Three antigens associated with glioblastoma multiforme have produced promising results for immunotherapy studied in laboratory and Phase I clinical trials, according to two articles in the July 15th issue of Cancer Research.

The antigens, previously associated with several other types of cancer, were recently found to be expressed in the most common and aggressive type of malignant brain tumor, glioblastoma multiforme. The research group generated cytotoxic T lymphocyte clones targeted against malignant cells expressing these antigens.

“In a Phase I clinical trial of 14 patients, we found that our dendritic cell vaccine not only generated an immune response against these antigens but it appeared to play a significant role in prolonging survival in patients with glioblastoma,” said Keith L. Black, MD, lead author of the studies.

The median length of survival of patients with recurrent glioblastoma whose treatment included the vaccine was 133 weeks. A similar group of patients receiving the same level of care but not the vaccine had a median survival of only 30 weeks.

John S. Yu, MD, senior author of the articles, said these findings represent a significant advance in the field of brain tumor immunotherapy: “This is the first time that a specific response to brain tumor antigens has been demonstrated as the result of an immunotherapy strategy. These antigens give us specific targets to aim for and they give us potent tools with which to measure immune responses.

Therefore, we have a better way of monitoring the progress of patients who undergo vaccination and we have a means of improving these therapies.”

“These three antigens ? HER2, gp100, and MAGE-1 ? have been described since the 1980s but we have only recently found them to be expressed in glioblastoma cells,” said Black.

HER-2 is expressed in a variety of normal tissues, but it is selectively overexpressed in a number of malignancies including breast and ovarian tumors.

Glycoprotein 100 (gp100) is an antigen previously linked to melanoma. MAGE-1, initially analyzed from melanomas and found to be expressed in a variety of tumor types, became the first identified tumor antigen recognized by the immune system’s protective T cells.

Dendritic cell immunotherapy is intended to stimulate a patient’s immune system to recognize and attack glioblastoma cells. Tumor cells that have been removed during surgery are cultured in the laboratory with dendritic cells, also called “antigen-presenting” cells, taken from the patient’s blood. The resulting cells are injected back into the patient, where they are designed to identify brain tumor cells as foreign and stimulate a strong response from tumor-infiltrating T lymphocytes.

In an earlier Phase I trial, tumor cells were grown in culture, and proteins from the cell surfaces were used in preparing the vaccine. In the Phase I trial described in the Cancer Research article, this process was refined.

“Now we take the proteins directly from the surgical specimen, which ensures that we are getting the relevant proteins and not antigens or proteins that are artifacts of the culturing process. This also avoids the technical problems of trying to grow out tumor cells that have been irradiated and undergone chemotherapy,” Yu said. “

In addition, instead of just drawing blood to obtain a patient’s dendritic cells, we’re using a process that allows us to get 25-fold more dendritic cells. This may account for the dramatic prolongation of survival that we see compared to our control patients.”

Black said a larger Phase II trial of the dendritic cell vaccine is now being completed and the researchers are preparing to apply for a randomized Phase III trial.