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 patients tumor," said Dr. Agarwala.
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 Pittsburghs 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 patients 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 Pittsburghs Cancer Information
and Referral Service toll-free at 1 (800) 237-4PCI (237-4724) or at