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New MRNA Cancer Vaccine Helps Immune System Fight Deadly Brain Tumors
Glioblastoma is the most common type of brain cancer, affecting about 3 in every 100,000 people globally each year.
Recent research shows that glioblastoma incidence is rising due to an aging population and environmental factors such as air pollution.
Glioblastoma is a challenging cancer to treat and has an average five-year survival rate of 6.9%.
Now, researchers from the University of Florida have developed a new mRNA cancer vaccine to retrain the body's immune system to attack and potentially treat glioblastoma. The results of this study were recently published in the journal Cell.
"Glioblastoma is the most common malignant brain tumor, and despite the boon in medical innovations, outcomes have not precipitously changed in decades," Elias Sayour, MD, PhD, the Stop Children's Cancer/Bonnie R. Freeman Professor for Pediatric Oncology Research in the Departments of Neurosurgery and Pediatrics at the University of Florida and lead author of this study told Medical News Today.
"Our brain tumor program has developed promising effects with other forms of immunotherapy against brain cancer and wanted to test a novel mRNA vaccine design to enhance responses for these difficult-to-treat diseases," Sayour added.
Ever since the mRNA vaccines were developed to fight the coronavirus, scientists have been studying their use for the treatment of other conditions, including cancer.
In this study, researchers used study participants' own tumor cells to create a personalized vaccine for their particular cancer.
"mRNA is the information from our genetic code that is turned into protein: the hardware that makes each of us — and each cancer — unique," Sayour explained.
"By targeting the unique mRNA repertoire of a patient's cancer, we can make exquisitely personalized vaccines unique to individual tumors in a manner that is feasible and commercializable to all."
The study evaluated the impact of the new mRNA vaccines by testing 10 pet dogs who had natural brain tumors and were enrolled in the study by their owners because they had no other treatment options.
Dogs treated with the mRNA cancer vaccine lived an average of 139 days, compared to the average 30- to 60-day survival rate for dogs with the condition.
After animal tests, the scientists expanded their research to a small FDA-approved clinical trial of four human study participants with glioblastoma.
After receiving the mRNA vaccine, researchers reported that in less than 48 hours, they were able to observe brain tumors moving from a "cold" silenced immune response to a "hot" active immune response.
"This is significant because it usually takes time — weeks to months with boosters — for vaccines to begin working," Sayour said. "We expect this work to create a new paradigm that rapidly activates the immune system against cancer."
"To win the war on cancer, the immune system needs a better head start. We hope this approach gives the immune system the head start it needs to win the race against rapidly evolving tumors. By getting rapid responses from a single vaccine, the immune system can be rapidly reprogrammed to fight cancer."
— Elias Sayour, MD, PhD, lead study author
Scientists said that while it is still too early to assess the clinical effects of the mRNA cancer vaccine, they did report that human study participants receiving the vaccine either lived disease-free longer than expected or survived longer than expected.
The researchers also stated the small clinical trial of four participants helped demonstrate early safety and feasibility before expanding to a larger clinical trial.
"We must validate these findings in (a) larger cohort of patients, identify a maximally tolerated dose, and begin phase II trials," Sayour said.
"We are also moving aggressively to launch this platform against pediatric brain tumors."
Wael Harb, MD, a board certified hematologist and medical oncologist at MemorialCare Cancer Institute at Orange Coast and Saddleback Medical Centers in Orange County, CA, told MNT that as glioblastoma is a very difficult cancer to treat, doctors are in need of new treatments. Harb was not involved in the study.
"The overall strategy is very interesting using the systemic immune response while reprogramming the tumor microenvironment is very promising — and in the larger context of immunotherapy research, I think this is a really exciting approach," Harb said.
"The next step would be [a] well-designed clinical trial looking at the safety and efficacy in a more diverse patient population to really understand how these RNA-LPAs (RNA lipid-particle aggregates) work in reprogramming the tumor microenvironment. "I would love to see, in addition to safety efficacy data, biomarkers to show that this is happening."
— Wael Harb, MD, hematologist and medical oncologist
"To me, this is a way of educating the immune cells [on] how to fight cancer," Harb continued.
"I think the crucial step would be to proceed with that to see the result of the early phase clinical trial — is that translating into what is the safety and efficacy, (and) are the biomarkers (that) we're seeing in humans correlating to what we saw in animal studies," Harb noted.
