
April 1929Autopsies carried out on tuberculosis patients show them less likely to have contracted cancerPearlJohns Hopkins University
1957 - 1959Concept developed that the immune system naturally protects against cancerBurnet, Lewis 
25 Jul 1959Mice injected with BCG vaccine shown to develop resistance to growth of implanted tumours. This was the first direct evidence of the immune system's ability to prevent cancer. Old, Clarke, BenacerrafMemorial Sloan Kettering Cancer Center
December 1966Scientists detect antibodies to the Epstein-Barr virus in patients with nasopharyngeal cancer which suggest the cancer is caused by a virus. Old, Boyse, OettgenMemorial Sloan Kettering Cancer Center
February 1969Team led by Karl and Ingegerd Hellstrom observe serum from mice with chemically induced tumours can block reaction of lymphocytesHellstrom, Evans, Heppner, Pierce, Yang Fred Hutchinson Cancer Center
June 1971Hellstom team suggest that antibodies bound to tumour cells mask their detection by the immune system Sjogren, Hellstrom, BansalFred Hutchinson Cancer Center
1972US National Cancer Institute recommended creation of international registry of immunotherapy trials 
1973First successful bone marrow transplant from unrelated donorGood, O'ReillyMemorial Sloan Kettering Cancer Center
8 Feb 1974Immune surveillance theory that immune system provides protection against cancer discredited by research showing that 'Nude' mice lacking immune system function no more likely to develop tumours than normal miceStutmanMemorial Sloan-Kettering Cancer Center
February 1975Natural killer cell identified in mice and shown to be important part of immune systemKiessling, Klein, Pross, WigzellKarolinska Institute
15 Apr 1975Human natural killer cell isolatedJondal, ProssKarolinska Institute
24 Apr 1975Discovery of unique molecular marker, idiotype, on blood cancer cells, opening new avenue for cancer diagnosis and therapyStevensonTenovus Research Laboratory
September 1975Tumour necrosis factor (TNF) was discovered. It was the first immune molecule shown to kill cancer cellsCarswell, Old, Kassel, Green, Fiore, WilliamsonMemorial Sloan Kettering Cancer Center
10 Sep 1976Discovery of first T cell growth factor, later named Interleukin-2 (IL-2)Morgan, Ruscetti, GalloLitton Bioethics Research Laboratories, National Cancer Institute
February 1977Scientists find a way to generate T cells in thymic tissue in test tubes, paving the way study mechanisms underlying the regulation of T cell developmentRobinson, OwenUniversity of Newcastle upon Tyne
1 Apr 1977Development of first anti-idiotype antibodies. These are shown to activate immune defense cells to attack tumour cells in guinea-pigsStevenson, ElliottTenovus Research Laboratory
July 1977T cell growth factor, later named Interleukin-2 (IL-2), discovered in mice, providing a means to grow and expand normal lypmphocytes in test tubesRuscetti, Morgan, GalloNational Cancer Institute
1978T cell-mediated immunity shown to aid tumour regressionBerendt, North, KirsteinTrudeau Institute
1980US National Cancer Institute added $13.5 million to its budget for new Biological Response Modifiers, igniting search for agents able to modify host's response to tumour cells 
1981First patient successfully treated with anti-idiotype monoclonal antibodyLevyStanford University Medical School
June 1982Steven Rosenberg and colleagues first describe lymphokine-activated killer cellsGrimm, Mazumder, Zhang, RosenbergNational Cancer Institute
November 1982James Allison and collegues use monoclonal antibody to provide first biochemical description of tumour specific antigen of murine T-lymphomaAllison, McIntyre, BlochUniversity of Texas System Cancer Center
1 Dec 1982First molecular markers, antigens, identified in melanoma tumours. These markers are now targeted by cancer drugsHoughton, Eisinger, Albino, Cairncross, OldMemorial Sloan Kettering Cancer Center
24 Mar 1983First cloning of Interleukin 2 (Il-2)Taniguchi, Matsui, Fujita, Takaoka, Kashmina, Yoshimoto, HamuroJapanese Foundation for Cancer Research, Ajinomoto Co Inc
November 1983A team of researchers including Philippa Marrack, John Kappler and James P Allison identified the first T cell antigen receptorKappler, Kubo, Haskins, Hannum, Marrack, Pigeon, McIntyre, Allison, TrowbridgeUniversity of Colorado, University of Texas System Cancer Center, National Jewish Hospital and Research Cener, Salk Institute
