Efficacy of Immunotherapy in Prostate and Stomach Cancer, and Potential Gene Therapy With p53 and E1A

In order for the immune system to protect against cancer, it must recognize tumors as "non-self." Markers present on the surface of tumors, known as antigens, allow the immune system to recognize tumors as non-self. However, in order for the immune system to mount a defense, antigens typically must be presented to the active parts of the immune system by the antigen-presenting cells. At the annual meeting of the American Association for Cancer Research (AACR), investigators reported on studies testing the use of antigen-presenting cells as immunotherapy in prostate cancer patients and the use of monoclonal antibodies in the treatment of stomach cancer.

Michael L. Salgaller, PhD, head of the immunotherapeutics division at Northwest Biotherapeutics, and colleagues at Pacific Northwest Cancer Foundation and Northwest Hospital in Seattle, used immunotherapy to effectively treat patients with prostate cancer. In a phase II clinical trial, the research team devised a system that would present the surface antigens on prostate cancer tumors to the T-cells of the immune system. They obtained dendritic cells from prostate cancer patients and treated the cells to make them present antigens associated with prostate cancer. The treated dendritic cells were then injected into individual patients in six infusions at 6-week intervals. Half of the patients also received treatment with granulocyte colony-stimulating factor (GM-CSF [Neupogen]).

An initial evaluation of 33 patients who completed both phase I and II clinical trials indicated nine partial responders (27%), with stable disease observed in another 11 patients (33%). "By better presenting the surface antigens, we were able to help the immune system mount a stronger response against the tumor," said Dr. Salgaller. "Although these results are preliminary, using dendritic cell immunotherapy is a technique that shows promise in the treatment of prostate cancer and may be transferable to other cancer."

Monoclonal Antibody for Treating Stomach Cancer

Another element necessary for an effective immune defense against cancer involves the production of monoclonal antibodies. Monoclonal antibody-based therapy theorectically targets specific types of tumor cells and triggers apoptosis (programmed cell death). H. Peter Vollmers, PhD, professor of experimental pathology at the Institute for Pathology at the University of Wurzburg, and colleagues reported preliminary results of a study using a human monoclonal antibody, known as SC-1, isolated from a patient with stomach cancer.

In this phase I/II study, eight patients with stomach cancer were infused with SC-1 before surgery. An evaluation of the patients’ tumors and lymph nodes after treatment revealed that seven of the primary tumors showed a significant increase in apoptotic tumor cells. Tumor regression, characterized by a decreased density of carcinoma cells, was also observed. All patients were alive 9 months after entering the study, and none developed any serious complications or toxic reactions to the treatment.

"This monoclonal antibody therapy is extremely promising in the treatment of one of the most deadly types of cancer in industrialized countries," said Dr. Vollmers. "We are continuing to investigate it in a larger number of patients."

p53 Gene Therapy Studied in a Variety of Cancers

In addition to immunotherapy, another area of cancer research receiving increased attention during the past year is the use of an adenovirus to deliver gene therapy. The Schering-Plough Gene Therapy Study Group used an adenovirus to deliver an intact p53 gene into the tumors of patients with various types of cancer.

The p53 tgene produces a protein that suppresses unregulated cell growth and tumor formation. When mutated, p53 cannot perform its normal tumor-suppressor activity and has been implicated in a variety of human cancers, including colon cancer. Previous research demonstrated that expressing the normal p53 gene in tumor cells lacking functional p53 resulted in suppression of the tumors, causing the cells to undergo apoptosis. It is thought, therefore, that expressing the normal p53 gene in human cancers lacking functional p53 may be an effective way to eradicate these tumors.

In this phase I study, the investigators gave various doses of a modified adenovirus containing p53 to 103 patients with colon cancer metastatic to the liver, ovarian cancer, melanoma, head and neck cancer, or non-small-cell lung cancer. Subsequent analysis of the patients’ tumors showed that, in a majority of cases, the treatment was successful and normal p53 tumor-suppressor activity was noted at the tumor site.

"The delivery of this tumor suppressor gene into the tumor is a novel method with the potential to induce tumor regression. These results are preliminary but the therapeutic impact of this gene therapy approach is promising," said Mary Ellen Rybak, MD, senior director of oncology at the Schering-Plough Research Institute.

Gene Therapy With NewE1A Tumor Suppressor Gene Feasible

In a phase I study, another tumor-suppressor gene, E1A, showed promise in the treatment of breast and ovarian cancers. Previous studies demonstrated that E1A suppresses metastases, induces apoptosis, and is associated with reversal of the overexpression of the breast cancer gene, HER-2/neu. Expression of HER-2/neu is linked to poor prognosis in breast and ovarian cancers, increased tumor formation and metastasis, and resistance to chemotherapeutic agents.

In a study presented at the AACR meeting, Naoto T. Ueno, MD, Gabriel N. Hortobagyi, MD, and Mien-Chie Hung, PhD, of The University of Texas M. D. Anderson Cancer Center and their colleagues at Targeted Genetics in Seattle and at the University of Pittsburgh attached the E1A gene to a liposome to improve its ability to penetrate human cells. They then treated 12 patients with metastatic or recurrent breast and ovarian cancers with weekly injections of the E1A-liposome complex to evaluate the efficacy of this method in delivering and expressing E1A in humans.

The first three patients evaluated showed E1A gene expression in both cancer and noncancer cells and the HER-2/neu gene was also suppressed in these patients.

"These findings led us to conclude that E1A gene therapy is feasible and that E1A gene expression can be detected," said Dr. Ueno. "As our understanding of the various genetic changes that cause cancer continues to grow, gene therapy could allow us to tailor treatment to the particular genetic error that causes cancer in each individual patient."