Jose Carrillo, MD, a board certified neurologist and neuro-oncologist at Pacific Neuroscience Institute and associate professor of neurology at the Saint John's Cancer Institute at Providence Saint John's Health Center in Santa Monica, CA, not involved in the study, told MNT his initial reaction to the findings was one of "cautious optimism."
"This study describes a novel technique for inducing an immune response in glioblastoma, which has been notoriously difficult to obtain significant advances in survival with immune therapies and clinical trials. I remain positive, however, based upon studies like these, that steady progress is being made in unraveling new discoveries that will get (us) one step closer to better treatments for our patients.
— Jose Carrillo, MD, neuro-oncologist
Etymology Of Cancer: Tracing The Origins Of A Medical Term To Ancient Greece And Rome
Melbourne Melbourne, May 6 (The Conversation) One of the earliest descriptions of someone with cancer comes from the fourth century BC. Satyrus, tyrant of the city of Heracleia on the Black Sea, developed a cancer between his groin and scrotum. As the cancer spread, Satyrus had ever greater pains. He was unable to sleep and had convulsions.
Advanced cancers in that part of the body were regarded as inoperable, and there were no drugs strong enough to alleviate the agony. So doctors could do nothing. Eventually, the cancer took Satyrus' life at the age of 65.
Cancer was already well known in this period. A text written in the late fifth or early fourth century BC, called Diseases of Women, described how breast cancer develops: hard growths form […] out of them hidden cancers develop […] pains shoot up from the patients' breasts to their throats, and around their shoulder blades […] such patients become thin through their whole body […] breathing decreases, the sense of smell is lost […] Other medical works of this period describe different sorts of cancers. A woman from the Greek city of Abdera died from a cancer of the chest; a man with throat cancer survived after his doctor burned away the tumour.
Where does the word 'cancer' come from? The word cancer comes from the same era. In the late fifth and early fourth century BC, doctors were using the word karkinos – the ancient Greek word for crab – to describe malignant tumours. Later, when Latin-speaking doctors described the same disease, they used the Latin word for crab: cancer. So, the name stuck.
Even in ancient times, people wondered why doctors named the disease after an animal. One explanation was the crab is an aggressive animal, just as cancer can be an aggressive disease; another explanation was the crab can grip one part of a person's body with its claws and be difficult to remove, just as cancer can be difficult to remove once it has developed. Others thought it was because of the appearance of the tumour.
The physician Galen (129-216 AD) described breast cancer in his work A Method of Medicine to Glaucon, and compared the form of the tumour to the form of a crab: We have often seen in the breasts a tumour exactly like a crab. Just as that animal has feet on either side of its body, so too in this disease the veins of the unnatural swelling are stretched out on either side, creating a form similar to a crab.
Not everyone agreed what caused cancer In the Greco-Roman period, there were different opinions about the cause of cancer.
According to a widespread ancient medical theory, the body has four humours: blood, yellow bile, phlegm and black bile. These four humours need to be kept in a state of balance, otherwise a person becomes sick. If a person suffered from an excess of black bile, it was thought this would eventually lead to cancer.
The physician Erasistratus, who lived from around 315 to 240 BC, disagreed. However, so far as we know, he did not offer an alternative explanation.
How was cancer treated? Cancer was treated in a range of different ways. It was thought that cancers in their early stages could be cured using medications.
These included drugs derived from plants (such as cucumber, narcissus bulb, castor bean, bitter vetch, cabbage); animals (such as the ash of a crab); and metals (such as arsenic).
Galen claimed that by using this sort of medication, and repeatedly purging his patients with emetics or enemas, he was sometimes successful at making emerging cancers disappear. He said the same treatment sometimes prevented more advanced cancers from continuing to grow. However, he also said surgery is necessary if these medications do not work.
Surgery was usually avoided as patients tended to die from blood loss. The most successful operations were on cancers of the tip of the breast. Leonidas, a physician who lived in the second and third century AD, described his method, which involved cauterising (burning): I usually operate in cases where the tumours do not extend into the chest […] When the patient has been placed on her back, I incise the healthy area of the breast above the tumour and then cauterize the incision until scabs form and the bleeding is stanched. Then I incise again, marking out the area as I cut deeply into the breast, and again I cauterize. I do this [incising and cauterizing] quite often […] This way the bleeding is not dangerous. After the excision is complete I again cauterize the entire area until it is dessicated.