1984Experiments show that injections with T-cell growth factor interleukin-2 can shrink tumours in humansRosenbergNational Cancer Institute
June 1984First clinical experiments demonstrate the possibility of training T cells to attack tumoursKnuth, Danowski, Oettgen, OldMemorial Sloan-Kettering Cancer Center
1985T cell surface proteins CD4 and CD8 cloned Maddon, Littman, Godfrey, Maddon Chess, AxelColumbia University
December 1985IL-2 based immunotherapy shown to reduce tumours in patients with melanoma and renal cell cancerRosenbergNational Cancer Institute
December 1986Anti-tumour responses observed in 3 out of 10 patients given high-doses of Interleukin-2 (IL-2) Rosenberg, Lotze, Chang, Seipp, Simpson, VettoNational Cancer Institute
1987 - 1989Scientists lay the foundation for the cloning of human tumour antigens recognised by cytotoxic T lymphocytes, a type of white blood cell that kills cancer cellsDe Plaen, BoonLudwig Institute for Cancer Research
15 Mar 1987First stable human anti-tumour cytotoxic T cell clones isolated and maintained in cultureHerin, Lemoine, Weynants, Vessiere, Van Pel, Knuth, Devos, BoonLudwig Institute
April 1987CD8 coreceptor proven to be actively involved in antigen recognition by killer T cellsDembic, Haas, Zamoyska, Parnes, Steinmetz, von BoehmerBasel Institute of Immunology
9 Apr 1987Successful results reported for trial using the cytokine IL-2 and lymphokine-activated killer cells to treat cancerRosenbergNational Cancer Institute
July 1987Identification of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)Brunet, Denizot, Luciani, Roux-Dosseto, Suzan, Mattei, GolsteinINSERM-CNRS
November 1987First evidence provided for the interaction between the surface molecule CD4 and major histocompatibility class IIDoyle, StromingerHarvard University
May 1988 - Oct 1989Cytotoxic T lymphocytes shown to recognise distinct surface markers on human melanomaWolfel, Knuth, Degiovanni, Van den Eynde, Hainaut, BoonLudwig Institute for Cancer Research
July 1988Biochemical initiators of T Cell activitation, CD4 and CD8-p56, discoveredRudd, Trevillyan, Dasupta, Wong, SchlossmanDana-Faber Cancer Institute, Harvard University, Tech University
1988 - 1989First evidence discovered of a physical link between oncoproteins and tumour suppressors 
December 1988Scientists report cloning the gene for the human cytotoxic T lymphocyte-associated antigen (CTLA-4)Dariavach, Mattei, Golstein, LefrancINSERM-CNRS
22 Dec 19889 out of 15 melanoma patients successfully treated with autologous tumor-infiltrating lymphocytes cultured with the cytokine IL-2RosenbergNational Cancer Institute
February 1989Scientists demonstrate the importance of CD28, a cell surface molecule found on T-cells, for the activation and survival of T cellsThompson, Lindsten, Ledbetter, Kunkel, Young, Emerson, Leiden, JuneHoward Hughes Medical Institute
May 1989First human test demonstrated safety of retroviral vector for gene therapy and potential of laboratory produced tumor killing cells for cancer immunotherapyAnderson, RosenbergNational Institutes of Health
September 1989Giorgio Trinchieri and colleagues identified interleukin-12 (IL-12), a cytokine that helps regulate the body’s resistance to infections and cancerKobayashi, Fitz, Ryan, Hewick, Clark, Chan, Loudon, Sherman, Perussia, TrinchieriWistar Institute
December 1989First use of genetically engineered T cells to redirect T cells to recognise and attack tumour cellsGross, Waks, EshharWeizmann Institute
1990US FDA approved BCG, a bacterial vaccine against tuberculosis, to treat early stage bladder cancer. It was the first FDA approved immunotherapyHerr, OettgenMemorial Sloan Kettering Cancer Center
15 Apr 1993Immune molecule, granulocyte-macrophage colony stimulating factor or GM-CSF, discovered to strengthen immunity against tumours Dranoff, Jaffee, Lazenby, Golumbek, Levitsky, Brose, Jackson, Hamada, Pardoll, MulliganMassachusetts Institute of Technology
1994 - 1995Identification and characterisation of the natural killer T cell, a lymphocyte able to bind and kill certain tumour and virus-infected cellsBendelacUniversity of Chicago
22 Mar 1996Mice experiments published demonstrating that blocking the CTLA-4 molecule on immune cells can cure cancerLeach, Krummel, AllisonUniversity California Berkeley
March 1996Hypothesis put forward that T cells unable to attack tumours because they are blocked by the cytotoxic T lymphocite-associated antigen (CTLA-4). Leach, Krummel, AllisonUniversity California Berkeley
