STOCKHOLM/LONDON (Reuters) - American James Allison and Japanese Tasuku Honjo won the 2018 Nobel Prize for Physiology or Medicine on Monday for game-changing discoveries about how to harness and manipulate the immune system to fight cancer.
Monday, 1 Oct 2018
The scientists' work in the 1990s has since swiftly led to new and dramatically improved therapies for cancers such as melanoma and lung cancer, which had previously been extremely difficult to treat.
"The seminal discoveries by the two Laureates constitute a landmark in our fight against cancer," the Nobel Assembly at Sweden's Karolinska Institute said as it awarded the prize of nine million Swedish crowns (766,930 pounds).
Allison and Honjo showed releasing the brakes on the immune system can unleash its power to attack cancer. The resulting treatments, known as immune checkpoint blockade, have "fundamentally changed the outcome" for some advanced cancer patients," the Nobel institute said.
The literature prize will not be handed out this year after the awarding body was hit by a sexual misconduct scandal. A Swedish court on Monday found a man at the centre of the scandal guilty of rape and sentenced him to two years in jail.
REVOLUTIONISED CANCER TREATMENT
Allison's and Honjo's work focussed on proteins that act as brakes on the immune system - preventing the body's main immune cells, known as T-cells, from attacking tumours effectively.
Allison, a professor at the University of Texas MD Anderson Cancer Center, worked on a protein known as CTLA-4 and realised that if this could be blocked, a brake would be released.
"It immediately occurred to me, and some of the people in my lab, that maybe we can use this to unleash the immune system to attack cancer cells," Allison told a news conference after getting the prize.
Honjo, a professor at Kyoto University since 1984, separately discovered a second protein called PD-1 and found that it too acted as an immune system brake, but with a different mechanism.
The discoveries led to the creation of a multibillion-dollar market for new cancer medicines.
Bristol-Myers Squibb's CTLA-4 therapy Yervoy was the first such drug to win approval, in 2011. However, it is medicines targeting PD-1 blockade that have proved a bigger commercial hit, led by Merck & Co's Keytruda in 2014.
These and rival drugs from Roche, AstraZeneca, Pfizer and Sanofi now offer new options for patients with melanoma, lung and bladder cancers.
Sales of such medicines, which are given as infusions, are expected to reach some $15 billion this year, according to Thomson Reuters consensus forecasts. Some analysts see eventual revenues of $50 billion.
Honjo, who is now 76, told a news conference in Tokyo he was honoured to get the Nobel, but his work was not yet done.
"I would like to keep on doing my research ...so that this immune treatment could save more cancer patients," he said.
Japanese Prime Minister Shinzo Abe congratulated Honjo in a phone call, telling him: "I believe the achievements of your research have given cancer patients hope and light."
Allison told a news conference he was in a "state of shock" hours after learning from his son that he had won a Nobel prize.
"As a basic scientist, to have my work really impact people is just one of the best things," he said. "I think it's everybody's dream. And I've been lucky enough to do work that is benefiting people now."
Commenting on the award, Kevin Harrington, a professor at the Institute of Cancer Research in London, said the work had revolutionised cancer treatment.
"We’ve gone from being in a situation where patients were effectively untreatable to having a range of immunotherapy options that, when they work, work very well indeed," he said in a statement. "For some patients we see their tumours shrink or completely disappear and are effectively cured."
Graphic of Nobel laureates: http://tmsnrt.rs/2y6ATVW
Early stage melanoma can often be difficult to distinguish from a moleCREDIT: CALLISTA IMAGES
The test could potentially allow early detection of melanoma, the most deadly form of skin cancer, and increase the prospects of treatment. It may also help to avoid invasive and costly biopsies.
Researchers said the test could prove more accurate than the current method of detection, which typically involves a doctor looking at the skin and assessing spots or changes to moles before removing a sample for further examination. But an early stage melanoma can often be difficult to distinguish from a mole.
