Aug. 3, 2004 ROCHESTER, Minn. -- Mayo Clinic and British researchers have developed a new approach to cancer vaccines that purposely kills healthy skin cells to target the immune system against tumors. The new approach has eradicated skin cancer tumors in mice. The approach and results challenge conventional thinking on the creation of cancer vaccines. Their report on the "heat shock" vaccine therapy appears in the August issue of Nature Biotechnology, (http://www.nature.com/nbt/). Results are promising because multiple rounds of treatment eradicated skin cancer in all the mice in the study. If this work can be extended to humans, it could have enormous benefits. Skin cancer is currently the most common form of cancer in the United States, with an estimated one million new cases diagnosed annually.
Significance of the Mayo Clinic Research
Normally, the destruction of healthy cells is undesirable. For example, in toxic conventional chemotherapies for cancer, the goal is to kill cancer cells and spare healthy cells. This new approach is significant for two reasons:
1) It turns the death of healthy cells into a therapeutic advantage by inflicting a stress known as "inflammatory cell death" on skin cells to which researchers attached a protein involved in heat shock. Researchers were able to trigger a healing immune response aimed at the skin cancer tumors. The response was so strong it eradicated the tumors.
2) Researchers avoided triggering autoimmune attacks, which are a common disabling side effect of most cancer vaccine attempts. In autoimmune attacks the body attacks and injures itself -- instead of the cancer. This new approach appears to breach a major obstacle to advancing cancer vaccine research from the laboratory into human trials.
"We're very encouraged by these results because our main interest is in generating cancer vaccines that will stimulate the immune system to recognize tumors and eradicate them. We hope our novel approach will be a more specific, and therefore gentler therapy for patients," says Mayo immunologist and lead researcher Richard Vile, Ph.D.
To test the idea that killing normal cells might trigger a specific immune system response, the team chose normal skins cells called melanocytes that are involved in the highly lethal cancer malignant melanoma. The researchers created a molecular scout to home in on and kill some of the melanocytes in mice. To the molecular scout they attached an unusual protein, called heat shock protein 70, or hsp70. It normally is not present in healthy cells, but when cells die under certain conditions, they release hsp70. "It's a danger-signal system that the body is in trouble," says Dr. Vile. "We hoped to trigger an anti-tumor response."
The unanticipated result was a two-step reaction with promising traits that may one day help skin cancer patients. In the first step, the heat shock protein recruited T cells -- the main warriors of the immune system -- that attacked melanocytes. The T cells killed all tumors in the mice.
Researchers also questioned whether a raging T-cell attack might prompt autoimmune disease. The immune system apparently anticipated that. In response to the vaccine, it sent out regulatory T cells to calm down the first group of fighting T cells.
Says Dr. Vile: "The nice twist is that originally we thought we would generate a very potent autoimmune disease before we killed the tumor. But we found just the opposite. What happens is that you get a burst of T cells that kill the melanoma, and then they are suppressed by regulatory T cells in the mouse before they cause autoimmune disease."
For humans, this is good news. "This is very hopeful because we think in the clinic there are good chances we can control anti-tumor effects before we get to the autoimmune problems," says Dr. Vile.
The Next Step
The researchers will pursue two basic paths. One will extend the current work on a heat shock vaccine to other tissue and tumor types to determine its effectiveness against breast, lung or prostate cancers. The other is to test this immunotherapy in clinical trials with humans.
In addition to Dr. Vile, co-investigators are: Gregory Daniels, M.D., Ph.D.; Luis Sanchez Perez; Rosa Maria Diaz, Ph.D.; Timothy Kottke; Jill Thompson; Maoyi Lai; Michael Gough; Mahzuz Karim and Andrew Bushell, Ph.D., Oxford University; Heung Chong; Alan Melcher, Ph.D., Cancer Research UK, Leeds; and Kevin Harrington, Ph.D., Institute of Cancer Research, London. Their work was supported by grants from the Mayo Foundation and the National Institutes of Health.
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