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Researchers Combine TP53 Gene Therapy and Chemotherapy in Advanced Cancer

Researchers Combine TP53 Gene Therapy and Chemotherapy in Advanced Cancer

Doctors at the University of Pittsburgh Cancer Institute are exploring a new experimental therapy in which they transfer the tumor-suppressing gene TP53 (alias p53) into patients to reverse tumor progression. University of Pittsburgh clinical investigators have opened the first nationwide clinical trial using TP53 gene therapy together with chemotherapy for patients with advanced head and neck cancer. Plans also are underway at the university to begin studies of TP53 gene therapy in patients with advanced primary liver cancer.

The gene therapy is based on the TP53 gene, whose protein, p53, regulates cell growth. In research protocols at the University of Pittsburgh, investigators are using a normal functioning TP53 gene that has been packaged inside a virus that enters cells but does not reproduce and spread throughout the body. This complex is directly injected into cancerous tissue.

"Because damage to the TP53 gene is fundamental to the development of the vast majority of cancers, we must design strategies to combat it," said Sanjiv Agarwala, MD, assistant professor of medicine and principal investigator for the TP53 head and neck cancer studies.

"In our clinical protocols, we are delivering a good version of the p53 gene so that the normal p53 protein will be produced to inhibit the growth of a patient’s tumor," said Dr. Agarwala.

Promising Results

At the 1998 annual meeting of the American Society of Clinical Oncology in Los Angeles, Dr. Agarwala reported findings from a preliminary TP53 gene therapy trial, showing that he could effectively deliver the gene to all patients in the study, and that some of the patients showed positive responses to this therapy.

"The addition of chemotherapy to TP53 gene therapy should significantly improve the outcome of patients with head and neck cancer," predicted Dr. Agarwala.

"Results of recent early clinical studies conducted elsewhere suggest that TP53 gene therapy shows great promise in treating patients with advanced disease," remarked Brian Carr, md, phd, director of the University of Pittsburgh’s Liver Cancer Center and co-investigator of the TP53 liver cancer study. Cliandra Belani, md, associate professor of medicine, is a co-investigator of the liver cancer study. Previous research has shown that when normal TP53 genes are added to cultures of growing cancer cells or to tumors in living animals, the cancer cells undergo apoptosis, according to the investigators.

Novel Clinical Strategy

The new TP53 clinical strategy departs from existing gene therapies at the University of Pittsburgh, in which genes that produce biological response modifiers are transferred into cancer patients. The biological response modifiers train a patient’s immune system to recognize and kill tumor cells.

"In this latest approach, we are delivering a gene that should block cancer growth by re-establishing normal regulation of genetic repair and cell division," said Dr. Agarwala, who added that the TP53 gene therapy also may stimulate an immune response against cancer.

As with other early-phase trials, the primary goals of this clinical research are to assess the safety of the approach and to determine at the molecular level whether the introduced normal TP53 gene functions as anticipated inside treated cancers. Doctors also will monitor whether the combination of chemotherapy with TP53 gene therapy results in shrinkage or disappearance of tumors.

In the trial for head and neck cancer, TP53 gene therapy will be combined with carboplatin (Paraplatin) and paclitaxel (Taxol). UPCI physicians expect to apply TP53 gene therapy to other cancers, including breast cancer, prostate cancer, and melanoma. In related preclinical research, University of Pittsburgh scientist Albert DeLeo, PhD, is incorporating parts of the p53 protein into a vaccine designed to prevent cancer development.

For more information about this study or other clinical trials offered at the University of Pittsburgh, patients and physicians should contact the University of Pittsburgh’s Cancer Information and Referral Service toll-free at 1 (800) 237-4PCI (237-4724) or at (412) 624-1115.

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