Cancer ‘vaccine’ eliminates tumors in mice

May 17, 2018

Ronald Levy (left) and Idit Sagiv-Barfi led the work on a possible cancer treatment that involves injecting two immune-stimulating agents directly into solid tumors. Steve Fisch

Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases, according to a study by researchers at the Stanford University School of Medicine.

The approach works for many different types of cancers, including those that arise spontaneously, the study found.

The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with bodywide immune stimulation.

“When we use these two agents together, we see the elimination of tumors all over the body,” said Ronald Levy, MD, professor of oncology. “This approach bypasses the need to identify tumor-specific immune targets and doesn’t require wholesale activation of the immune system or customization of a patient’s immune cells.”

One agent is already approved for use in humans; the other has been tested for human use in several unrelated clinical trials. A clinical trial was launched in January to test the effect of the treatment in patients with lymphoma. (Information about the trial is available online.)

Levy, who holds the Robert K. and Helen K. Summy Professorship in the School of Medicine, is the senior author of the study, which was published Jan. 31 in Science Translational Medicine. Instructor of medicine Idit Sagiv-Barfi, PhD, is the lead author.

‘Amazing, bodywide effects’

Levy is a pioneer in the field of cancer immunotherapy, in which researchers try to harness the immune system to combat cancer. Research in his laboratory led to the development of rituximab, one of the first monoclonal antibodies approved for use as an anti-cancer treatment in humans.

Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient’s immune cells to be removed from the body and genetically engineered to attack the tumor cells. Many of these approaches have been successful, but they each have downsides — from difficult-to-handle side effects to high-cost and lengthy preparation or treatment times.

“All of these immunotherapy advances are changing medical practice,” Levy said. “Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, bodywide effects, including the elimination of tumors all over the animal.”

Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.

Levy’s method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. (A microgram is one-millionth of a gram). One, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells. Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are “prescreened” by the body to recognize only cancer-specific proteins.

Cancer-destroying rangers

Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.

The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors.

Mice genetically engineered to spontaneously develop breast cancers in all 10 of their mammary pads also responded to the treatment. Treating the first tumor that arose often prevented the occurrence of future tumors and significantly increased the animals’ life span, the researchers found.

Finally, Sagiv-Barfi explored the specificity of the T cells by transplanting two types of tumors into the mice. She transplanted the same lymphoma cancer cells in two locations, and she transplanted a colon cancer cell line in a third location. Treatment of one of the lymphoma sites caused the regression of both lymphoma tumors but did not affect the growth of the colon cancer cells.

“This is a very targeted approach,” Levy said. “Only the tumor that shares the protein targets displayed by the treated site is affected. We’re attacking specific targets without having to identify exactly what proteins the T cells are recognizing.”

The current clinical trial is expected to recruit about 15 patients with low-grade lymphoma. If successful, Levy believes the treatment could be useful for many tumor types. He envisions a future in which clinicians inject the two agents into solid tumors in humans prior to surgical removal of the cancer as a way to prevent recurrence due to unidentified metastases or lingering cancer cells, or even to head off the development of future tumors that arise due to genetic mutations like BRCA1 and 2.

“I don’t think there’s a limit to the type of tumor we could potentially treat, as long as it has been infiltrated by the immune system,” Levy said.

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

The study’s other Stanford co-authors are senior research assistant and lab manager Debra Czerwinski; professor of medicine Shoshana Levy, PhD; postdoctoral scholar Israt Alam, PhD; graduate student Aaron Mayer; and professor of radiology Sanjiv Gambhir, MD, PhD.

Levy is a member of the Stanford Cancer Institute and Stanford Bio-X.

Gambhir is the founder and equity holder in CellSight Inc., which develops and translates multimodality strategies to image cell trafficking and transplantation.

The research was supported by the National Institutes of Health (grant CA188005), the Leukemia and Lymphoma Society, the Boaz and Varda Dotan Foundation and the Phil N. Allen Foundation.

Stanford’s Department of Medicine also supported the work.