November 1996Experiments demostrate antigen-specific CD4+ and T cells become tolerant during tumour growth in test tubes 
1997FDA approved the first monoclonal antibody cancer drug for the American marketLevy, RastetterStanford University Medical School, Idec Pharmaceuticals
2000First clinical trials launched to test first immune checkpoint inhibitor drug containing a monoclonal antibody against CTLA-4 (ipilimumab, Yervoy®)AllisonMedarex, University of California Berkley
14 Sep 2002Regulatory T cells discovered to restrain cytolytic T cells attacking cancer via messanger chemical called TGF-betaHerlyn, SomasundaramWistar Institute
17 Sep 2002Cancer cells shown to be capable of hijacking PD-1 protein to evade destruction by immune systemIwai , Ishida, Tanaka, Okazaki, Honjo, MinatoJapan Science and Technology Corporation
2003Genetic switch identified that controls the development of T cells, an important immune cell that controls against autoimmunity and excess inflammationFontenot, Gavin, RudenskyHoward Hughes Medical Institute, University of Washington
May 2005Medarex and Ono Pharmaceuticals entered research alliance to develop a fully human anti-PD-1 antibody for the treatment of cancerMedarex, Ono Pharmaceutical
24 Nov 2008First anti-PD-1 antibody entered phase 1 clinical trial for cancerMedarex, Ono Pharmaceutical
25 Mar 2011First immune checkpoint inhibitor drug targeting CTLA4 (ipilimumab, Yervoy®), approved by the FDAAllisonMedarex, University of California Berkley
April 2012First child with leukaemia treated with adoptive cell therapy (CAR-T therapy)June, WhiteheadChildren's Hospital of Philadelphia, University of Pennsylvania
22 Dec 2014First immune checkpoint inhibitor drug targeting PD-1 (nivolumab, Opdivo®) approved in US Honko, Freeman, LonbergMedarex, Bristol-Myers Squibb, Ono Pharmaceutical
April 2015 - Aug 2016Adoptive cell therapy (CAR-T therapy) trial conducted with 63 leukaemia patients in 11 countriesJuneNovartis
5 Jun 2015Two immunotherapy drugs reported to stop cancer cells avoiding destruction by immune system  
27 Aug 2015Experiments with mice showed that azacytidine treatment enhanced the responsiveness of tumors to anti–CTLA-4 therapy 
25 Mar 2016Common tags discovered on the surface of cancer cells opening up new avenues for immunotherapyMcGranahan, Furness, Rosenthal, Ramskov, Lyngaa, Saini, Jamal-Hanjani, Wilson, Birkbak, Hiley, Watkins, Shafi, Murugaesu, Mitter, Akarca, Linares, Marafioti, Henry, Van Allen, Miao, Schilling, Schadendorf, Garraway, Makarov, Rizvi,m Snyder, Hellman, MerghUniversity College London, Cancer Research UK, Francis Crick Insitute, Dana-Farber Cancer Institute, Broad Institute, University Duisburg-Essen, Memorial Sloan Kettering Cancer Center, Columbia Univertsity, Weill Cornell Medical College, Harvard Medical S
15 Apr 2016Gene editing used to prompt immune cells to combat cancerQuezada, Johnson, Menger, Sledzinska, Bergerhoff, Vargas, Smith, Poirot, Pule, Hererro, PeggsUniversity College London, Cancer Research UK, Cellectis
21 Jun 2016US NIH Recombinant DNA Advisory Committee approved first study in 15 patients using CRISPR/Cas 9 to genetically modify immune cells to attack cancerJuneUniversity of Pennsylvania
August 2016Marker identified for myeloid-derived suppressor cells, a type of cell associated with tumour resistance to certain cancer treatmentsWistar Institute
9 Oct 2016Nivolumab (Opdivo®) shown to be promising treatment for head and neck cancer in randomised control trials with 351 patientsFerrisUniversity of Pittsburg, MD Anderson Cancer Center
24 Oct 2016FDA approved pembrolizumab (Keytruda®) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test.Merck
23 Mar 2017US FDA granted accelerated approval to avelumab for the treatment of patients 12 years and older with metastatic Merkel cell carcinomaEMD Serono
12 Jul 2017US FDA Oncologic Drugs Advisory Committee recommended the approval of the first adoptive cell therapy (CAR-T cell therapy) for B cell acute leukaemiaNovartis, University of Pennsylvania
30 Aug 2017USA FDA approved CAR-T therapy for certain pediatric and young adult patients with a form of acute lymphoblastic leukemiaNovartis, University of Pennsylvania
20 Sep 2017Nivolumab (Opdivo®) made available for NHS patients with advanced lung cancer Honko, FreemanMedarex, Bristol-Myers Squibb, Ono Pharmaceutical

