Cancer vaccines that attempt to stimulate an immune system assault fail because the killer T cells aimed at tumors instead find the vaccination site a more inviting target, scientists at The University of Texas MD Anderson Cancer Center report in Nature Medicine.
A common substance used in many cancer vaccines to boost immune attack betrays the cause by facilitating a buildup 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, Ph.D., in MD Anderson's Department of Melanoma Medical Oncology.
The result: largely unscathed tumors while an overstimulated immune response can cause lesions at the injection site. The team found that a major culprit in this failure is incomplete Freund's adjuvant (IFA), a mineral oil-based adjuvant included in many vaccines to stoke 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," 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."
Eventually, the T cells die. "The vaccination site increasingly resembles a viral infection, with lots of damaged tissue and antigens," Overwijk said.
Peptide antigens are available for almost all types of cancer, Overwijk said. A saline adjuvant could change the poor performance of cancer vaccines.
A clinical trial of the concept is 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.
Overwijk and colleagues noted 98 federally approved U.S. clinical trials of vaccines against a variety of cancers have almost all failed, while another 37 trials are open, enrolling patients. The U.S. Food and Drug Administration 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," 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 experiments and clinical trials, tumors were rarely examined for evidence of T cell penetration. In people, they are often 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," he said.
Mouse studies reveal vaccine self-sabotage
The team studied 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 dropped to nearly undetectable levels after three weeks and did not rebound 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 research team fluorescently tagged T cells in the mouse model to see where they went.
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 experiments showed the antigen/IFA-driven T cells were forced to kill themselves at the vaccination site by a variety of cell suicide-inducing proteins.Reducing vaccine depots at injection site
They tested a vaccine based on a saline solution instead of IFA and found that antigens cleared more quickly but did not 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.
"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. Fortunately, our results also directly instruct us how to design new, more powerful vaccine formulas for treating people with cancer."
Co-authors are first author Yared Hailemichael, Zhimin Dai, Nina Jaffarzad, Yang Ye, Miguel Medina, Xue-Fei Huang, Stephanie Dorta-Estremera Nathaniel Greeley, , Giovanni Nitti, Weiyi Peng, Chengwen Liu, Yanyan Lou, Brian Rabinovich and Patrick Hwu, all of MD Anderson's Department of Melanoma Medical Oncology; Zhiqiang Wang, Wencai Ma, and Richard Davis, of MD Anderson's Department of Lymphoma and Myeloma; and Kimberly Schluns, of MD Anderson's Department of Immunology.
Dorta-Estremera, Greeley, and Nitti are graduate students in The University of Texas Graduate School of Biomedical Sciences, a graduate school operated jointly by MD Anderson and The University of Texas Health Science Center at Houston. Schluns, Davis, Hwu and Overwijk also are on the GSBS faculty.
Grants from the National Cancer Institute of the National Institutes of Health (RO1 1CA143077 and PO1 CA128913) and an award from the Melanoma Research Alliance funded this research.
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute. For nine of the past 11 years, including 2012, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report. MD Anderson receives a cancer center support grant from the National Cancer Institute of the National Institutes of Health (P30 CA016672).
Get M. D. Anderson News Via RSS Follow MDAnderson News on Twitter
Scott Merville | EurekAlert!
Scientists develop tiny tooth-mounted sensors that can track what you eat
22.03.2018 | Tufts University
NIH scientists describe potential antibody treatment for multidrug-resistant K. pneumoniae
14.03.2018 | NIH/National Institute of Allergy and Infectious Diseases
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.
In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...
19.03.2018 | Event News
16.03.2018 | Event News
13.03.2018 | Event News
22.03.2018 | Trade Fair News
22.03.2018 | Earth Sciences
22.03.2018 | Earth Sciences