Sarah Goodwin

Kathi Ovnic
Holly Korschun
JUNE 24, 1999

Scientists at Emory University School of Medicine are creating a tumor vaccine with a novel technique they developed using recombinant proteins to stimulate an immune response. The new technique takes advantage of the same principles that have been successfully used to stimulate the immune system through gene transfer, but without the drawbacks and risks of gene therapy.

The protein transfer technique, developed by Periasamy Selvaraj, Ph.D., Emory associate professor of pathology and laboratory medicine, is based on the fact that the immune system requires two signals in order for T cells to become activated as they divide and proliferate to attack foreign cells. The first signal comes from MHC (major histocompatibility complex) molecules on the foreign cell surface that present antigens to the immune system. The second signal is generated by cell-surface molecules, such as B7-1 (CD80) and ICAM-1, called costimulatory or immunostimulatory molecules. Although most tumors express MHC molecules and tumor-specific antigens to create a first signal, many do not express costimulatory molecules. This lack of a second signal causes T cells to become inactive, allowing tumors to escape immune surveillance.

Scientists already have demonstrated that by transferring the genes that express one or more costimulatory molecules into a tumor, they can elicit an immune response that attacks tumor cells in mice. Rather than transferring the genes themselves, the Emory investigators are introducing the same kinds of costimulatory molecules through protein transfer, avoiding the need to use foreign molecules or vectors to facilitate the transfer, Dr. Selvaraj explains.

Using recombinant techniques, Dr. Selvaraj first constructs a hybrid molecule by combining the costimulatory molecule with a gene that encodes a type of protein that anchors itself solidly to cell membranes via a special anchor called a GPI anchor (glycolipid anchor). He expands this molecule by placing it into a rapidly growing cell line. After purifying the new hybrid molecules, he places them into the tumor cells or cell membranes, then injects these back into the mice to stimulate an immune response. The protein transfer process takes only about two hours. Once the immune system is stimulated, immune cells also can attack tumors that lack the costimulatory molecules.

"Putting genes into tumor cells is a time-consuming and difficult process," explains Dr. Selvaraj. "Gene therapy also is risky because it requires using a foreign vector to transfer the gene. Anything foreign like this can cause an adverse reaction, especially upon subsequent booster immunization. Also, the vector could go to the wrong place in the genome, causing a mutation."

"We believe protein transfer will be a very simple and novel technique, especially in the clinical setting," Dr. Selvaraj says. "We can take a tumor membrane or frozen tumor cells, modify the proteins, give them back to patients and boost the immune system without much complication. There is nothing foreign involved and no genes, only purified proteins. Even tumor tissues frozen five years ago can be used to create a vaccine and immunize patients."

Although the current technique would necessitate using a patient's own tumor tissue, in the future Dr. Selvaraj hopes that by finding out the exact type of tumor-specific antigens in a particular kind of tumor, he will be able to manufacture a vaccine without needing the tissue itself.

Dr. Selvaraj has tested the hybrid protein vaccine in mice that have an induced T lymphoma tumor. When he immunized the mice with the modified protein vaccine, he measured a good T cell response as well as a strong cytotoxic T cell response and protection from tumor challenge. He now plans to test the vaccine against tumors that already are established in mice. After expanding his studies to include melanoma, breast cancer, and prostate cancer tumors, he hopes to begin human clinical trials with the new vaccines in the near future.

Dr. Selvaraj's research, which was reported in the May 15, 1999 issue of the journal Cancer Research, is supported by the National Institutes of Health. ##