In an article published in Nature Medicine, scientists at the University of Texas MD Anderson Cancer Center report that vaccines designed to stimulate an immune system assault fail because killer T cells aimed at tumors instead find the vaccination site a more inviting target.
“Vaccines stimulate production of T cells primed to attack the target cancer, and there are many T cells in the bloodstream after vaccination. We found that only a few get to the tumor while many more are stuck at, or double back to, the vaccination site,” comments senior author Willem Overwijk, Ph.D., in MD Anderson’s Department of Melanoma Medical Oncology.
Dr. Willem Overwijk
The phenomenon results in largely unscathed tumors and an overstimulated immune response that can cause lesions at the injection site. The MD Anderson research team found that a major culprit in this dynamic is incomplete Freund’s adjuvant (IFA) – a mineral oil-based adjuvant included in many vaccines to boost immune response.
“IFA sticks around the vaccination site for up to three months, along with the antigen designed to trigger immunity against the tumor,” Dr. Overwijk explains. “T cells keep attacking and secreting chemokines to call for reinforcements – but it’s an unkillable target; T cells can’t kill mineral oil.” Eventually, the T cells die. “The vaccination site increasingly resembles a viral infection, with lots of damaged tissue and antigens,” Overwijk adds. The report notes that almost all of 98 federally approved U.S. clinical trials of vaccines against a variety of cancers have failed. “People kept trying because of these beguiling T cell levels in the blood,” Dr. Overwijk says, but our data suggest that the very nature of IFA-based vaccines may make it almost impossible for them to work well.”
Switch From IFA To Saline Adjuvant Reverses Effect
However, “Switching to a saline-based adjuvant in a melanoma vaccine reversed the T cell effect in mice,” says Dr. Overwijk. “Major accumulations of T cells gathered in tumors, shrinking them, with minimal T cell activity at the vaccination site.” With Peptide antigens available for almost all types of cancer, Dr. Overwijk suggests that a saline adjuvant could change the poor performance of cancer vaccines. A clinical trial of the concept expected to open later this year led by Craig Singluff Jr., M.D., professor of surgery at the University of Virginia Medical School, and Patrick Hwu, M.D., chair of MD Anderson’s Department of Melanoma Medical Oncology.
Meanwhile, Dr. Overwijk and his colleagues provisionally infer that a possible solution would be to reduce the size and persistence of vaccine “depots” at the injection site. They’ve tested a vaccine based on a saline solution instead of IFA, and found antigens cleared more quickly but didn’t spark the desired T cell response. A combination of three stimulatory molecules (covax) was added to the saline/peptide vaccine, producing a strong T cell response. IFA/peptide vaccine produced a strong T cell response but also stronger post-peak T cell suicide.
A comparison of saline/peptide/covax vs. IFA/peptide/covax showed the saline version caused T cells to home to the tumor and destroy them, while the IFA version focused T cells at the vaccination site, killing normal tissue and inducing chemokines that damaged and killed T cells.
“It’s an engineering flaw in those vaccines that we didn’t appreciate until now, observes Dr. Overwijk. “Fortunately, our results also directly instruct us how to design new, more powerful vaccine formulas for treating people with cancer.”