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, 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.