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Steve Johnson thinks he would be a dead man now, if he did not use a therapy that transformed cancer care, but seemed to be a failure for his diagnosis: a tumor that spread from prostate to prostate cancer. other parts of the body.
Johnson only learned that he had the disease, which kills about 30,000 Americans every year, when doctors in Florida discovered that it was the cause of a fractured hip hair. They told him that he was probably one to three years old to live.
They also advised him to visit the MD Anderson Cancer Center.
At Houston's elite research hospital, where more clinical trials are taking place than any of the country's cancer centers, Johnson initially benefited from standard treatment regimens (Cockroaches). drugs reducing testosterone, surgery and chemotherapy), which have been functioning for a while. Then the cancer came back roaring.
Nobel Prize in Medicine or Physiology 2018
Jim Allison and Takusu Honjo for their discovery of cancer therapy by inhibiting negative immune regulation
Previous winners
Cancer Therapy
1966: Charles Huggins for his work showing that estrogen therapy or androgenic ablation could control prostate cancer.
1988: Trudy Elion and George Hitchens for the development of anti-cancer drugs, thioguanine and mercaptopurine, widely used in the treatment of various leukemias, as well as an anti-drug (allopurinal) and antibacterial (trimethoprim) drug.
1990: E. Donnall Thomas for the development of bone marrow transplantation as a treatment for leukemia.
Discovery of cancer
1966: Peyton Rous for his discovery of tumor-inducing virus.
1975: David Baltimore, Renato Dulbecco and Howard Martin Temin for their discoveries concerning the interaction between tumor viruses and the genetic material of the cell.
2008: Harald zur Hausen for his discovery of the human papillomavirus causing cervical cancer.
1989: J. Michael Bishop and Harold E. Varmus for their discovery of the cellular origin of retroviral oncogenes.
Source: NobelPrize.org
MD Anderson's physicians asked Johnson if he would like to participate in an immunotherapy trial, a breakthrough treatment that has helped long-term survivors of many patients whose cancer was considered incurable. Dr. Jim Allison, MD Anderson's Immunologist, responsible for the new success of this field, was awarded the Nobel Prize for Medicine last week for his discovery of a brake on the immune system and the development of a drug that would allow him to to fight against tumors.
"It sounds good," Johnson, now 63, told the doctors. "When you think you're going to die, you're ready for anything."
There was a problem, though. In trials with patients with advanced prostate cancer resistant to testosterone-lowering drugs, Allison's drug had failed. Thus, a drug for a second brake was identified by a Japanese scientist, Tasuku Honjo, who shared the 2018 Nobel Prize.
Failure is not difficult to explain. Prostate cancer is considered "immunologically cold," a term for tumors characterized by a lack of T-cells, the foot soldiers of the immune system. Disabling T cells is not very useful if there are not many people to launch an attack.
Allison and Dr. Padmanee Sharma, his wife and head of the prostate cancer trial, did not end up deadlocked. From tumor biopsies collected at MD Anderson, they found that Allison's drug, Yervoy, had actually introduced T cells into the tumor, but had been neutralized when the cancer had exploited the second brake of the immune system.
Sharma and Allison have assumed that the combination of the two drugs could give a better effect. Johnson has tried this hypothesis.
A next chapter
Combination therapy represents the next chapter of the book on immunotherapy, according to researchers, the best hope of extending treatment to more people.
Therapy won the 2018 Nobel Prize, the culmination of nearly 25 years of research, mainly on the basis of interventions with a single drug. That followed Allison's discovery that a protein – CTLA-4 – was the immune system, the development of the first drug targeting this protein, and his willingness to convince pharmaceutical companies to invest in this idea.
The remedies have been the most dramatic and striking in cases of advanced melanoma and lung cancer, two cancers historically considered to be life sentences. Yervoy and the drugs that target the second brake – the PD-1 protein – have provided lasting benefits, never seen before with surgery, radiation and chemotherapy, traditional pillars of treatment. Suddenly, patients once diagnosed with stage 4 disease were cancer free and thrived more than a decade after treatment.
