Cancer vaccines have a less-than-stellar history. Having been studied in almost 100 clinical trials in the United States, only one therapeutic vaccine, for prostate cancer, has received Food and Drug Administration (FDA) approval.
Although in recent trials some vaccines have shown promise, most have not been found to cause tumor regression despite increasing levels of tumor-specific T cells. Now, a research team from the University of Texas M. D. Anderson Cancer Center has proposed that the fault lies not in the peptides contained in the vaccine, but in how the vaccines are formulated.
Many cancer vaccines are composed of short, minimal determinant peptides formulated in incomplete Freund’s adjuvant (IFA). These have been shown to induce tumor-specific T cell responses, but objective tumor responses have been rare. In an article published in Nature Medicine, the M. D. Anderson research team proposes that IFA undermines the vaccine’s effectiveness by triggering a build-up of T cells at the vaccination site rather than at the tumor.1
“Vaccines stimulate production of T cells primed to attack the target cancer, and there are many T cells in the bloodstream after vaccination,” said Willim Overwijk, PhD, the research team leader. “We found that only a few get to the tumor while many more are stuck at or double back to the vaccination site.”
As a result, tumors remain largely unaffected by the increased T cell levels while the enhanced immune response may cause a lesion at the injection site. “The vaccination site increasingly resembles a viral infection, with lots of damaged tissue and antigens,” Overwijk said.
IFA is a mineral oil-based adjuvant included in many vaccines to accelerate the immune response. “IFA sticks around the vaccination site for up to 3 months, along with the antigen designed to trigger immunity against the tumor,” Overwijk said. “T cells keep attacking and secreting chemokines to call for reinforcements. But it’s an un-killable target; T cells can’t kill mineral oil.”
Few clinical trials of cancer vaccines have examined tumors for evidence of T cell penetration, but those that did found little evidence that T cells were getting where they were needed.
The M. D. Anderson research team compared the effects of vaccination of mice with a gp100 peptide with and without IFA on melanoma-specific CD8-positive T cells. Although T cell blood levels rose after administration of both vaccines, they dropped to undetectable levels within 3 weeks in the mice that received a vaccine containing IFA but persisted in the mice that received the vaccine without IFA. Fluorescent tagging of T cells showed that they were accumulating in the tumor in the mice that had not received IFA and at the injection site in mice that had. At the injection site, T cells became dysfunctional and underwent apoptosis, which resulted in hyporesponsiveness to further vaccination.
“IFA-based vaccination sites essentially outcompete tumor sites for T cell recognition and accumulation, chemokine production, and tissue damage,” Overwijk said. “It’s an engineering flaw in those vaccines that we didn’t appreciate until now.”
1) Hailemichael Y, Dai Z, Jaffarzad N, et al. Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat Med. 2013 Mar 3. doi: 10.1038/nm.3105. [Epub ahead of print]