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.
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.
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.
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 San Francisco. 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.
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
|1910||Austrian physicians Ernest Freund and Gisa Kaminer observed that something in blood serum from cancer patients pervents the destruction of cancer cells||Freund, Kaminer||Rudolf-Stiftung Hospital|
|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.||Freund, Kaminer||Rudolf-Stiftung Hospital|
|February 1969||Team led by Karl and Ingegerd Hellstrom observe serum from mice with chemically induced tumours can block reaction of lymphocytes||Hellstrom, Evans, Heppner, Pierce, Yang||Fred Hutchinson Cancer Center|
|June 1971||Hellstom team suggest that antibodies bound to tumour cells mask their detection by the immune system||Sjogren, Hellstrom, Bansal||Fred Hutchinson Cancer Center|
|July 1987||Identification of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)||Brunet, Denizot, Luciani, Roux-Dosseto, Suzan, Mattei, Golstein||INSERM-CNRS|
|December 1988||Scientists report cloning the gene for the human cytotoxic T lymphocyte-associated antigen (CTLA-4)||Dariavach, Mattei, Golstein, Lefranc||INSERM-CNRS|
|May 1990||Discovery of lymphocyte activation gene 3 (LAG3)||Triebel, Jitsukawa, Baixeras, Roman-Roman, Genevee, Viegas-Pequinot, Hecend||Institut Gustave-Roussy|
|November 1992||PD-1 (programmed cell death protein 1) discovered by team led by Tasuku Honjo||Honjo||Kyoto University|
|1 Jan 1995||Two teams, one led by James Alison and the other by Jeffrey Bluestone, independently show CTLA-4 can inhibit the activity of T cells||Allison, Bluestone, Leach, Krummel||University of California Berkeley, University of California San Francisco|
|22 Mar 1996||Mice experiments published demonstrating that blocking the CTLA-4 molecule on immune cells can cure cancer||Leach, Krummel, Allison||University California Berkeley|
|March 1996||Hypothesis put forward that T cells unable to attack tumours because they are blocked by the cytotoxic T lymphocite-associated antigen (CTLA-4).||Leach, Krummel, Allison||University California Berkeley|
|2000||First clinical trials launched to test first immune checkpoint inhibitor drug containing a monoclonal antibody against CTLA-4 (ipilimumab, Yervoy®)||Allison||Medarex, University of California Berkley|
|October 2000||PD-1 protein shown to be important mechanism in dampening down the immune response||Freeman, Long, Iwai||Dana-Farber Cancer Institute|
|2002||T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) discovered|
|17 Sep 2002||Cancer cells shown to be capable of hijacking PD-1 protein to evade destruction by immune system||Iwai , Ishida, Tanaka, Okazaki, Honjo, Minato||Japan Science and Technology Corporation|
|25 Mar 2011||First immune checkpoint inhibitor drug targeting CTLA4 (ipilimumab, Yervoy®), approved by the FDA||Allison||Medarex, University of California Berkley|
|September 2014||FDA approved nivolumab (Opdivo®), an immune checkpoint inhibitor targeting PD1, for treating melanoma|
|22 Dec 2014||First immune checkpoint inhibitor drug targeting PD-1 (nivolumab, Opdivo®) approved in US||Allison||Medarex, Bristol-Myers Squibb, University of California Berkley|
|27 Aug 2015||Experiments with mice showed that azacytidine treatment enhanced the responsiveness of tumors to anti–CTLA-4 therapy|
|9 Oct 2016||Nivolumab (Opdivo®) shown to be promising treatment for head and neck cancer in randomised control trials with 351 patients||Ferris||University of Pittsburg, MD Anderson Cancer Center|
|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.||Merck|
|23 Mar 2017||US FDA granted accelerated approval to avelumab for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma||EMD Serono|
Austrian physicians Ernest Freund and Gisa Kaminer observed that something in blood serum from cancer patients pervents the destruction of cancer cells
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.
Team led by Karl and Ingegerd Hellstrom observe serum from mice with chemically induced tumours can block reaction of lymphocytes
Hellstom team suggest that antibodies bound to tumour cells mask their detection by the immune system
Identification of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)
Scientists report cloning the gene for the human cytotoxic T lymphocyte-associated antigen (CTLA-4)
Discovery of lymphocyte activation gene 3 (LAG3)
PD-1 (programmed cell death protein 1) discovered by team led by Tasuku Honjo
1 Jan 1995
Two teams, one led by James Alison and the other by Jeffrey Bluestone, independently show CTLA-4 can inhibit the activity of T cells
22 Mar 1996
Mice experiments published demonstrating that blocking the CTLA-4 molecule on immune cells can cure cancer
Hypothesis put forward that T cells unable to attack tumours because they are blocked by the cytotoxic T lymphocite-associated antigen (CTLA-4).
First clinical trials launched to test first immune checkpoint inhibitor drug containing a monoclonal antibody against CTLA-4 (ipilimumab, Yervoy®)
PD-1 protein shown to be important mechanism in dampening down the immune response
T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) discovered
17 Sep 2002
Cancer cells shown to be capable of hijacking PD-1 protein to evade destruction by immune system
25 Mar 2011
First immune checkpoint inhibitor drug targeting CTLA4 (ipilimumab, Yervoy®), approved by the FDA
FDA approved nivolumab (Opdivo®), an immune checkpoint inhibitor targeting PD1, for treating melanoma
22 Dec 2014
First immune checkpoint inhibitor drug targeting PD-1 (nivolumab, Opdivo®) approved in US
27 Aug 2015
Experiments with mice showed that azacytidine treatment enhanced the responsiveness of tumors to anti–CTLA-4 therapy
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