BioWorld International Correspondent

LONDON - A clinical trial of gene therapy for bowel cancer will begin in the UK next year, following a successful pilot study in which the genetically engineered lymphocytes of patients with bowel cancer were shown to be capable of killing tumor cells in the laboratory.

Robert Hawkins, of the Cancer Research UK Department of Medical Oncology at the Paterson Institute in Manchester, said, "What we have done in this new study is give immune cells the equipment they need to recognize, home in on and destroy cells from tumors, allowing us to harness the power of the immune system to tackle the disease. We have shown that the technique works 100 percent of the time in the laboratory, but the real test will be whether it works in cancer patients."

Robert Souhami, director of clinical research at Cancer Research UK, the UK's largest cancer research charity, which funded the study, cautioned that the new technique still needed further development before it could be considered for routine clinical use. Nevertheless, he added, this strategy "does seem to hold promise for the treatment of cases which are out of the reach of conventional medicine."

Hawkins and his colleagues report their findings in a paper in the April 1, 2003, British Journal of Cancer titled "T Lymphocytes Isolated from Patients with Advanced Colorectal Cancer are Suitable for Gene Immunotherapy Approaches."

Bowel cancer is the third most common cancer in the UK, with more than 35,500 cases diagnosed each year, and more than 16,000 deaths annually. Despite improvements in survival, mainly as a result of earlier diagnosis, the outlook for those with metastatic bowel cancer is poor, with little improvement in the five-year survival of the group.

Richard Sullivan, head of clinical programs at Cancer Research UK, told BioWorld International, "Bowel cancer is very difficult to treat once it has spread to other organs such as the liver. What we need is some way of waking up the immune system so that it recognizes these cells and attacks them."

Hawkins and his colleagues, Sullivan said, have focused on a molecule called carcinoembryonic antigen (CEA), which is found on the surface of most bowel cancer cells, as a way of enabling cells of the immune system to distinguish cancer cells from normal body cells.

The strategy involves genetically modifying T lymphocytes from patients so that the DNA of those cells includes two additional genes. The first is part of a gene encoding an antibody fragment that binds to CEA. The second is a gene encoding a protein fragment called CD3 zeta. That protein fragment is part of a cluster of proteins found on the surface of all cells.

As a result of this manipulation, the lymphocytes display a composite molecule on their surfaces called a chimeric immune receptor. Once returned to the same patient's body, this would allow them to latch on to bowel cancer cells via CEA, and to strengthen their grip by simultaneously attaching to the CD3 zeta receptors that also are present on the cancer cells.

Sullivan said, "This arrangement makes sure that the binding of the lymphocytes to the cancer cells is strong enough and lasts long enough for the cytotoxic T cells to become activated and trigger a more general immune response." It also circumvents the body's normal method of activating cytotoxic T cells, during which other cells of the immune system present antigens, held in the cleft of molecules of the major histocompatibility complex.

For the experiments described in the paper, Hawkins and his team used either an antibody fragment specific for CEA, or a control antibody fragment, coupled to the CD3 zeta chain fragment. They particularly wanted to find out if T lymphocytes from patients with bowel cancer would react only to cancer cells, given that there had been several reports of abnormal function in T lymphocytes from patients with other types of cancer.

Ten patients took part in the trial. All were about to undergo surgery for bowel cancer that had metastasized to the liver. The researchers isolated T lymphocytes from the blood of the patients, and transduced the cells with recombinant retroviruses encoding either the experimental chimeric immune receptor or a control chimeric immune receptor. Each population of cells was expanded by adding the cytokine interleukin-2 to the growth medium.

Tests on the cells obtained showed that those that had the CEA antibody fragment were indeed capable of killing tumor cells bearing CEA on their surfaces, while there was negligible killing of tumor cells by those that had the control chimeric immune receptor.

A Phase I clinical trial involving about 10 patients will begin at the Christie Hospital in Manchester, UK, next year.