May 1893

First successful treatment of cancer patient with immunotherapy

1895

Humans treated with antiserum prepared against human cancer. This established the principle of using serotherapy to fight cancer

1899

First commercial vaccine developed for treatment of sarcoma

1901 - 1903

First successful transplants of tumours in animals reported, providing a new experimental system for studying the role of the immune system in cancer

1902

First attempt to vaccinate against cancer with a patient's own tumour tissue

1908

Paul Ehrlich reports that spontaneously developed tumours can be suppressed by the immune system

1910

Austrian physicians Ernest Freund and Gisa Kaminer observed that something in blood serum from cancer patients pervents the destruction of cancer cells

1914

Experiments by James B Murphy demonstrate that lymphocytes help animals reject grafted tumours

1915

James B Murphy puts forward hypothesis that the nonspecific stimulation of lymphocytes could provide a cure for cancer based on experiments he and John J Morton carried out on mice

1916 - 1922

Disappointing results reported from clinical trials treating breast cancer patients with low doses of X-ray radiation following tumour removal, discrediting the theory that stimulation of lymphocytes could help cure cancer.

1924

Austrian physicians Ernest Freund and Gisa Kaminer discover a substance in intestines of cancer patients that reduce ability of normal serum to dissolve cancer cells.

1929

First molecular marker, antigen, identified on a tumour, laying foundation for use of antibodies to diagnose and treat cancer

Apr 1929

Autopsies carried out on tuberculosis patients show them less likely to have contracted cancer

1957 - 1959

Concept developed that the immune system naturally protects against cancer

25 Jul 1959

Mice injected with BCG vaccine shown to develop resistance to growth of implanted tumours. This was the first direct evidence of the immune system's ability to prevent cancer.

Dec 1966

Scientists detect antibodies to the Epstein-Barr virus in patients with nasopharyngeal cancer which suggest the cancer is caused by a virus.