This article was originally published by: http://med.stanford.edu/news/all-news/2018/01/cancer-vaccine-eliminates-tumors-in-mice.html

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Have researchers really discovered a ‘new miracle drug to cure nine in 10 cancers’? No, but the research is fascinating

October 18, 2015

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You may have seen some of the headlines today reporting a new ‘miracle drug’ that could cure nine out of 10 cancers. It sounds amazing, but is it true?

Unfortunately, the answer is no. At least for now. But that’s not to say this isn’t important, promising new research.

The reports centre on the supposedly serendipitous discovery of a link between an experimental malaria vaccine for pregnant women and a molecule that sits on the surface of cancer cells.

So what did the study – published in the journal Cancer Cell – actually show?

What they did

The researchers – based at the University of Copenhagen – had been studying malaria in pregnant women, and the role a particular type of sugar molecule, called chondroitin sulphate, plays in the disease.

They already knew that the molecule, which is found on the surface of cells in the placenta, sticks to a protein – called VAR2CSA – that’s produced by the malaria parasite Plasmodium falciparum. And the team have been working on an experimental vaccine that uses the sticky interaction between chondroitin sulphate and VAR2CSA as a possible way to prevent malaria in pregnant women.

But the latest study behind today’s headlines showed something new – the specialised sugar molecule can also be found on the surface of some cancer cells. So the researchers decided to see if tweaking their experimental malaria vaccine might turn it into something that could kill cancer cells.

To test this, they added a toxin designed to kill cancer cells to the VAR2CSA protein, and added the modified vaccine to cancer cells grown in the lab. They also tested the vaccine by treating mice with prostate cancer, melanoma and a type of lymphoma.

Their experiments showed that the VAR2CSA was able to stick to the chondroitin sulphate on the cancer cells, delivering the deadly toxin that killed the cancer cells, but left healthy cells alone.

It’s exciting stuff. But did this research show that this modified malaria vaccine could be a ‘cure’ for nine in 10 cancers?

The short answer is no. (We think this press release might be where that misleading figure came from).

Not nine in 10

What the researchers actually showed was that in the group of cancer cells they studied – which didn’t include all types of cancer – the majority (95 per cent) of them also produced chondroitin sulphate on their surface.

This means that the malaria vaccine could potentially be used to target these cancers in the future. But not without a lot more research.

This study was done in mice, meaning before this modified malaria vaccine can be used to treat cancer in people we need to understand more about it, and whether it’s safe to be used in humans.

This would also require larger studies to see if the vaccine kills cancer cells in the same way in people, while leaving healthy cells alone and which patients with which cancers could benefit.

Only more research and clinical trials will be able to answer these questions.

So while this certainly is exciting research that could one day help cancer patients in the future, at the moment, it is not a ‘miracle’ drug that will cure nine out of 10 cancers.

http://scienceblog.cancerresearchuk.org/2015/10/14/have-researchers-really-discovered-a-new-miracle-drug-to-cure-nine-in-10-cancers-no-but-the-research-is-fascinating/

C. difficile vaccine proves safe, 100 percent effective in animal models

August 3, 2014

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An experimental vaccine protected 100 percent of animal models against the highly infectious and virulent bacterium, Clostridium difficile, which causes an intestinal disease that kills approximately 30,000 Americans annually. The research is published ahead of print in Infection and Immunity.

In the study, the vaccine protected the mice and non-human primates against the purified toxins produced by C. difficile, as well as from an orogastric spore infection, a laboratory model that mimics the human disease, after only two immunizations.

“Animals that received two immunizations did not get sick or show signs of C. difficile-associated disease,” says corresponding author Michele Kutzler, of Drexel University College of Medicine, Philadelphia.

“While our research was conducted in animal models, the results are very translatable to the clinic,” says Kutzler. “In some cases, patients who acquire C. difficile can develop serious complications including severe diarrhea, toxic megacolon, bowel perforation, multi-organ failure, and death. Once fully developed, our DNA vaccine could prevent the deadly effects of C. difficile infection when administered to hospital patients at risk of acquiring C. difficile.”

The protection following just two immunizations is especially important since the time window in humans between colonization with C. difficile and the onset of disease symptoms can be a mere 10-14 days, says Kutzler.

The vaccine protects against the bacterial toxins by mustering anti-toxin neutralizing antibodies, says Kutzler.

