James Allison, Immune checkpoint blockade for treatment of cancer

T-cells are lymphocytes, a potent type of white blood cell with receptors that recognize and bind to antigens. T-cells launch immune responses to destroy these pieces of invading organisms, abnormal cells or proteins, which are captured and presented to the T-cells by antigen-presenting cells.

James Allison, a long-time cancer researcher who began his career at the University of Texas Cancer Center in 1978, studied why T-cells failed to recognize or attack certain cancers, evading the body’s natural immune system. Allison’s seminal discoveries in T-cell biology include the T-cell antigen receptor used by T-cells to bind to and recognize antigens; that T-cells require a second signal to launch an immune response after they are bound to an antigen (B7 molecules on presenting cells must engage a surface molecule called CD28 on the T-cell); and how a molecule called CTLA-4 that protrudes from the T-cells’ surface inhibits activated T-cells to protect normal cells from attack as well as protecting cancer cells from attack.

Years of research led Allison to the development of an antibody against CTLA-4 that resulted in the creation of a drug called ipilimumab. The drug blocks CTLA-4, which allows the immune system over time to recognize and attack cancer cells. This new approach to cancer treatment is called immune checkpoint blockade because instead of the traditional approach of attacking cancers directly, it aids the body’s immune system in attacking the cancerous cells.

Allison believes that the new approach combined with targeted cancer therapy can turn cancer’s genomic instability, which it uses to build resistance to drugs, against it. He says when you kill tumor cells with a targeted drug, you cause inflammatory cell death, which introduces lots of new antigens into the system. Combine checkpoint blockade with the drug and the antigens become targets for the immune system, turning one drug into many drugs.

About 25 percent of patients with late stage metastatic melanoma who took ipilimumab in clinical trials have lived for five years or longer. It is the first drug ever to improve the survival rate of such patients. The drug was approved by the U.S. Food and Drug Administration in May 2011 and is marketed by Bristol-Myers Squibb as Yervoy. The company reported Yervoy sales of US$706 million for the full year 2012. It has been used on more than 4,000 patients with a variety of cancers, including clinical trials for prostrate, renal, lung and ovarian cancers.

Allison and other researchers hope that anti-CTLA-4 may be just the first of a series of anti-cancer immunotherapies. Treating the immune system, rather than specific tumors, is an approach that will work across many types of cancer, Allison notes. Allison today is professor and chair of The University of Texas MD Anderson Cancer Centre Department of Immunology.

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James Allison, Immune checkpoint blockade for treatment of cancer

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