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Helping the Immune System Fight Cancer

Posted on May 7, 2014, 6:22 AM
Helping the Immune System Fight Cancer

By Lauren Pecorino, PhD

Author of “Why Millions Survive Cancer” and “ The Molecular Biology of Cancer: Mechanisms, Targets, and Therapeutics”.

“The cure for cancer may be inside us.” It sounds dramatic, but a flurry of recent reports about the success of cancer immunotherapy has been headline news.

Stimulating the immune system to fight disease by vaccination is one of the greatest accomplishments of modern medicine. The armament of vaccines distributed in childhood has curtailed many infectious diseases from diphtheria to pertussis to chicken pox, and has eradicated small pox and nearly eradicated polio worldwide. Although fighting cancer is more complex than fighting a foreign infectious agent such as a virus, we are learning how to use the immune system to fight cancer.

The textbook definition of cancer is that it is a set of diseases characterized by abnormal cell growth and the ability to spread or metastasize. The most difficult part of curing cancer is being able to attack all the cancer cells that have spread throughout the body. Immunotherapies promise to do just that. Like vaccines, their effect may be durable and last for years and even decades.

This is how it works. The immune system consists of several types of cells that play a role in the body’s natural defense against invaders. T cells, a type of white blood cell, act as “warrior cells” and have the potential to recognize and kill cancer cells. Recognition of tumor cells is based on proteins on their cell surface called tumor-associated or tumor-specific antigens. These tumor antigens are normal proteins expressed in abnormally high amounts or are products of genes that are mutated in cancer cells, respectively. The trigger for the attack is the presentation of tumor antigens to T cells by other cells of the immune system called antigen-presenting cells. But without medical interventions, a T-cell response is either inhibited by tumor cells or there are just not enough of them to conquer cancer.

So there are things that a scientist developing immunotherapies for cancer must do.  They must identify the inhibitors of T cells that are released from tumor cells and/or they must figure out how to expand the army of T cells that are capable of attacking the tumor.

Early progress has been demonstrated on both fronts. First, several inhibitors of a T-cell response have been identified. An immune response needs to be controlled and switched off to prevent it from attacking the body’s own cells and the molecules involved in the switch are called checkpoints. Some of the inhibitors identified are molecules of these checkpoints and others are molecules are from tumors that activate these checkpoints. This has enabled scientists to use a reliable “tried and tested tool” to block the checkpoints. The tools, called antibodies, are also part of our body’s immune system and target antigens but we have learned how to produce and use them as drugs. Such antibodies act as “checkpoint blockades” and are being tested in clinical trials. They block the inhibitors to stimulate the immune response.

Two “Dream Teams” funded by SU2C are exploring immunotherapeutic therapies.

The SU2C-CRI Dream Team is looking for ways to combine different immunotherapy approaches with each other and with other known cancer drugs to see if combinations are better than one approach. Exploring combinations of cancer drugs is a current trend of research, especially after the success of drug combinations against human immunodeficiency virus (HIV) infection. The team will also investigate biomarkers, such as biochemical products detectable in the blood or urine of patients, to predict which patients are most likely to respond to immunotherapies.

The SU2C-St. Baldrick’s Pediatric Cancer Dream Team is focusing on childhood cancers. These cancers usually do not have many proteins produced from mutated genes that new molecular therapies are able to target. They plan to identify cancer-specific antigens for childhood cancers and design immunotherapies that will target them. Ed.

One such drug called ipilimumab, developed by Bristol-Myers Squibb, is now approved by the FDA. It is an antibody that targets an inhibitor molecule of T cells, called cytotoxic T-lymphocyte antigen 4 (CTLA-4), and has been successful in treating some patients with melanoma – a cancer that had few treatment options before ipilimumab was developed.

Another approach is a more tailored strategy to amplify the number of T cells that are capable of attacking the tumor and may include two designs. The first design is to expand the army of T cells by isolating a subset of cells from a patient’s tumor and expanding the T cell population in the lab.

The other approach is to genetically modify a patient’s T cells in the lab so that they produce engineered molecules that can recognize an individual’s tumor cells and then inject the altered T cells back into patient. The engineered molecules are called CARs (chimaeric antigen receptors) and are designed to recognize specific tumor antigens which match those on patient’s tumor cells. In this way, a “trained” and expanded cell population is given to the patient.

Immunotherapy that engages with our body’s immune system promises to yield effective, durable and broadly applicable treatments to fight cancer. A characteristic of immunotherapies is that they may take longer to show an effect, but results may be more efficient and longer lasting than previous types of cancer drugs.

Immunotherapies, such as those that stop immunosuppression, may be appropriate for a range of cancer types. But first we must understand why only some patients respond, and design means of identifying such patients. We must also overcome potential side effects such as overstimulation of the immune response. Nevertheless, immunotherapy is the great new hope for cancer.

Lauren Pecorino was born in New York City, USA. She received her PhD from the State University of New York at Stony Brook in Cell and Developmental Biology. She crossed the Atlantic to carry out a postdoctoral tenure at the Ludwig Institute for Cancer Research, London. She is a Principal Lecturer at the University of Greenwich where teaches Cancer Biology and Therapeutics. The teaching of this course motivated her to write The Molecular Biology of Cancer: Mechanisms, Targets, and Therapeutics, now in its third edition. Feedback on the textbook posted on Amazon from a cancer patient drove her to write a book on cancer for a wider audience: Why Millions Survive Cancer: the Successes of Science.

Further reading:

Couzin-Frankel, J. (2013) Cancer Immunotherapy. Science 342:1432-1433.

Graziani, G., Tentori, L., and Navarra, P. (2012) Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol. Res. 65:9-22.

Sliwkowski and Mellman (2013) Antibody Therapeutics in Caner. Science 341: 1192-1198.

Weintraub, K. (2013) Releasing the breaks. Nature 504:S6-S8.

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