The cost of fighting the half million C. difficile infections that occur annually in the US is estimated to be nearly $10 billion, most of which could be saved by a successful preventive vaccine, says Kutzler. Morbidity and mortality have risen over the last decade, likely due to increased prevalence of relapsing disease, and hypervirulent strains, she adds.

Treating the disease is especially difficult, as the bacterial spores persist in the hospital environment, where most infections occur. There is no standard, effective treatment for recurrent disease, but a small number of experimental fecal transplants for C. difficile have had a very high success rate, with no adverse reactions.

“Since our vaccine was safe, effective after only two immunizations, and performed exceptionally well, we feel that this success warrants further studies using human patients,” says Kutzler.


Story Source:

The above story is based on materials provided by American Society for Microbiology. Note: Materials may be edited for content and length.

Nonablative Laser Light Increases Influenza Vaccine Response 4 to 7-fold

August 3, 2014

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Influenza imposes a heavy annual public health burden, and lies historically at the heart of a number of global pandemics that killed tens of millions.  To overcome the challenges of manufacturing enough vaccines such that we may stave off the next epidemic, medical researchers are searching for ways to strengthen or extend the power of existing and stockpiled vaccines.  Now a team of scientists in Boston has just developed a new method of using laser light to stimulate and enhance the immune response to a vaccine by a remarkable 4 to 7-fold against disease agents. Such treatments that assist vaccines but are not vaccines themselves are known as adjuvants.

Interestingly, the improved 4 to 7-fold laser adjuvant could not be matched even when compared against increasing the vaccine dosage 10-fold.  Efficacy of the vaccine was measured by the level of influenza-specific antibodies generated in an inoculated person.  The new method improves on an existing adjuvant hampered by harmful side effects which thus far has prevented its usage broadly.  Although the results were obtained in the context of two animal models, adult and aged mice, as well as pigs, its fairly general immunological basis is expected to translate to humans.

Before inoculation, the injection site is exposed to laser light for a short time. The light does not perforate the outer layers of the skin, but rather injures the dermis.  Because of the way the laser light is arranged, this creates a number of “microthermal zones.”  In each zone, dermal cells that are damaged stimulate inflammation, signaling danger to the immune system, which in turn attracts antigen-presenting cells (APCs) to the damaged area. APCs are cells that occur naturally in the body that bind antigens of harmful disease agents so as to prepare the rest of the immune system to recognize and neutralize the threat.  Each zone is only 200 micrometers by 300 micrometers.  Given that there are 54 zones, the total area is less than 2 square millimeters.

Non-ablative fractional lasers are used for cosmetic purposes

The damaged area is so small such that that self-healing occurs within 72 hours. The inspiration for the adjuvant comes from a type of skin treatment used in cosmetic dermatology.  In the cosmetic context, the laser light is used to stimulate lightly skin with aged appearance.  Post-damage, epithelial cells quickly grow to surround the microthermal zone to give rise to more youthful looking skin.  The same class of non-ablative lasers were used in this study.

The researchers, led by first author Dr. Ji Wang and Professor Mei Wu at the Massachusetts General Hospital, and the Harvard-MIT Division of Health Science and Technology, discovered that the process is driven by attraction of plasmacytoid dendritic cells (pDCs), a type of immune cell.  The researchers used three methods to block pDCs to verify these cells are essential.

Causing controlled skin injury to enhance the efficacy of the vaccination is called micro-sterile inflammation increase.  Other similar preclinical studies have fared worse because of greater damage at the site of application, leading to severely inflamed skin legions. Most importantly the results show increased effectiveness in influenza vaccine.

The studies have important implications for elderly patients, who are more susceptible to opportunistic or idiopathic conditions, i.e. conditions caused by the treatment itself.  Since only the vaccine and not the adjuvant needs to be injected, the adjuvant’s efficacy and safety are both increased for the individual.  From a public health perspective, the adjuvant is a major boon as it cuts down on the costs and extends the power of existing vaccines, vital steps forward in augmenting our ability to deal with future pandemics.

The research was published in Nature Communications.

http://www.neomatica.com/2014/07/28/nonablative-laser-light-increases-influenza-vaccine-response-4-7-fold/