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