Feb 1969

Team led by Karl and Ingegerd Hellstrom observe serum from mice with chemically induced tumours can block reaction of lymphocytes

Jun 1971

Hellstom team suggest that antibodies bound to tumour cells mask their detection by the immune system

1972

US National Cancer Institute recommended creation of international registry of immunotherapy trials

1973

First successful bone marrow transplant from unrelated donor

8 Feb 1974

Immune surveillance theory that immune system provides protection against cancer discredited by research showing that 'Nude' mice lacking immune system function no more likely to develop tumours than normal mice

Feb 1975

Natural killer cell identified in mice and shown to be important part of immune system

15 Apr 1975

Human natural killer cell isolated

24 Apr 1975

Discovery of unique molecular marker, idiotype, on blood cancer cells, opening new avenue for cancer diagnosis and therapy

Sep 1975

Tumour necrosis factor (TNF) was discovered. It was the first immune molecule shown to kill cancer cells

10 Sep 1976

Discovery of first T cell growth factor, later named Interleukin-2 (IL-2)

Feb 1977

Scientists find a way to generate T cells in thymic tissue in test tubes, paving the way study mechanisms underlying the regulation of T cell development

1 Apr 1977

Development of first anti-idiotype antibodies. These are shown to activate immune defense cells to attack tumour cells in guinea-pigs

Jul 1977

T cell growth factor, later named Interleukin-2 (IL-2), discovered in mice, providing a means to grow and expand normal lypmphocytes in test tubes

1978

T cell-mediated immunity shown to aid tumour regression

1980

US National Cancer Institute added $13.5 million to its budget for new Biological Response Modifiers, igniting search for agents able to modify host's response to tumour cells

1981

First patient successfully treated with anti-idiotype monoclonal antibody

Jun 1982

Steven Rosenberg and colleagues first describe lymphokine-activated killer cells

Nov 1982

James Allison and collegues use monoclonal antibody to provide first biochemical description of tumour specific antigen of murine T-lymphoma

1 Dec 1982

First molecular markers, antigens, identified in melanoma tumours. These markers are now targeted by cancer drugs

24 Mar 1983

First cloning of Interleukin 2 (Il-2)

Nov 1983

A team of researchers including Philippa Marrack, John Kappler and James P Allison identified the first T cell antigen receptor

1984

Experiments show that injections with T-cell growth factor interleukin-2 can shrink tumours in humans

Jun 1984

First clinical experiments demonstrate the possibility of training T cells to attack tumours

1985

T cell surface proteins CD4 and CD8 cloned

Dec 1985

IL-2 based immunotherapy shown to reduce tumours in patients with melanoma and renal cell cancer

Dec 1986

Anti-tumour responses observed in 3 out of 10 patients given high-doses of Interleukin-2 (IL-2)

1987 - 1989

Scientists lay the foundation for the cloning of human tumour antigens recognised by cytotoxic T lymphocytes, a type of white blood cell that kills cancer cells

15 Mar 1987

First stable human anti-tumour cytotoxic T cell clones isolated and maintained in culture

Apr 1987

CD8 coreceptor proven to be actively involved in antigen recognition by killer T cells

9 Apr 1987

Successful results reported for trial using the cytokine IL-2 and lymphokine-activated killer cells to treat cancer

Jul 1987

Identification of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)

Nov 1987

First evidence provided for the interaction between the surface molecule CD4 and major histocompatibility class II

May 1988 - Oct 1989

Cytotoxic T lymphocytes shown to recognise distinct surface markers on human melanoma

Jul 1988

Biochemical initiators of T Cell activitation, CD4 and CD8-p56, discovered

1988 - 1989

First evidence discovered of a physical link between oncoproteins and tumour suppressors

Dec 1988

Scientists report cloning the gene for the human cytotoxic T lymphocyte-associated antigen (CTLA-4)

22 Dec 1988

9 out of 15 melanoma patients successfully treated with autologous tumor-infiltrating lymphocytes cultured with the cytokine IL-2

Feb 1989

Scientists demonstrate the importance of CD28, a cell surface molecule found on T-cells, for the activation and survival of T cells

