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 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

E. Freund, G. Kaminer, 'Ueber die Beziehungen zwischen Tumorzellen und Blutserum', Biochem. Ztschr, 26 (1910) 26, 312-24.1910-01-01T00:00:00+0000E. Freund, G. Kaminer, Wiener Klinische Wochenschrift, Jan 19241924-01-01T00:00:00+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+0000JF Brunet et al, 'A new member of the immunoglobulin superfamily--CTLA-4', Nature 328 (1987), 267-70. 1987-07-16T00:00:00+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+0000F. Triebel, S. Jitsukawa, E. Baixeras, G. Roman-Roman, C. Genevee, E. Viegas-Pequinot, T. Hecend, 'LAG-3, a novel lymphocyte activation gene closely related to CD4', Journal Experimental Medicine, 171 (1990), 1393-1405. 1990-05-01T00:00:00+0000Y. Ishida, Y. Agata, T. Honjo, 'Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death', EMBO J, 11 (1992), 3887-95.1992-11-01T00:00:00+0000E. R. Kearney, T. L. Walunas, R. W. Karr, P. A. Morton, D. Y. Loh, J. A. Bluestone, M. K. Jenkins, 'Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4', Journal of Immunology, 155/3 (1995), 1032-36; M.F. Krummel, J.P. Allison, 'CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation', J Exp Med, 182/2 (1995), 459-6. 1995-01-01T00:00:00+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+0000Launched by the biotechnology company Medarex in collaboration with Jim Allison. 2000-01-01T00:00:00+0000G.J. Freeman, A.J. Long, Y. Iwai, et al, 'Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation', J Exp Med, 192/7 (2000), 1027–34.2000-10-01T00:00:00+0000L. Mooney, C. A. Sabatos, J.L. Gaglia, A. Ryu, H. Waldner, T. Chernova, S. Manning, E. A. Greenfield, A. J. Coyle, R.A. Sobel, G. J. Freeman, V. K. Kuchroo, Nature, 2002, 415/6871, 536-41.2002-01-01T00:00:00+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+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+0000The drug was developed by scientists at Medarex2014-09-01T00:00:00+0000The drug, a monoclonal antibody, was approved by the FDA for the treatment of patients with melanoma. 2014-12-22T00:00:00+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+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, a form of immunotherapy, is a PDL1 checkpoint inhibitor.2017-09-20T00:00:00+0000
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
1 Jan 1995Two teams, one led by James Alison and the other by Jeffrey Bluestone, independently show CTLA-4 can inhibit the activity of T cellsAllison, Bluestone, Leach, KrummelUniversity of California Berkeley, University of California San Francisco
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
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 
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
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
September 2014FDA approved nivolumab (Opdivo®), an immune checkpoint inhibitor targeting PD1, for treating melanoma 
22 Dec 2014First immune checkpoint inhibitor drug targeting PD-1 (nivolumab, Opdivo®) approved in US Honko, Freeman, LonbergMedarex, Bristol-Myers Squibb, Ono Pharmaceutical
27 Aug 2015Experiments with mice showed that azacytidine treatment enhanced the responsiveness of tumors to anti–CTLA-4 therapy 
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
20 Sep 2017Nivolumab (Opdivo®) made available for NHS patients with advanced lung cancer Honko, FreemanMedarex, Bristol-Myers Squibb, Ono Pharmaceutical

1910

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

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.

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

Jul 1987

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

Dec 1988

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

May 1990

Discovery of lymphocyte activation gene 3 (LAG3)

Nov 1992

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

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).

2000

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

Oct 2000

PD-1 protein shown to be important mechanism in dampening down the immune response

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

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

Sep 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

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

20 Sep 2017

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