Common Cancer Vaccine Ingredient Diverts T cells from Tumors

Scientists from the University of Texas MD Anderson Cancer Center (Houston, USA) reported their findings March 3, 2013, in the journal Nature Medicine.

A common substance used in many cancer vaccines to boost immune attack betrays the cause by facilitating an accumulation of T cells at the vaccination site, which then summon more T cells to help with the perceived threat. “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,” said senior author Willem Overwijk, PhD, in MD Anderson’s department of melanoma medical oncology.

The result of this process is mostly unscathed tumors while an overstimulated immune response can cause lesions at the injection site. The investigators found that a key perpetrator in this failure is incomplete Freund’s adjuvant (IFA), a mineral oil-based adjuvant included in many vaccines to trigger the 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 said. “T cells keep attacking and secreting chemokines to call for reinforcements. But it’s an unkillable target; T cells can’t kill mineral oil.”

Ultimately, the T cells die. “The vaccination site increasingly resembles a viral infection, with lots of damaged tissue and antigens,” Dr. Overwijk said. “Switching to a saline-based adjuvant in a melanoma vaccine reversed the T cell effect in mice. Major accumulations of T cells gathered in tumors, shrinking them, with minimal T cell activity at the vaccination site.”

Peptide antigens are available for almost all types of cancer, according to Dr. Overwijk. A saline adjuvant could alter the weak performance of cancer vaccines. A clinical trial of the model is expected to open later 2013 at the University of Virginia (Charlottesville, USA) and MD Anderson. Dr. Overwijk and colleagues noted 98 US- approved clinical trials of vaccines against a range of cancers have nearly all failed, while another 37 trials are open, enrolling patients. The US Food and Drug Administration (FDA) has approved only one therapeutic vaccine, for treatment of prostate cancer, out of all of those trials.

“Our group and many other researchers have been trying for years to improve the performance of cancer vaccines, to no avail,” Dr. Overwijk said. “People kept trying because of these beguiling T cell levels in the blood. But our data suggest that the very nature of IFA-based vaccines may make it almost impossible for them to work well.”

In past studies and clinical trials, tumors were seldom evaluated for evidence of T cell penetration. In humans, they are frequently inoperable, and there was no indication that it needed to be done. “But a few researchers did analyze human tumors for T cell infiltration and largely found what we found in our mouse experiments,” Dr. Overwijk said.

The scientists examined the fate of melanoma-specific CD8-positive T cells after vaccination with the gp100 peptide with and without IFA. Both vaccines increased levels of the desired T cells in the blood, but with IFA, the T cells decreased to nearly undetectable levels after three weeks and did not recover even with an engineered virus-based booster. The vaccine-lacking IFA produced similar peak amounts of the T cells, a response that persisted over time.

The researchers fluorescently tagged T cells in the mouse model to see where they went. The study’s findings revealed that mice without IFA had the bulk of T cells light up in their tumors with minimal presence at the vaccination site. Moreover, T cells generated at the injection site in mice that received IFA-based vaccine, with a tiny showing in the tumor. Response duration was tested in gp100/IFA and control IFA vaccines. The antigen/IFA combination gathered and persisted at the vaccination site, where it could still stimulate the proliferation of injected T cells 96 days after vaccination.

A separate set of research showed the antigen/IFA-driven T cells were forced to kill themselves at the vaccination site by a variety of cell suicide-inducing proteins. Dr. Overwijk and colleagues suggested that a possible answer to the problem was to decrease the size and persistence of vaccine “depots” at the injection site. They evaluated a vaccine based on a saline solution instead of IFA and found that antigens cleared more quickly but did not trigger 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 demonstrated that the saline version caused T cells to zoom in on the tumors and killed them, whereas the IFA version focused T cells at the vaccination site, killing normal tissue and inducing chemokines that damaged and killed T cells.

“IFA-based vaccination sites essentially outcompete tumor sites for T cell recognition and accumulation, chemokine production, and tissue damage,” Dr. Overwijk concluded. “It’s an engineering flaw in those vaccines that we didn’'t appreciate until now. Fortunately, our results also directly instruct us how to design new, more powerful vaccine formulas for treating people with cancer.”

Related Links:
University of Texas MD Anderson Cancer Center