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Using a protein to attack the Achilles’ heel of cancers

— Photo: G.P. Sampath Kumar

Potent weapon: Inflammatory lesions, as seen here in the lungs, can vanish when the newly discovered protein is used.

In Greek mythology, Achilles was made pretty much indestructible when, in his infancy, his mother Thetis held him by his feet and dipped him in the magical river Styx, which was believed to make him immortal.

When as a man he fought the Trojans to avenge the abduction of Helen, he was shot dead with a poisoned arrow by Paris, the prince of Troy. (Incidentally, the French city is not named after him, but after the Gaulish tribe Parisii).

Paris shot him in the heel, a part that was not wetted by the river, since Thetis held him by the heel. Hence the phrase Achilles Heel to denote a vulnerable spot. Where is the Achilles’ heel of cancers? This set of diseases arises when some of the otherwise well-behaved cells of our body turn rogue.

Triggered by a host of factors — radiation, smoking, certain aromatic chemicals — these rogue cells go on a frenzy of uninhibited division and growth, often into tumours. These eat up all nutrition in the system, weakening it and ultimately causing death.

Surgeons try and cut off the tumours or kill them with anti-cancer drugs, but the treatment often turns out to be as bad as the disease itself.

And some of the rogue cells escape away from the site of treatment (metastatize), causing cancer elsewhere. The question thus is – how does one tame, treat or destroy the rogues, yet leave the rest of the cells, tissues and organs safe and healthy? In other words, where is the Achilles’ heel of cancer cells?

A clue to this identification of cancer cells came in 1997 when the research group of Dr. Lloyd Old at the Cornell University Medical College in New York discovered a protein that was present only in the esophageal cancer cells of a patient, which was not seen in the other normal cells of his body (PNAS, 94: 1914, 1997). This protein was christened NY-ESO1 (presumably denoting the esophageal cancer cells of the patient in New York).

NY-ESO1 has since been found in a whole array of human cancers — skin, breast, bladder, prostate, liver, to name some.

It appears hat this protein is aberrantly produced in human cancer cells, and can therefore serve as a marker ‘antigen’ or bait that could be targeted by immunological means. Further studies revealed that NY-ESO1 indeed generates immune response in the human body. A group of cells that protect the body from ‘foreign’ invasion, called CD4 T cells were seen to elaborate in the cancer patient’s body, which were holding on to a portion of the NY-ESO1 protein, heroically attempting to initiate steps that would get rid of the cancer cells.

Working with others at the Sloan Kettering Cancer Center New York and a group at Frankfurt, Germany, Old’s group showed in 2003 (PNAS 100, 8862, 2003) that the T cells do not need the whole protein to attach to. Even certain short segments of the NY-ESO1 molecule (which could be easily synthesized in the chemistry lab as short peptide chains) are recognized. Thus, an antibody response, specifically targeting the cancer cells became possible.

This leads to the idea that immunology, rather than (or besides) chemo-or radiation therapy could become an option that needs to be improved and advanced. Indeed there has been some preliminary work suggesting the possibility of a vaccine against some forms of cancer.

The human hepatitis B vaccine (HBV) appears to offer some protection against liver cancer, and some benefits are anticipated from the HPV vaccine against cervical cancer, not only for prevention but also as therapy.

While these two vaccines are specific to certain cancers (liver, cervix), the molecule NY-ESO1 or its fragment peptides appear common to many (some say over 75 per cent) different forms of cancer, and respond to the action of the immunity cells, namely CD4 T cells. If only we could clone these cells and make billions of them and inject them into the body, so that they could overpower the cancer cells and get rid of them!

This is precisely what Dr. Cassian Yee and colleagues at the Fred Hutchinson Cancer Research Center at Seattle, WA, USA have been able to do.

They were treating a 52-year-old man with recurrent melanoma (skin cancer). He did not respond to high dose interferon alpha, or interleukin 2, or local incision surgery. And his cancer had spread from the skin to the groin and lungs.

This was when Dr. Yee and his colleagues decided to extract the CD4 T cells from the patient, and also a little of his dendritic cells (which help in presenting the antigen), and cultured the two (in 10:1 ratio) in the presence of a 14-amino acid-long peptide segment of NY-ESO1 as the antigen.

This generated billions of T cells specifically recognizing the cancer cell through its antigen, leaving the other cells alone. The Achilles’ heel was captured and targeted.

These primed cells were then injected into the patient. Within two months, all cancer cells in his body — skin, lung, groin and all — vanished and the patient is healthy! (June 18 issue of the New England Journal of Medicine).

The body’s own immune system turned into a weapon against cancer. This is perhaps one of the most remarkable advances in cancer therapy to date (The Hindu, June 20, 2008).

Clearly NY-ESO1 might not be the only cancer cell-specific marker or antigen. The search for other molecules is being made by several groups, including that of Dr. Pramod Srivastava of Connecticut (earlier at CCMB Hyderabad).

Also, there might be other ways of priming the body’s immune system. As Dr. Ghanshyam Swarup of CCMB remarks, there are several nutritional, plant extract-based, or even using methods of mental stimulation (psychophysiological?!) approaches that might strengthen and prime the immuno-defences of the body.

While all these need to be studied, validated and understood, the work of Drs. Old and Yee give us molecular insights into the process.

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