“While clinicians do a fantastic job with the tools available, relying on biopsies alone can be problematic,” said Pauline Zaenker, from Edith Cowan University.
“The body starts producing these antibodies as soon as melanoma first develops which is how we have been able to detect the cancer in its very early stages with this blood test. No other type of biomarker appears to be capable of detecting the cancer in blood at these early stages.”
Melanoma, which are typically caused by exposure to the sun, can, if undetected, spread to other parts of the body such as the lungs, liver and brain. These secondary melanomas can be more dangerous and harder to treat.
A trial of the new blood test involving 209 people found the cancer during its early stages in 81.5 per cent of cases.
Actor Hugh Jackman recently revealed he had been treated for skin cancer - a basal cell carcinoma - after seeking advice for a mark on his nose. CREDIT: @REALHUGHJACKMAN / INSTAGRAM
Detection of melanoma before it spreads can result in a 90 to 99 per cent five-year survival rate but the survival rate for people with secondary forms is less than 50 per cent.
The researchers said the test could be used for routine screening of people with a higher risk of melanoma, such as those with a large number of moles, pale skin or a family history of the disease.
“It’s critical that melanoma is diagnosed more accurately and early,” said Professor Mel Ziman, from Edith Cowan University.
“So a blood test would help in that identification particularly at early stage melanoma, which is what is the most concerning and would be most beneficial for everybody if it was identified early.”
The researchers plan to conduct clinical trials and believe the test could be available in three to five years.
The World Health Organization says skin cancers are more common for Caucasians, particularly people with pale or freckled skin, fair or red hair, or blue eyes.
Australia has one of the world’s highest rates of melanoma, with 14,000 new diagnoses and almost 2000 deaths each year.
Professor Rodney Sinclair, from the University of Melbourne, said the test was not 100 per cent accurate and results would still need to be interpreted with caution, potentially with a check by a dermatologist.
The research findings were published in the journal Oncotarget.
The use of immunotherapies is a dangerous game. “We’re playing with fire,” he told the NYT, shortly after losing a female patient to the treatment’s after-effects ... We’re already seeing these treatments being put to use by oncologists who are completely unprepared to address the multitude of unusual side effects ...
December 20, 2016
Story at-a-glance
Immunotherapy drugs, aka checkpoint inhibitors, are considered a breakthrough in cancer treatment, but side effects are severe, even lethal, and occur in anywhere from 20 to more than 50 percent of patients
Chimeric antigen receptor technology (CAR-T) involves genetically reengineering a patient’s immune cells to target tumor-associated antigens, thereby destroying malignant cells
While effective in killing cancer, the treatment often creates out-of-control cytokine storms, resulting in life-threatening effects, as well as acute onset of type 1 diabetes and other surprising ailments
By Dr. Mercola
Immunotherapy drugs are considered the latest and greatest breakthrough in conventional cancer treatment. Chimeric antigen receptor technology (CAR-T) has raised a great deal of hope, and an equal measure of concern.
CAR-T involves genetically reengineering a patient’s immune cells to target tumor-associated antigens, thereby destroying the malignant cells.
Alas, while these therapies appear to be quite effective at attacking and destroying malignant cells, they can also take a toll on healthy tissues and organs, leaving many patients struggling for their lives, albeit for an entirely different reason.
There’s also another important issue at stake here. CAR-T cell therapies such as the one developed by Novartis (see below) have been granted PRIME1 (Priority Medicine) status by the European Medicines Agency (EMA).
PRIME is similar to the Breakthrough Therapies program2 offered by the U.S. Food and Drug Administration (FDA). Both of these priority medicine programs aim to speed up approval of novel drugs in order to bring hope to patients for whom there is little or no hope.
While this is admirable, it’s also a slippery slope that can end up affecting people with non-lethal diseases as well — people who are NOT quite as keen on playing Russian roulette with their health for a chance of survival.
