An experimental cancer vaccine using defanged listeria bacteria is showing great promise in animal studies, successfully treating new cancers that have spread into the lungs of mice.
The mouse study, reported in the Sept. 21 issue of the journal Proceedings of the National Academy of Sciences by scientists at Cerus Corp. in Concord, Calif., employs a genetically engineered listeria bacteria based on a strain created by coauthor and University of California, Berkeley, microbiologist Daniel Portnoy. Buoyed by the success of the new cancer vaccine, Cerus scientists now are aiming for human trials.
Cerus ultimately hopes to use the genetically engineered listeria vaccine to target cancers such as pancreatic and ovarian cancer, and possibly leukemia and various solid tumors.
Upon entering a cell, the listeria bacterium takes over the cellular machinery and builds a rocket sled that propels it out of the cell and into another, spreading the infection.
The listeria bacteria are uniquely effective vehicles for a cancer vaccine, Portnoy said, because the bacteria incite a strong "innate" response from the immune system and at the same time sneak cancer antigens into cells to optimally stimulate a potent "acquired" immune response. Together, these two independent arms of the human immune system can deliver a one-two punch to cancer cells. Antigens are like a red flag to a bull - they draw an attack from cells of the immune system - but the strength of the immune response depends on how the flag is waved.
"This immune therapy uses bacteria that induce both inflammation and an immune response to specific tumor antigens," which together hit the tumor with generalized antitumor chemicals, such as interferon and tumor necrosis factor, as well as activated T-cells that attack and kill the tumor, Portnoy said. "Listeria is the best bug so far to induce that response. With listeria, innate and acquired immunity work in concert."
Portnoy, a professor of molecular and cell biology and of public health and a member of UC Berkeley's Health Sciences Initiative, identified the genes in listeria that make it virulent and, with Cerus scientists, knocked them out. The modified bacteria ignite a full-blown "innate" immune response in the vaccinated mice, but with a thousand-fold less toxicity than the wild bacteria.
Cerus then took the genetically engineered listeria and inserted cancer antigens, again using a technique developed by Portnoy, then infused the vaccine into the mice. All showed tumor regression and reduced lung metastases, and 40 percent of the mice were long-term survivors.
"These studies address one of the major barriers to using listeria therapeutically, which is, how you create a strain that is safe enough to move forward into the clinic," said David Cook, vice president of research and development for Cerus. "With this strain, we are now moving from essentially pure research to developing clinical applications, planning for manufacturing and performing toxicity studies to submit to the FDA."
One hope for this and other cancer vaccines is that they will stimulate the immune system to seek out metastatic cancer cells that have been shed by the original tumor and kill them before they can establish themselves elsewhere in the body.
"The first place to start is to treat patients with minimal residual disease, that is, use the vaccine to prevent recurrence after surgery and chemotherapy," Cook said. Ovarian cancer is a good example of a tumor that has a high recurrence rate that could potentially be knocked back with a listeria-based vaccine.
Listeria is ideal as a vehicle for cancer vaccines because it normally induces a strong innate immune response in humans as well as a potent induced immune response. The innate response is a generalized attack on any invader, characterized by secretion of chemicals called cytokines - including tumor necrosis factor and interferon - that mobilize generalized killing machines such as macrophages, neutrophils and natural killer cells.
Mammals have, in addition, an adaptive response that targets specific invaders. This involves antibody-producing B cells and cancer-killing T cells mobilized against antigens, which are molecular targets expressed by microbes, viruses or cancer cells. One of the problems with cancer antigens is that that cancer cells look like the body's own cells, and so the immune system doesn't attack them. Listeria breaks that "self tolerance" and mobilizes the T cells to recognize and attack cancer cells expressing these antigens.
It is not yet completely clear what makes listeria such a good inducer of immunity, Portnoy said, but it probably has to do with its cell biology, the fact that it grows directly in the cell cytosol. There it stimulates the one pathway that produces cytotoxic T cells - often called CD8+ cells - that can attack and destroy tumors. Portnoy recently showed that live, but not killed, listeria induce the production of beta-interferon, which may explain this effect.
"The unique ability of listeria to get into the cytosol is the key to its effectiveness," Cook added. "Listeria not only stimulates this additional innate immune response, but it also puts the antigen into exactly the pathway we want and gives us a robust antigen-specific response."
Listeria also can avoid antibodies, whereas other microbial vectors set up an antibody response that prevents them from being used more than once. A listeria-based cancer vaccine could thus be given periodically until a tumor has responded.
Despite these attributes, the one problem with listeria has been toxicity. Though a relatively rare disease, listeriosis has a high fatality rate of between 20 and 30 percent. It made headlines two years ago when 20 people, including several children, died of listeriosis from tainted hamburger, forcing the largest meat recall in history. Several thousand people come down with listeriosis each year, and several hundred die from it.