Antigen-Based Antitumor Vaccines Seem Most Promising

NEW ORLEANS--The next decade will be a critical time for translating new cancer vaccine approaches into standard therapies, said Drew Pardoll, MD, PhD, of Johns Hopkins University School of Medicine. In a talk at the plenary session of the 89th annual meeting of the American Association for Cancer Research, Dr. Pardoll noted that antigen-based anticancer vaccines offer perhaps the most promising approach.

The problems of developing therapeutic cancer vaccines are much different from those for prophylactic vaccines traditionally used for infectious diseases.

Key differences are that prophylactic vaccines work through neutralizing antibodies, whereas in therapeutic vaccines, T-cell responses are key; the immune system of a person receiving a prophylactic vaccine is naïve to the vaccinating antigen, whereas with a therapeutic vaccine, the immune system has already been exposed to the antigen; and the relevant antigens in a prophylactic vaccine are known, whereas those in a therapeutic vaccine may not be.

Stimulating T Cells to Attack

In therapeutic vaccines, the role of T cells is critical, Dr. Pardoll said. Any genetic change that takes place in a tumor has the potential to be recognized by T cells, so there are plenty of potential targets. Yet the immune system generally tolerates tumors. "Resolving this apparent paradox is necessary to create vaccines that stimulate T cells to attack tumors," Dr. Pardoll said.

The currently accepted answer to this paradox, based on a model proposed 30 years ago by Peter Bretscher and Mel Cohn, is that T cells require two signals before they are activated. One signal is the antigen itself, and the other is the "costimulatory signal," for example, a cytokine such as granulocyte-macrophage colony-stimulating factor (GM-CSF).

A cell that has been invaded by a virus releases both viral antigens and cytokines; the cytokines stimulate certain progenitor cells to differentiate into antigen-presenting cells, which then present both the viral antigens and the cytokines to T cells. The result is activation. In contrast, a tumor cell releases only its own antigens; without the costimulatory signal, the immune system tolerates the tumor cell.

"Many of the advances in the design of new approaches for vaccination come from the elucidation of the specific molecules that represent these signals," Dr. Pardoll said. "Clearly, GM-CSF seems to be a very important signal to convert these bone marrow progenitors into these very potent antigen-presenting cells," which are now called dendritic cells. One approach being tested is the use of GM-CSF-transduced vaccines so that T cells receive the two signals they need to activate against the tumor.

One goal now is to base vaccines on specific tumor antigens rather than using tumor cells, he said. An antigen-based vaccine could be completely defined and could also be manipulated to enhance its presentation to the immune system. These antigen-based vaccines have already become more complex in both the antigen used and the adjuvant.

The first and simplest vaccines were based on a specific peptide delivered in a lipid-based adjuvant such as Freund’s adjuvant. "Most recently, one of the most interesting and complex forms of antigen-delivery systems is to use dendritic cells themselves," Dr. Pardoll said. Dendritic cells can be loaded with peptides, proteins, or RNA.

There are still many challenges remaining, Dr. Pardoll said. "We have to understand tolerance; understand more about antigen processing; define immunodominant tumor antigens; understand the genetics of the immune response; and, ultimately, take advantage of this knowledge to build better vaccine vectors."