Immunotherapy Drug Trials Show Severe Side Effects Are Common
A study3 published in 2010 found that ipilimumab — an immunotherapy drug that blocks cytotoxic T-lymphocyte antigen-4, used against advanced melanoma — caused severe side effects in nearly 20 percent of patients.
Another study4 published in 2015 found adverse events in 24 percent of patients receiving ipilimumab, and when used in combination with nivolumab, another immunotherapy drug, severe adverse reactions occurred more than half the time.
Despite that, the study, funded by Bristol-Myers Squibb, concluded that the combination therapy “had an acceptable safety profile.”
Most recently, a study5 published this summer found 30 percent of patients receiving either pembrolizumab or nivolumab suffered “interesting, rare or unexpected side effects” from the treatment.
No less than 242 different side effects were noted in all, including skin, gastrointestinal, liver, endocrine and renal system effects, diabetes mellitus and pancreatitis. One-quarter of these reactions were severe or life-threatening and required hospitalization.
Novartis is now seeking approval for CTL109, a drug shown to be effective against pediatric B-cell acute lymphoblastic leukemia.6 In its phase 2 study, 82 percent of pediatric and young adult patients experienced complete remission.
However, for many the victory was short-lived. Six months later, 40 percent of them had relapsed. Some of the side effects were also severe. Fifteen percent of patients experienced grade 3 neurological and psychiatric events, including encephalopathy (abnormal brain function) and delirium.
Adult Leukemia Trial Put on Hold After Additional Deaths
Juno Therapeutics7 is working on an immunotherapy for adults with refractory B cell acute lymphoblastic leukemia.
Its phase 2 trial was recently placed on hold for the second time this year following the death of two patients who developed cerebral edema, just days after receiving their treatment.8 One of the patients was under the age of 30.
In July, the FDA ordered a clinical hold on the trial following the death of three patients. They too died from cerebral edema. As reported by CNN:9
“… [I]nvestigators pinpointed the likely culprit as the addition of fludarabine to the pre-conditioning regimen. Fludarabine is a chemotherapy drug used here as a one-time primer for treatment … in an effort to increase the effectiveness of the experimental therapy.
In this particular course of treatment, pre-conditioning consists of a heavy dose of chemotherapy to kill off existing cancer cells in order to give the new cancer-killing T-cells room to grow.
It's like hitting a reset button to restart the immune system. But an unforeseen interaction between fludarabine and genetically modified JCAR015 cells proved to be lethal.”
The trial was given the green light to resume in August — this time without the use of fludarabine. Still, two patients are dead from the same exact problem as the initial three, suggesting the chemotherapy drug wasn’t the problem after all.
Brad Loncar, founder of a cancer immunotherapy fund told STAT News10 that Juno was “going way too fast. It’s just terrible. They’ve killed a couple of people, and it seems like, in part, it’s because of the rush to judgment.”
Out-of-Control Immune System Attacks Healthy Organs
The New York Times (NYT) recently published a very comprehensive article well worth the read that details the struggles of Chuck Peal, who took part in a melanoma study at Yale. He received the ipilimumab with nivolumab combination.
Seven weeks later, he developed acute-onset diabetes — a brand new form of type 1 diabetes, to be exact, associated with these kinds of immune-altering drugs.
Type 1 diabetes typically strikes during childhood, but these drug-induced cases involve older patients who very suddenly lose all of their insulin production. As reported in the article:11
“He slipped in and out of consciousness, his blood pressure plummeted, his potassium levels soared and his blood sugar spiked to 10 times the normal level …
[He] spent 24 days in the hospital … First his pancreas failed, then his bowels inflamed and his kidneys became dysfunctional, and 'to top it off, he has a fever of 103 for which we can’t find a source,' Dr. [Harriet] Kluger said in an interview during the crisis …
Peal’s body was attacking itself, a severe reaction by his immune system that was a side effect of a seemingly miraculous cancer treatment aimed at saving his life … [A]s their use grows, doctors are finding that they pose serious risks that stem from the very thing that makes them effective.
