21 Immune checkpoint inhibitors | Summary

Immune checkpoint inhibitors

Checkpoint inhibitors are drugs that help release the brakes cancer cells put on the immune system to prevent their destruction. This is usually achieved with an antibody which is used to block certain proteins carried on the surface of cancer cells that prevent their recognition by the immune system and hence their destruction. In 2015 Jimmy Carter, the former president of the US, announced he was free of melanoma that had spread to his liver and brain. He had improved following treatment with an immune checkpoint inhibitor drug. How do checkpoint inhibitors work? Such therapy is designed to block the biological pathways cancer cells use to disguise themselves from the immune system and prevent their destruction. Immune checkpoint inhibitors are now considered one of the most promising avenues for the treatment of advanced cancer. Their development grew out of research to understand the regulation of immune responses.

Metatastic melanoma cells dividing and spreading. Immune checkpoint inhibitor drugs are now a promising treatment for advanced melanoma. Credit: Julio C Valencia, NCI Center for Cancer Research.

Definition

Checkpoint inhibitors are drugs that help release the brakes cancer cells put on the immune system to prevent their destruction. This is usually achieved with an antibody which is used to block certain proteins carried on the surface of cancer cells that prevent their recognition by the immune system and hence their destruction.

Importance

Immune checkpoint inhibitor drugs have been hailed as a major breakthrough for cancer treatment by oncologists. What is particularly impressive is how durable and long-lasting the responses are. Patients originally given just weeks to live, survive for many years following treatment. Where the drugs have proven particularly helpful has been in the treatment of patients with metastatic cancer, particularly melanoma and lung cancer. Here the drugs have helped convert what were once considered fatal diseases into a chronic condition. The drugs are also thought to have potential for the treatment of renal cell carcinoma, non–small cell lung cancer, urothelial cancer, head and neck cancer, ovarian cancer and various lymphomas.

As of March 2017 the US FDA had approved five checkpoint inhibitor drugs: ipilimumab (Yervoy®), pembrolizumab (Keytruda®), nivolumab (Opdivo®), atezolizumab (Tecentriq®) and avelumab (Bavencio®). Dozens of clinical trials were also underway with immune checkpoint inhibitors for a broad range of conditions. Just how far the field has progressed can be seen from that the fact that analysts from Visiongain have forecast that the overall global market for immune checkpoint inhibitors for cancer will be just over $16 billion in revenue by 2020.

Discovery

The history of checkpoint inhibitors stretches back to the early twentieth century. In 1910 two Jewish Austrian physicians, Ernest Freund and Gisa Kaminer based at the Rudolf-Stiftung Hospital in Vienna, noticed that blood serum taken from healthy individuals could dissolve cancer cells whereas that of cancer patients could not. By 1924 they had found a substance in the intestines of cancer patients which when added to normal serum reduced its ability to dissolve cancer cells. News of their finding quickly spread across the world. Their discovery, however, was soon forgotten and in 1938, following the annexation of Austria by Nazi Germany, both physicians fled to London where they soon died.

Many years later, in 1966, Karl and Ingegerd Hellstrom, a Swedish couple based at the Fred Hutchinson Cancer Center spotted that serum taken from mice with chemically induced tumours suppressed the reaction of lymphocytes. They attributed this to some sort of blocking factor. In 1971 they published a paper in Advances in Immunology suggesting that 'blocking antibodies bind to the target tumour cells and thereby mask their antigens from detection by immune lymphocytes'. By 1982 this paper had been cited 653 times, making it a citation classic. It would take some time before the exact blocking mechanism was unravelled. This was eventually pieced together as a result of a discovery made in 1987. That year a French group of researchers, led by Jean-Francoise Brunet, detected a new protein on the surface of T lymphocytes. They called the new molecule ‘cytotoxic T lymphocyte-associated antigen 4’ (CTLA-4).

For a number of years it remained unknown what role CTLA-4 played. The mystery was finally solved in 1995 by two teams working independently from each other: one led by James Allison at the University of California at Berkeley and the other by Jeffrey Bluestone at the University of California. They showed that CTLA-4 could inhibit the activity of T cells. Allison was the first to realise the same mechanism could provide a means of treating cancer. To this end he developed a monoclonal antibody (Mab) to block CTLA-4. Encouragingly, the Mab inhibited the growth of tumours in mice. The University of California soon took out a patent on his technique.

Based on his results Allison began looking for a commercial partner to develop his idea further. Most companies, however, were reluctant to take on such a venture. In part this was because he was suggesting the suppression of a natural brake on the immune system to unleash an attack on the cancer. This contrasted other forms of immunotherapy, most of which were designed to ramp up the immune system to attack cancer. Many immunology researchers were additionally sceptical about the efficacy of an antibody based treatment for cancer.

By 1999, however, Allison’s patent had been licensed to Medarex, a small biotechnology company founded in Princeton in 1987. This was instigated by two of the company’s key scientists, Alan Korman and Nils Lonberg, who were some of the first to grasp the potential of Allison’s work. In 2000 Medarex launched its first clinical trials with a human Mab binding to CTLA-4. This paved the way to the approval of ipilimumab for the treatment of metastatic melanoma by the FDA in 2011. It was the first immune checkpoint inhibitor to reach market.