May 1989

First human test demonstrated safety of retroviral vector for gene therapy and potential of laboratory produced tumor killing cells for cancer immunotherapy

Sep 1989

Giorgio Trinchieri and colleagues identified interleukin-12 (IL-12), a cytokine that helps regulate the body’s resistance to infections and cancer

Dec 1989

First use of genetically engineered T cells to redirect T cells to recognise and attack tumour cells

1990

US FDA approved BCG, a bacterial vaccine against tuberculosis, to treat early stage bladder cancer. It was the first FDA approved immunotherapy

15 Apr 1993

Immune molecule, granulocyte-macrophage colony stimulating factor or GM-CSF, discovered to strengthen immunity against tumours

1994 - 1995

Identification and characterisation of the natural killer T cell, a lymphocyte able to bind and kill certain tumour and virus-infected cells

22 Mar 1996

Mice experiments published demonstrating that blocking the CTLA-4 molecule on immune cells can cure cancer

Mar 1996

Hypothesis put forward that T cells unable to attack tumours because they are blocked by the cytotoxic T lymphocite-associated antigen (CTLA-4).

Nov 1996

Experiments demostrate antigen-specific CD4+ and T cells become tolerant during tumour growth in test tubes

1997

FDA approved the first monoclonal antibody cancer drug for the American market

2000

First clinical trials launched to test first immune checkpoint inhibitor drug containing a monoclonal antibody against CTLA-4 (ipilimumab, Yervoy®)

14 Sep 2002

Regulatory T cells discovered to restrain cytolytic T cells attacking cancer via messanger chemical called TGF-beta

17 Sep 2002

Cancer cells shown to be capable of hijacking PD-1 protein to evade destruction by immune system

2003

Genetic switch identified that controls the development of T cells, an important immune cell that controls against autoimmunity and excess inflammation

May 2005

Medarex and Ono Pharmaceuticals entered research alliance to develop a fully human anti-PD-1 antibody for the treatment of cancer

24 Nov 2008

First anti-PD-1 antibody entered phase 1 clinical trial for cancer

25 Mar 2011

First immune checkpoint inhibitor drug targeting CTLA4 (ipilimumab, Yervoy®), approved by the FDA

Apr 2012

First child with leukaemia treated with adoptive cell therapy (CAR-T therapy)

22 Dec 2014

First immune checkpoint inhibitor drug targeting PD-1 (nivolumab, Opdivo®) approved in US

Apr 2015 - Aug 2016

Adoptive cell therapy (CAR-T therapy) trial conducted with 63 leukaemia patients in 11 countries

5 Jun 2015

Two immunotherapy drugs reported to stop cancer cells avoiding destruction by immune system

27 Aug 2015

Experiments with mice showed that azacytidine treatment enhanced the responsiveness of tumors to anti–CTLA-4 therapy

25 Mar 2016

Common tags discovered on the surface of cancer cells opening up new avenues for immunotherapy

15 Apr 2016

Gene editing used to prompt immune cells to combat cancer

21 Jun 2016

US NIH Recombinant DNA Advisory Committee approved first study in 15 patients using CRISPR/Cas 9 to genetically modify immune cells to attack cancer

Aug 2016

Marker identified for myeloid-derived suppressor cells, a type of cell associated with tumour resistance to certain cancer treatments

9 Oct 2016

Nivolumab (Opdivo®) shown to be promising treatment for head and neck cancer in randomised control trials with 351 patients

24 Oct 2016

FDA approved pembrolizumab (Keytruda®) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test.

23 Mar 2017

US FDA granted accelerated approval to avelumab for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma

12 Jul 2017

US FDA Oncologic Drugs Advisory Committee recommended the approval of the first adoptive cell therapy (CAR-T cell therapy) for B cell acute leukaemia

30 Aug 2017

USA FDA approved CAR-T therapy for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia

20 Sep 2017

Nivolumab (Opdivo®) made available for NHS patients with advanced lung cancer