The class of drugs, called checkpoint inhibitors, is now approved not only for melanoma and lung cancer, but also for Hodgkin's lymphoma and cancers of the kidney, bladder, stomach, liver, colon and rectum, as well as for the head and neck variety of tumor types for a class of drugs.
Nevertheless, immunotherapy efforts are still at a relatively early stage of development, considering only a minority of patients benefiting from this approach. At MD Anderson and across the country, scientists are striving to extend benefits to more patients.
"The combination therapy promises to make many cancers what immunotherapy a single agent does not have," said Allison last week, still brilliant after her Nobel Prize. "We need to do even more trials in combination, coupled with basic scientific research, to understand why the intervention works or not."
Allison says that there are nearly 2,000 immunotherapy trials underway in the country – most combining approaches – including about 200 at MD Anderson. Just over half of these, part of the institution's Moon Shots initiative, involve tissue biopsies from trial participants to achieve the kind of basic science that Allison deems necessary.
This effort provides essential insights into the successes and failures of immunotherapy, the multiple mechanisms that tumors use to resist the immune system.
The prostate cancer trial, Yervoy and the PD-1 checkpoint inhibitor, Opdivo, is expected to provide one of the first evidences of this effort. The results in his 90 patients are not yet ready – they will be reported at a conference early next year. But Sharma said they were promising enough to hope to design a larger trial, including at least 200 patients, which, if successful, could lead to the approval of the Food and Drug Administration.
Johnson, who owns a Florida construction company, is a child of the trial poster. Returning to work and doing "wonderful" 16 months after the start of the experimental treatment, he states that the combination of the two checkpoint inhibitors "has given me back my life".
Custom vaccines
J.T. Burk had a grim diagnosis in 2014: his colorectal cancer had spread to his lungs. His tumor type was not one of the 2% of these cancers that responds dramatically to checkpoint inhibitors.
In these patients, the tumor is considered immunologically hot. In all other cases, the immune system does not recognize the tumor.
To help the immune system, MD Anderson's scientists are experimenting with therapeutic vaccines, tailored to each patient's tumor. The custom vaccine is based on 10 specific targets that the researchers identified after analyzing the tumor surgically removed from the patient.
"It's about improving the immune system," said Dr. Scott Kopetz, a professor of gastrointestinal medical oncology and one of the study's leaders. "These custom-made vaccines inform the immune system:" Here is the fragrance you are looking for. "
The trial combines Keytruda vaccine, a PD-1 checkpoint inhibitor, to prevent T cells from stopping the immune response.
Burk spent 3 ½ years in chemotherapy before work on the vaccine was ready, a difficult time, he said, but it kept him alive. Subsequently, he only received the vaccine, which worked about a year before having to give up the study when his tumor increased by 20%.
After a few months of chemotherapy, Burk moved on to the second stage of the trial, Keytruda plus the vaccine. He received both drugs for one year and now, two months after the end of the trial, he is still stable. The tumors are there, but they have not grown.
"I have the impression of playing with the house money," said Burk, 67, a Houston architect. He is once again able to work, eat what he wants and watch the Astros with his friends in sports bars.
"After the diagnosis, I never felt like living that long. People are watching me and can not believe I have stage 4 cancer, "he said. "It's amazing."
Kopetz is encouraged by the positive responses, but says it is too early to draw any conclusions as not all trial participants will have completed their treatment for six months. He plans to release the results of the study by the end of 2019.
The stakes are considerable. Colorectal cancer kills more than 50,000 patients a year, the second cancer killer behind lung cancer.
Handicapping the Nobel
People were predicting that Allison would have won the Nobel Prize since the middle of the decade – he was the choice of 2016 Nobel Prize winner David Pendlebury – but the timing of his selection in 2018 is still pretty good. surprised because checkpoint inhibitors only became a real force in clinics that in about five years earlier. Nobel Prizes are often awarded only decades later.
