Cytotoxic T-Cells Versus Cancer13 years, 9 months ago
Posted on Oct 31, 2006, 11 a.m.
By Bill Freeman
A University of Pennsylvania immunologist's work with the human body's protectors, called cytotoxic T-cells, has led to an increasingly successful effort to develop a vaccine for breast cancer -- one that, after injection, would actually eradicate the disease. In 1993, Yvonne Paterson, a University of Pennsylvania immunologist, was studying listeria, a harmless germ to most. She wondered why this bacteria took a different path from its biological cousins through the cells it invaded. Maybe that difference was important in some way.
A University of Pennsylvania immunologist's work with the human body's protectors, called cytotoxic T-cells, has led to an increasingly successful effort to develop a vaccine for breast cancer -- one that, after injection, would actually eradicate the disease.
In 1993, Yvonne Paterson, a University of Pennsylvania immunologist, was studying listeria, a harmless germ to most. She wondered why this bacteria took a different path from its biological cousins through the cells it invaded. Maybe that difference was important in some way.
Looking through her microscope, Paterson saw a cellular melee breaking out as the immune system's "killer" T-cells began tearing the listeria germ to pieces.
``You have to listen to data, especially when you see something you didn't expect," said Paterson, herself a survivor of breast cancer. "You have to listen to what it's telling you."
What the data was telling Paterson at that moment was: Maybe those nasty T-cells could be prodded to destroy something equally fiendish -- tumors.
That idea has led to an increasingly successful effort to develop a vaccine for breast cancer -- one that, after injection, would actually eradicate the disease. Scientists at a tiny North Brunswick, N.J., biotech company, Advaxis Inc., are transforming Paterson's research into a commercial product.
``Dr. Paterson's science is superb and this is cutting edge, absolutely science fiction stuff," said John Rothman, a former Roche executive who is vice president of clinical development for Advaxis. "If we are really successful, we could change the landscape."
Researchers at Advaxis are using a genetically engineered version of the common bacterium listeria to provoke T-cells to attack cancerous tumors.
Other research groups are using different proteins to attack tumors -- from the mammaglobin-A protein being studied at the Washington University School of Medicine in St. Louis, to the telomerase protein being targeted at the Abramson Cancer Center of the University of Pennsylvania.
Because the body's immune system is so complex, success won't come without dazzling scientific insights, according to one expert.
``The challenge involved in designing a breast cancer vaccine is convincing our immune system to target the cells of our own body -- and cancer cells are part of us -- for demolition," said William Hait, an oncologist and director of the Cancer Institute of New Jersey. "With a clear understanding of how the immune system works, we might be in a position to create a vaccine."
Hait, a physician-researcher who has been studying breast cancer for decades, said the key to a successful vaccine may rest in finding a way to harness a group of cells known as regulatory lymphocytes, the cells that control the body's ability to recognize whether a substance is foreign.
Rothman knows that he has taken on an intimidating task. Taking Paterson's research insights published over the past decade, Rothman and other members of the eight-person company are trying to prove that what she has seen in the lab -- mouse tumors that melted away after vaccine injections -- can be reproduced and that the substance is not dangerous to human health.
Paterson's research is supported by the U.S. Department of Defense and the National Cancer Institute.
But the scientists at the small biotech firm are on their own conducting early clinical trials.
``We are really knocking on the door of a very important immunotherapy," Rothman said. "Whether ours will be the one is too early to tell." The company has licensed Paterson's patented work from the University of Pennsylvania in Philadelphia.
The human immune system, Rothman said, did not evolve to cure cancer. That's why the company must genetically modify the listeria bacterium to contain HER-2/Neu, a protein that stimulates the fearsome T-cells into action. The protein is produced in about 25 percent of all breast cancers, as well as in cancers of the ovaries, lung, pancreas and gastrointestinal tract.
Healthy, nonpregnant people can easily survive infection by listeria, often found in dairy products. Paterson found that its unusual behavior -- that it likes to swim in the cell's goopy innards known as the cytoplasm -- makes it perfect for drawing the attention of killer T-cells which are only clued in to that region.
By fusing the HER-2/Neu protein to the listeria bug, Paterson was able to draw out killer T-cells attracted to the listeria and "train" them to seek out and destroy anything containing HER-2/Neu. In the case of her experiment, that meant that the T-cells decimated breast cancer tumors in mice with the disease.
Rothman sees it as a way of fooling nature for a good cause.
``We are co-opting the immune system," Rothman said. "We are using a bug most people don't get sick from and inducing an immunity to cancer by masquerading as this bug. The body thinks it's dealing with this bug and mounting an immune defense. It's self versus non-self."
Thalachallour Mohanakumar, the Jacqueline G. and William E. Martize professor of Immunology and Oncology at Washington University School of Medicine, believes he has selected an excellent target for the immune system. The protein mammaglobin-A is found in 80 percent of breast cancers.
Mohanakumar and his research team have constructed a DNA vaccine that contains copies of the genetic sequence that produces the protein in humans. The idea is that the vaccine will rev up T-cells to recognize the protein as a foreign molecule when it is displayed on the surface of cells. The "primed" T-cells would then proliferate and attack the protein whenever they run across it.
The research team transferred vaccine-primed T-cells into mice with growing tumors. Some contained mammaglobin-A. Some did not.
Researchers found that the tumors with the protein stopped growing, then shrank. The others continued to grow.
The research, funded by the Susan G. Komen Breast Cancer Foundation and the U.S. Department of Defense, is now expanding into clinical trials testing the safety and effectiveness of such vaccines in humans with breast cancer.
``To me, it was a big surprise that it worked," Mohanakumar said. "But it's simple. And, just like everything else, very simple things are often what people overlook. And, usually, they work."
Having survived cancer and a mastectomy in the '80s, Paterson is using her experience to fuel her work.
``I survived, but I have to say that I didn't feel lucky at the time," said Paterson, now 65. "Now I realize I was lucky. As you get older, and more and more of your friends and loved ones are dying of cancer, you think, if you can do anything about it, you should."