While not as toxic as other therapy approaches, cancer vaccines have also not been very effective. Despite many attempts by researchers, the only therapeutic cancer vaccine that has been approved by the Food and Drug Administration (FDA) is sipuleucel-T (Provenge), which is approved specifically for men with metastatic prostate cancer.
Now, new research suggests that the formulation of a cancer vaccine may affect its efficacy. A group of scientists showed that the most commonly used cancer vaccine delivery system—incomplete Freund’s adjuvant (IFA), a mineral oil-based formulation—only leads to immune cell accumulation at the site of vaccine injection and confers no antitumor response. The authors, led by Willem Overwijk, an assistant professor in the Department of Melanoma Medical Oncology at MD Anderson Cancer Center in Houston, Texas, have designed and tested a new vaccine delivery method that results in an efficient antitumor response. These experiments were conducted in mice, but are likely to have broad implications for cancer vaccine therapies, suggesting that certain formulations actually inhibit vaccine activity.
Overwijk and colleagues set out to address whether the IFA delivery method may at least partly explain the poor efficacy track record of cancer vaccines. Recent clinical trials have shown that vaccination often prompts the immune system to increase blood levels of tumor-targeting T cells; however, this does not ultimately result in tumor regression.
“Our work may provide an explanation for why vaccines don’t yet work as well as we might expect from the levels of cancer-killing T cells they induce in the blood,” Overwijk says.
The researchers injected an IFA formulation of the gp100 peptide melanoma vaccine into mice that had been engineered to have melanoma tumors. Rather than causing an enrichment of T-cells at the tumor site, the vaccine instead drew T cells to the injection site. This accumulation also led to dysfunctional T cells and, ultimately, their programmed cell death (apoptosis), which could explain the ineffectiveness other IFA vaccines.
In an attempt to improve on the water-oil emulsion delivery system, Overwijk and colleagues injected gp100 peptide in a saline solution. But this did not prove more effective. They then created a vaccine combining the gp100 peptide with three immune system-stimulating molecules (covax), also in a saline solution. This new formulation led to stronger T-cell responses, with no accumulation of vaccine-induced T cells at the injection site. Rather, the T cells localized to tumor sites and displayed antitumor activity.
The saline-based formulation is believed to work better because it is more biodegradable (short-lived) at the injection site compared to the mineral-oil emulsion. This allows for stronger and importantly, more persistent T-cell responses.
Most peptide vaccines are made up of short peptides suspended in the IFA water–mineral oil emulsion. According to the published report of Overwijk and colleagues’ study, 98 clinical trials using this type of vaccine delivery system have been executed and 37 more are currently ongoing. Overwijk’s new findings may partly explain the lack of clinical benefit of vaccines that use the water-in-oil system. His research could lead to new classes of vaccines that induce T cells to track efficiently to the tumor rather than accumulating at the vaccination site.
The new, covax plus saline solution vaccine has not yet been tested in clinical trials. “It has been challenging to get all the clinical agents we need for this vaccine approach,” says Patrick Hwu, chair of the Department of Melanoma Medical Oncology at University of Texas MD Anderson Cancer Center and one of the study authors. Hwu, along with Craig Slingluff of the University of Virginia, are starting a clinical trial to compare the two vaccine types in melanoma patients.
The current study highlights the need to strive for better next generation vaccines with new adjuvants and immunomodulators, Hwu says. “We are very optimistic about the future of cancer vaccines.”