Cancer vaccines self-sabotage, channel immune attack to injection site
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.
Switch from IFA to saline adjuvant reverses effect
"Switching to a saline-based adjuvant in a melanoma vaccine reversed the T cell effect in mice," Overwijk said, "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, 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.
- Mice without IFA had the bulk of T cells light up in their tumors with minimal presence at the vaccination site.
- T cells built up at the injection site in mice that received IFA-based vaccine, with a tiny showing in the tumor.
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
Overwijk and colleagues inferred that a possible answer to the problem was to reduce the size and persistence of vaccine "depots" at the 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."
More information: dx.doi.org/10.1038/nm.3105
Journal reference: Nature Medicine
Provided by University of Texas M. D. Anderson Cancer Center
- Tattooing improves response to DNA vaccine Feb 07, 2008 | not rated yet | 0
- Hybrid vaccine demonstrates potential to prevent breast cancer recurrence May 17, 2012 | not rated yet | 0
- New Strategy Produces Promising Advance in Cancer Vaccines Feb 15, 2010 | not rated yet | 0
- Another potential obstacle to developing an HIV vaccine Dec 27, 2011 | not rated yet | 0
- Novel antigen-cloning technique may boost efforts to develop a melanoma vaccine Apr 15, 2007 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be villous adenoma in colon, if there are no villi there
13 hours ago As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
- More from Physics Forums - Medical Sciences
More news stories
Every day, their baby stopped breathing, his collapsed bronchus blocking the crucial flow of air to his lungs. April and Bryan Gionfriddo watched helplessly, just praying that somehow the dire predictions ...
Medical research 4 hours ago | 5 / 5 (1) | 0
The human gut is loaded with commensal bacteria – "good" microbes that, among other functions, help the body digest food. The gastrointestinal tract contains literally trillions of such cells, and yet the ...
Medical research 8 hours ago | 5 / 5 (1) | 0 |
Medical research 8 hours ago | 4.7 / 5 (3) | 0 |
On May 22, JoVE will publish details of a technique to measure the health of human genetic material in relation to a patient's age. The method is demonstrated by the laboratory of Dr. Gil Atzmon at New York's Albert Einste ...
Medical research 11 hours ago | not rated yet | 0
(Medical Xpress)—Scientists supported by the National Institutes of Health have a new theory as to why a woman's fertility declines after her mid-30s. They also suggest an approach that might help slow ...
Medical research 13 hours ago | not rated yet | 0 |
4 hours ago | 5 / 5 (1) | 0 |
8 hours ago | not rated yet | 0 |
5 hours ago | 5 / 5 (1) | 2 |
5 hours ago | not rated yet | 0 |
(HealthDay)—Implementation of systematic monitoring for medication adherence will allow for identification of barriers to adherence and tailoring of interventions, according to a viewpoint piece published ...
3 hours ago | not rated yet | 0
Calorie information in fast food restaurants used by 40 percent of 9-18 year olds when making food choices
A new study published online today (Thursday) in the Journal of Public Health has found that of young people who visited fast food or chain restaurants in the U.S. in 2010, girls and youth who were obese were more likely ...
1 hour ago | not rated yet | 0