BioWorld International Correspondent

LONDON - Trials of a new type of immunotherapy for cancer could begin in humans within about two years, an international team of researchers predicted, following their latest attempt to stimulate the cells of the immune system to attack tumor cells.

The strategy involved using a retrovirus to insert a murine gene into the patient's own T cells. The murine gene encodes a T-cell receptor that locks on to a common tumor antigen. Once expressed in the recipient cells, it converts those into tumor-killing machines.

Matthias Theobald, professor of medicine at Johannes Gutenberg University in Mainz, Germany, told BioWorld International that the team already has conducted studies of the therapy in animal tumor models, although the results have not yet been published.

"We are planning to go on to human trials, although, as this involves retroviral gene therapy and we need to complete all the preliminary and safety studies required by the authorities, these will not begin for about two years," he said.

Theobald and his colleagues in Mainz, together with their Swiss and American collaborators, published their latest results in the Jan. 25, 2005, issue of Immunity in a paper titled "Cooperation of Human Tumor-Reactive CD4+ and CD8+ T Cells after Redirection of Their Specificity by a High-Affinity p53A2.1-Specific TCR."

The normal immune response to bacterial infection or the presence of abnormal tumor cells relies on an antigen-presenting cell showing (or presenting) foreign protein fragments (peptides), held in the cleft of a major histocompatibility complex (MHC) protein on its surface. The MHC molecules play a role in determining self from non-self. If the peptide is held in a Class II MHC molecule, then it can bind to the T-cell receptor on a CD4+ T cell. But if the peptide is held in a Class I MHC molecule, then it can bind to the T-cell receptor on the surface of a CD8+ T cell.

The result of binding is a cascade of cell division and release of chemicals, all designed to produce cells that target the intruder and eliminate it. Activation of both CD4+ and CD8+ T cells is needed to provide the right type of sustained response.

Cancer cells are different from normal body cells, and researchers have reasoned that if they could identify what the differences are, those could provide the basis for targeted cancer therapy - possibly including that mediated by the immune system.

One difference between human cancer cells and normal cells is the expression of the tumor-suppressor protein p53. About half of all human cancers overexpress a mutant version of the tumor-suppressor protein p53. In a majority of the rest, the expression of proteins that are involved somewhere along the p53 pathway is altered.

If researchers could get the body's immune cells to attack cells expressing abnormal p53, therefore, that could be the basis for a new type of cancer therapy. Unfortunately, many normal cells express low levels of normal p53, so the CD4+ and CD8+ T cells do not recognize the mutant protein as a foreign antigen.

Theobald and his team have been investigating ways of overcoming that tolerance to p53. They used transgenic mice that lacked a functional CD8+ co-receptor on their T cells, which normally is involved in the development of tolerance to self, to generate T cells that had T-cell receptors that were specific for tumor-associated p53. They then isolated the gene encoding that receptor and engineered it into human CD4+ and CD8+T cells.

Studies carried out in the laboratory showed that the engineered CD4+ and CD8+ T cells attacked tumor cells.

Theobald said: "So here we have a T-cell receptor, generated by circumventing self-tolerance, that is specific for an almost universal human tumor-associated antigen, that is able to both functionally reprogram human CD8+T cells and, simultaneously, to reprogram CD4+ cells, too."

To use that to treat human cancer patients, the person's own T cells would have to be harvested, and the murine gene - which could be "humanized" - would be engineered into their DNA. The altered cells then would be infused back into the patient.

Theobald concluded: "This work sets the stage for the investigation of what characteristics a T-cell receptor needs to have in order to simultaneously redirect both CD4+ helper T cells and CD8+ T killer T cells and hence to maximize its therapeutic potential."

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