Cancer was generally regarded as an incurable disease, and so it was feared. Some people with cancer, such as the poet Silius Italicus (26-102 AD), died by suicide to end the torment.
Patients would also pray to the gods for hope of a cure. An example of this is Innocentia, an aristocratic lady who lived in Carthage (in modern-day Tunisia) in the fifth century AD. She told her doctor divine intervention had cured her breast cancer, though her doctor did not believe her.
From the past into the future We began with Satyrus, a tyrant in the fourth century BC. In the 2,400 years or so since then, much has changed in our knowledge of what causes cancer, how to prevent it and how to treat it. We also know there are more than 200 different types of cancer. Some people's cancers are so successfully managed, they go on to live long lives.
But there is still no general "cure for cancer", a disease that about one in five people develop in their lifetime. In 2022 alone, there were about 20 million new cancer cases and 9.7 million cancer deaths globally. We clearly have a long way to go. (The Conversation) NSA NSA
(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)
Intermittent Fasting Protects Against Liver Inflammation And Liver Cancer
Fatty liver disease often leads to chronic liver inflammation and can even result in liver cancer. Scientists from the German Cancer Research Center (DKFZ) and the University of Tübingen have now shown in mice* that intermittent fasting on a 5:2 schedule can halt this development. The fasting regime reduces the development of liver cancer in mice with pre-existing liver inflammation. The researchers identified two proteins in liver cells that are jointly responsible for the protective effect of fasting. An approved drug can partially mimic this effect.
The most common chronic liver condition is non-alcoholic fatty liver disease. It can have serious consequences: If left untreated, it can lead to liver inflammation (metabolic dysfunction-associated steatohepatitis, MASH), liver cirrhosis and even liver cancer. Fatty liver disease is largely considered to be a direct consequence of obesity. It is not only people in Europe and the USA who have put on enormous amounts of weight in recent decades; obesity is also becoming increasingly widespread in emerging countries such as India and China. As a result, the number of cases of liver failure and liver cancer is rising sharply in the countries affected.
"The vicious circle of an unhealthy diet, obesity, liver inflammation and liver cancer is associated with major restrictions and suffering for those affected and also represents a considerable burden on healthcare systems," says Mathias Heikenwälder, DKFZ and University of Tübingen. "We have therefore investigated whether simple dietary changes can specifically interrupt this fatal process."
Intermittent fasting has already been shown in several studies to be an effective means of reducing weight and alleviating certain metabolic disorders. Heikenwälder's team has now tested in mice whether this approach can also protect the liver from fatty degeneration and chronic inflammation.
Resistance to liver inflammation is independent of calorie intake
The animals were fed with a high-sugar and high-fat diet correspondind to the typical Western diet. One group of mice had constant access to the food. As expected, these animals gained weight and body fat and developed chronic liver inflammation.
The mice in the other group were given nothing to eat on two days a week (5:2 intermittent fasting, or 5:2 IF for short), but were allowed to eat as much as they wished on the other days. Despite the high-calorie diet, these animals did not put on weight, showed fewer signs of liver disease and had lower levels of biomarkers that indicate liver damage. In short, they were resistant to the development of MASH.
Interestingly, resistance to the development of a fatty liver was independent of the total calorie intake, as the animals immediately made up for the lost rations after the end of the fasting periods.
When experimenting with different variants of intermittent fasting, it was found that several parameters determine protection against liver inflammation: The number and duration of fasting cycles play a role, as does the start of the fasting phase. A 5:2 dietary pattern works better than 6:1; 24-hour fasting phases better than 12-hour ones. A particularly unhealthy diet requires more frequent dieting cycles.
Heikenwälder's team now wanted to find out the molecular background of the response to fasting. To this end, the researchers compared protein composition, metabolic pathways and gene activity in the liver of fasting and non-fasting mice. Two main players responsible for the protective fasting response emerged: the transcription factor PPARα and the enzyme PCK1. The two molecular players work together to increase the breakdown of fatty acids and gluconeogenesis and inhibit the build-up of fats.
"The fasting cycles lead to profound metabolic changes, which together act as beneficial detoxification mechanisms and help to combat MASH," says Heikenwälder, summarizing the molecular details.