An unleashed immune system can attack healthy, vital organs: notably the bowel, the liver and the lungs, but also the kidneys, the adrenal and pituitary glands, the pancreas and, in rare cases, the heart.
Doctors at Yale believe immunotherapy is causing a new type of acute-onset diabetes, with at least 17 cases there so far, Mr. Peal’s among them.”
Playing With Fire
According to Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, the use of immunotherapies is a dangerous game. “We’re playing with fire,” he told the NYT, shortly after losing a female patient to the treatment’s after-effects.
Weeks after the drug sent her cancer into remission, she suddenly developed cold and flu-like symptoms that quickly killed her. The real cause of death? A massive, out-of-control inflammatory response mounted by her altered immune system. As reported in the featured article:12
“[W]ith lives to be saved and billions of dollars to be made — $250,000 or more is the list price for a year of some regimens — not enough research has been done into the risks of the new therapies, said William Murphy, [Ph.D.,] a professor of dermatology at the University of California, Davis, who reviews immunotherapy-related grants for the government.
It is ‘a massively understudied area,’ Murphy said, adding: ‘The No. 1 priority is anti-tumor effects. Everything else, however severe, is considered the price worth paying.’”
Indeed, according to Murphy, only three of the 500 research proposals he reviewed were focused on toxicity. We see the same problem in other drug and vaccine research as well. Drug developers are primarily interested in finding out if the drug works. Is it effective? However, if a drug is effective in treating the ailment at hand, yet kills the patient, what has been gained?
Breakthrough Therapy Program Raises Stakes for Patients
The FDA’s Breakthrough Therapy program (and the European PRIME) worsens the situation. By rushing approvals, toxicology research ends up lagging even further behind, which means more patients end up being used as guinea pigs without actually being enrolled in a formal study.
This is a particularly frightening prospect in light of the fact that drug developers are increasingly starting to look to vaccines (categorized as “biologicals” by the FDA) as the pharmaceutical product of choice for all sorts of ailments. Clearly, drug companies want vaccines to largely replace prescription drugs as a primary source of profit-making because there’s no product liability in civil court when toxic vaccines cause serious brain and immune system damage, even if people die.
This month, Congress and the U.S. Supreme Court went one step further in giving the pharmaceutical industry a free pass when it comes to requiring drug companies to provide solid scientific evidence that experimental drugs and vaccines are effective and will not harm people before they are sold and used by millions of Americans.
After two years of influence peddling by more than 1,000 pharmaceutical industry lobbyists determined to lower FDA licensing standards, Congress passed the 21st Century Cures Act so that new drugs and vaccines can be fast-tracked to market without holding large clinical trials to prove safety and effectiveness.13
As for immunotherapy drugs, we’re already seeing these treatments being put to use by oncologists who are completely unprepared to address the multitude of unusual side effects. As noted by Timmerman, the oncologist who lost a patient to flu-like symptoms:14 “If we had only known the power we had unleashed that was causing such a toll on her organ system, we might have saved her.”
Cancer is largely a metabolic, not a genetic. disease, and not all treatments will work for all cancers. That said, I believe great strides will be made — even for hard-to-treat cancers — once the metabolic underpinnings of cancer become more widely recognized.
It is profoundly tragic that the current focus is to employ genetically engineered immune cells to combat cancer, unleashing what amounts to an uncontrolled cytokine storm in the body, when addressing cancer metabolism can be done without harmful side effects.
Two excellent books written on this topic are “Cancer as a Metabolic Disease: On the Origin, Management and Prevention of Cancer,” by Thomas Seyfried, Ph.D.,15 and “Tripping Over the Truth: The Metabolic Theory of Cancer” by Travis Christofferson. Seyfried is one of the pioneers in the application of nutritional ketosis for cancer, a therapy based on the work of Dr. Otto Warburg, who received the Nobel Prize in Physiology or Medicine in 1931 for the discovery of metabolism of malignant cells.