Three years later the FDA approved another immune checkpoint inhibitor, nivolumab, developed by Medarex. This was founded on the back of the discovery of another protein related to CTLA-4 on T cells that could inhibit their activity. Called PD-1, this protein was first spotted in 1992 by Tasuku Honjo and his colleagues at Kyoto University, but its function remained an enigma until the late 1990s when it was shown to help dampen the immune response after the elimination of a disease. Soon after this, Gordon Freeman and colleagues at the Dana-Farber Institute demonstrated that cancer cells were capable of hijacking the PD-1 protein to evade attack by the immune system.

Following the success of ipilimumab several other immune checkpoint pathways have begun to be explored the treatment of cancer. This has been aided by ongoing research into the regulation of immune responses. These have uncovered a number of important molecules, including the lymphocyte activation gene 3 (LAG3), T cell immunoglobulin and mucin domain-containing 3 (TIM3) protein, Indoleamine-2,3-dioxygenase (IDO) and VISTA, short for V-domain Ig suppressor of T cell activation. Out of all of the molecules now being investigated, the greatest progress has made so far with LAG3.

In 2015 it was estimated that there more than 1,000 immune checkpoint clinical trials underway. Such trials are exploring not only new immune checkpoint pathways but also different combinations of immune checkpoint inhibitors together with radiation, chemotherapy and targeted therapies.

Application

Cancer immunotherapy is designed to induce, enhance, or suppress the body’s immune system to combat tumours by using the body’s own properties, or cells grown in the laboratory. It exploits the fact that cancer cells often carry markers on their surface, known as tumour-associated antigens, that can be detected by the immune system.

Cancer immunotherapy generally takes two different forms. The first, known as active immunotherapy, aims to stimulate the immune system, and the second, known as passive immunotherapy, aims to strengthen the cancer patient's immune system.

Immunotherapy is achieved through a number of different approaches. These range from re-activating a switch in immune cells that tumour cells turn off to prevent their own destruction, to tagging cancer cells for their elimination by immune cells, or genetically modifying a patient’s own T cells, the foot soldiers of the immune system, to directly destroy cancer cells. Immunotherapy developped on the back of knowledge accumulated from the early development of vaccines and serum therapies for infectious diseases.

Issues

While immune checkpoint inhibitor drugs now offer a promising treatment for advanced cancer, they can cause serious side effects some of which can be fatal. Ipilimumab, for example, can cause lung inflammation and hepatitis. In some cases patients find the toxicity of ipilimumab so intolerable that they stop taking it. Managing the adverse events can also be expensive.

Another major problem with immune checkpoint inhibitors is that they only work for about a quarter of all cancers. One of the reasons for this is that cancer cells not only inhibit pathways that affect T cell functions. This is beginning to be addressed by the use of a combination of different drugs and the development of treatments that targeting other immune-evasion mechanisms.

In addition to the above, the costs of treatment with checkpoint inhibitor medications are substantial which is imposing a significant burden on healthcare resources. The high price tag associated with checkpoint inhibitors are not unique and are reflective of an ongoing issue with other antibody based treatments and innovative medicines.


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 and interviews conducted by Lara Marks with Nils Lonberg and Donald Drakeman, March 2017.

Immune checkpoint inhibitors: timeline of key events

Date Event People Places
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
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
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
July 1987Identification of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)Brunet, Denizot, Luciani, Roux-Dosseto, Suzan, Mattei, GolsteinINSERM-CNRS
December 1988Scientists report cloning the gene for the human cytotoxic T lymphocyte-associated antigen (CTLA-4)Dariavach, Mattei, Golstein, LefrancINSERM-CNRS
May 1990Discovery of lymphocyte activation gene 3 (LAG3)Triebel, Jitsukawa, Baixeras, Roman-Roman, Genevee, Viegas-Pequinot, Hecend Institut Gustave-Roussy
November 1992PD-1 (programmed cell death protein 1) discovered by team led by Tasuku HonjoHonjoKyoto University
January 1, 1995Two teams, one led by James Alison and the other by Jeffrey Bleusteon, indepdently show CTLA04 can inhibit the activity of T cellsLeach, Krummel, AllisonUniversity of California Berkeley, University of California San Francisco
March 22, 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
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
October 2000PD-1 protein shown to be important mechanism in dampening down the immune responseFreeman, Long, IwaiDana-Farber Cancer Institute
2002T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) discovered
September 17, 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
March 25, 2011First immune checkpoint inhibitor drug targeting CTLA4 (ipilimumab, Yervoy®), approved by the FDAAlisonMedarex, University of California Berkley
September 2014FDA approved nivolumab (Opdivo®), an immune checkpoint inhibitor targeting PD1, for treating melanoma
December 22, 2014First immune checkpoint inhibitor drug targeting PD-1 (nivolumab, Opdivo®) approved in US AlisonMedarex, Bristol-Myers Squibb, University of California Berkley
October 9, 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
October 24, 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
March 23, 2017US FDA granted accelerated approval to avelumab for the treatment of patients 12 years and older with metastatic Merkel cell carcinomaEMD Serono

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