The fact that these correlations are not just a mouse phenomenon was shown when tissue samples from MASH patients were examined: Here, too, the researchers found the same molecular pattern with reduced PPAR α and PCK1. Are PPAR α and PCK1 actually responsible for the beneficial effects of fasting? When both proteins were genetically switched off simultaneously in the liver cells of the mice, intermittent fasting was unable to prevent either chronic inflammation or fibrosis.
The drug pemafibrate mimics the effects of PPARα in the cell. Can the substance also mimic the protective effect of fasting? The researchers investigated this question in mice. Pemafibrate induced some of the favorable metabolic changes that were observed with 5:2 fasting. However, it was only able to partially mimic the protective effects of fasting. "This is hardly surprising, as we can only influence one of the two key players with pemafibrate. Unfortunately, a drug that mimics the effects of PCK1 is not yet available," explains Mathias Heikenwälder.
Intermittent fasting as liver therapy
While Heikenwälder and his team initially focused on the effects of intermittent fasting on the prevention of MASH, they then investigated whether the 5:2 diet could also alleviate existing chronic liver inflammation.
To this end, the team examined mice that had developed MASH after months of being fed a high-sugar, high-fat diet. After a further four months of 5:2 intermittent fasting (on the same diet), these animals were compared with the non-fasting control group. The fasting mice had better blood values, less fatty liver and liver inflammation and above all: they developed less liver cancer and had fewer cancer foci in the liver.
"This shows us that 5:2 intermittent fasting has great potential - both in the prevention of MASH and liver cancer, as well as in the treatment of established chronic liver inflammation," summarizes principal investigator Heikenwälder. "The promising results justify studies in patients to find out whether intermittent fasting protects against chronic liver inflammation as well as in the mouse model."
The 5:2 fasting regimen is popular. It is considered comparatively easy to integrate into everyday life, as the fasting days can be tailored to personal needs and no specific foods are prohibited. "Nevertheless, there will always be people who can't stick to a strict diet in the long term," says Heikenwälder. "That's why we want to continue to investigate which combinations of drugs we can use to fully mimic the protective effects of fasting."
Publication:
Suchira Gallage, Adnan Ali, Jose Efren Barragan Avila, Nogayhan Seymen, Pierluigi Ramadori, Vera Joerke, Laimdota Zizmare, Jan Kosla, Xin Li, Enrico Focaccia, Suhail Yousuf, Tjeerd Sijmonsma, Mohammad Rahbari, Katharina S. Kommoss, Adrian Billeter, Sandra Prokosch, Ulrike Rothermel, Florian Mueller, Jenny Hetzer, Danijela Heide, Tim Machauer, Nisar P. Malek, Thomas Longerich, Adam J. Rose, Susanne Roth, Johannes Schwenck, Christoph Trautwein, Mohammad M Karimi, Mathias Heikenwälder: PPAR alpha agonist pemafibrate recapitulates aspects of hepatic fasting response
Cell Metabolism 2023, DOI: https://doi.Org/10.1016/j.Cmet.2024.04.015
* Why was it necessary to study mice for this experiments?
A high-calorie, unbalanced diet and a sedentary lifestyle are contributing to the sharp rise in the proportion of obese people in many parts of the world. Obesity also increases the risk of a whole range of secondary diseases for those affected, including cardiovascular diseases, metabolic diseases, cancer and joint problems. Understanding these correlations and, ideally, intervening in a targeted manner is an extremely important research goal.
Several organs and organ systems are jointly involved in the development of obesity-related health consequences. The liver, pancreas, brain, lymphatic organs and fatty tissue work together here, which cannot be simulated in the culture dish. The intestine can also play a role in the development of MASH. The spontaneous development of liver cancer from a fatty liver can therefore only be recapitulated and investigated if all these factors interact.
Also crucial is the influence of immune cells that migrate from the periphery of the body into the fatty liver, are activated there and migrate back into the body, where they interact with the fatty tissue. This can only be investigated in an intact organism. Experiments with mice are also necessary to understand which length of fasting periods achieves the most favorable health results in the context of the circadian (day/night) rhythm.
With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany's largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:
National Center for Tumor Diseases (NCT, 6 sites)
German Cancer Consortium (DKTK, 8 sites)
Hopp Children's Cancer Center (KiTZ) Heidelberg
Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ
DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
National Cancer Prevention Center (jointly with German Cancer Aid)
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.
Article TitlePPAR alpha agonist pemafibrate recapitulates aspects of hepatic fasting response
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