• Immunology

    New Strategies in Tumor Vaccines

    Glenn Dranoff, MD, knows this for sure: if immune T cells are present in tumors, cancer patients have a better chance of benefiting from surgery, radiation, or chemotherapy. "The work has become quite convincing in the last five years, where it is now clear that whether it is colon, ovarian, lung or breast cancer, or lymphoma, melanoma or kidney cancer, the people who live the longest and have the best response to treatment are those whose tumors show evidence of an immune response," Dranoff says.

    Unfortunately, most patients do not have an appreciable T-cell response, and that is where tumor vaccines come in. Dranoff, of the Department of Medical Oncology, is a leader in finding ways to boost anti-tumor immune responses. His approach of engineering a patient's own tumor cells to produce the immunostimulatory cytokine, GM-CSF, has been clinically tested so far in nine different kinds of cancers. In each case, the vaccine elicited an increased T-cell response to tumors.

    But stimulating the immune system is not enough, Dranoff has found. Not all T cells are helpful: some are devoted to killing cancer cells, while others shut off the immune response, partly to protect against harmful autoimmune reactions. "Every time the immune system gets a signal to start a reaction, as with a vaccine, it also has signals built in to ultimately turn off that response," he explains. "And in cancer patients, their immune system has a lot of these control points triggered to turn off the response, because in many ways their tumor is part of themselves."

    In the past year, Dranoff and colleagues have reported on two approaches to get around the shutdown response by using combinatorial vaccines. In one, they used an antibody to block temporarily the action of the negative regulatory receptor, CTLA4, after vaccination. Through a study of 20 patients, they found that those who developed the highest ratio of killer cells to regulatory cells responded the best. "CTLA4 antibodies are being tested widely now and we may find out in the near future whether or not they reach the level of activity that's going to be required to seek FDA approval," Dranoff says. In another combination approach, they found that giving a vaccine shortly after bone marrow transplant preferentially promotes the formation of killer T cells over negative regulatory T cells.

    Other work has focused on identifying the tumor-specific proteins that are most likely to trigger a successful T-cell response. Using sera from patients who responded well to immunization, Dranoff and colleagues identified antibodies to MICA, a protein that appears on the outer surface of stressed or damaged cells and tags them for destruction by killer T cells. In additional studies, they found a soluble form of MICA in blood that acted to suppress the anti-tumor immune response. The therapyinduced antibodies overcame this immune suppression and boosted cytotoxic T-cell responses.

    kai-wucherpfennig.jpgKai Wucherpfennig, MD, PhD 

    Now, Dranoff is working with Kai Wucherpfennig, MD, PhD, of the Department of Cancer Immunology and AIDS, to isolate and analyze the anti-MICA antibodies. Wucherpfennig, who has made major contributions to the basic understanding of how immune cells recognize antigens at the molecular level, recently developed a technique to isolate the one in ten thousand immune cells that reacts to a specific antigen. Using blood samples from immunized patients, the researchers are looking for the proverbial needle in a haystack, Wucherpfennig says. If they are successful, it will give them the ability to produce a recombinant anti-MICA antibody in unlimited amounts that can be rigorously tested for anti-tumor activity.

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