These two books made so much sense to me that I wrote a practical how-to guide on how to help people make the transition to burning fat as your primary fuel, which is the precise metabolic shift most everyone needs in order to most effectively treat not only cancer, but also heart and neurodegenerative diseases. The book, “Fat for Fuel,” will be out in May 2017.
You Don’t Need Drugs to Correct Dysfunctional Energy Metabolism
Warburg discovered that cancer is really caused by a defect in the cellular energy metabolism of the cell, primarily related to the function of the mitochondria (the little power stations within your cells). In my view, this information is the game changer that not only is the foundation for nearly all cancers but virtually every disease known to man, because at the core of most serious ailments you find mitochondrial dysfunction.
At present, the cancer industry is focusing on the downstream effects of the problem, which is why the “war on cancer” has been such a miserable failure. In my interview with Seyfried, he specifically critiqued immunotherapy, saying: “Personalized medicines, checkpoint inhibitors — all of these kinds of therapies are basically looking at downstream effects of the disease.”
Checkpoint inhibitor is another name for CAR-T or immunotherapy drugs. As described by Dana-Farber Cancer Institute on their “Immune Checkpoint Inhibitor Definition” page,16 it’s a descriptive term, as these drugs basically prevent cancer cells from using immune checkpoint molecules to hide and evade attack by immune system T cells. By making sure the T cells can recognize the cancerous cells as malignant, your immune system can successfully rid itself of the cancer — sometimes rather rapidly.
However, as we’ve just discussed, the effects can be severe and/or lethal. And if Seyfried and others who are studying the metabolic theory of cancer are correct, such trauma is entirely unnecessary. Many cancer recurrences are also likely due to the initial treatment.
On the other hand, when you view cancer as a metabolic disease, you can target and manage the disease without creating systemic toxicity. As explained by Seyfried, you do this by targeting the fuels the cancer cells are using, primarily glucose and glutamine.
“What we have to recognize ... is that if cancer is a mitochondrial metabolic disease and you get cancer because of mitochondrial failure in certain populations of cells and certain tissues, if you prevent your mitochondria from entering into this dysfunctional state ... [then] the probability of getting cancer is going to be significantly reduced.
To what percent? I would say a minimum of 80 percent. Cancer is probably, as I said in my book, one of the most manageable diseases that we know of ... Once you realize what cancer is, that it’s a metabolic disease, you can take charge of those kinds of things.”
Resources and Upcoming Lectures
To learn more about the metabolic theory of cancer, please see my previous interviews with Seyfried and Travis Christofferson. I’ve also interviewed and written about the work done by other progressive researchers in this field, including Dominic D'Agostino, Ph.D., who is an assistant professor in the Department of Pharmacology and Physiology at the University of South Florida College of Medicine, and Dr. Gary Fettke, an orthopedic surgeon who believes in the nutritional “treatment” of cancer, as well as Dr. Jeanne Drisko, who uses nutritional ketosis clinically for a wide variety of ailments and diseases. Randy Evans, who works with Drisko, will also be there.
My new book, “Fat for Fuel,” will teach you in great detail how to optimize your mitochondrial health. If you want to learn more from the leading experts in nutritional ketosis, you can also join me at the Low Carb USA conference in San Diego in August 2017. It’s shaping up to be the best nutritional ketosis event of the year, with an expected 500 to 1,500 attendees. You can view the speakers and see that this is an extraordinary panel.
For a more intimate setting, there’s also a smaller event in West Palm Beach, Florida, January 20 to 22, 2017. You can see all the speakers here. D'Agostino, Dr. Zac Bush and I will be there all three days. Miriam Kalamian, who is helping me write “Fat for Fuel,” will also be there. She is Seyfried's nutritionist and has helped over 400 cancer patients implement this program, and for many it would be worth it just to see her.
