Immune checkpoint inhibitors

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.

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.

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 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.

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 profile was written by Lara Marks in May 2017. Thanks go to Nils Lonberg and Donald Drakeman for reading earlier drafts of the work. For a fuller history of checkpoint inhibitors see L. Marks, 'The changing fortune of immunotherapy', in L. Marks, ed. Engineering Health: Biotechnology and Medicine, Royal Society of Chemistry, 2018.

Immune checkpoint inhibitors: timeline of key events

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