The timing was more in keeping with Allison's historical discoveries of the immune system, which occurred in the mid-1990s.
This double discovery made the Allison-Honjo Prize unique. There have already been Nobels projects for the discovery of cancer (a number of them associating viruses and cancer) and for the treatment of cancer (estrogen therapy to control prostate cancer, bone marrow transplantation to treat leukemia), but none of those that combined the two, a success to which the committee's literature is alluded.
"Given perhaps unprecedented research activities in the area of immune checkpoints, it is likely that therapy will evolve dramatically at all levels," says the Nobel Committee summary. "It shows how important the discoveries of Allison and Honjo have been. Their discoveries have conferred a great advantage on humanity; they add a new pillar to existing cancer treatments. "
Pendlebury, who conducts research on newspaper quotes for Clarivate Analytics, said Allison had checked all the boxes that the Nobel Committee generally likes: highly cited articles; a demystification of conventional wisdom; many rewards already earned, such as the Lasker; and a discovery that had a dramatic effect.
Indeed, the impact of checkpoint inhibitors is particularly dramatic compared to the history of cancer treatment, which is characterized by extremely slow and gradual progress and usually only concerns one single patient. type of tumor. In addition, some seemingly dramatic advances often do not last. For example, drugs that target cancer at the molecular level looked like a house in the early 2000s, but it became clear that the cancer would eventually find a way to surpass it.
It also did not detract from the fact that Allison's breakthrough finally realized the potential of an area that had been appealing to researchers for decades.
"The checkpoint inhibitors are distinguished by the fact that they can, at best, induce long-term remissions – and apparently healings – in patients with advanced disease," he said. Dr. Bert Vogelstein, Director of the Ludwig Center, Johns Hopkins, UK. Maryland. "No other therapy does that."
A powerful weapon
Heather Handsford came to MD Anderson from the Dallas area this year, four years after the diagnosis of stage 2 triple negative breast cancer – one of the most harmful forms of the disease – and six months after the spread of the tumor in the spine and neck. The one on his neck protruded like a big bulb.
Radiation therapy and chemotherapy reversed tumors, but follow-up analyzes showed that new ones had grown.
Thinking that a clinical trial was probably the only way to prolong his life, Handsford, 46, found the way for Dr. Jennifer Litton, who conducts 14 studies on breast cancer with immunotherapy and a second therapy. One of the studies, intended for patients with triple-negative breast cancer, combines chemotherapy with a new experimental immunotherapy, which eliminates an immune brake and blocks a different type of protein that suppresses the immune system.
Studies combining immunotherapy and conventional treatment are lagging behind the use of two immunotherapies, mainly because the effects on the immune system are unknown. But this weapon is considered a potentially powerful weapon, as the debris of dead cancer cells can be a target for the immune system.
Breast cancer is another immunologically cold tumor and has thus escaped the success of immunotherapy, a limitation that has not had as much impact as some cancers because, detected early, most forms of the disease respond well. existing treatment.
Nevertheless, since the disease kills 40,000 women a year, there is a need, says Litton. Breast cancers such as triple-negative and inflammatory breast cancer are resistant to most existing treatments and, when all types spread to other organs, most treatments only work for a period of time before they fail.
"We need something that produces lasting responses to metastatic cancer," said Litton. "Something less toxic, that lasts longer, that eliminates more deeply all the tumors."
Handsford was one of the first patients in the Litton triple negative breast cancer trial, which began in mid-September. She reports a marked improvement over these three weeks, particularly the immediate narrowing of the prominent cervical tumor. She said it was no longer visible and harder to find to the touch, a dramatic advantage she had not seen before during her four years of treatment.
Of course, three weeks means little in such unexplored waters – only time will tell if the profit will last. Nevertheless, Handsford said that she felt "very positive about the treatment – I have fewer side effects, less pain, my prospects are much better".
That's what Allison likes to hear.
"I hope the Nobel Prize gives patients more hope, makes them more likely to participate in trials, less likely to think the disease is a death sentence," Allison said. "We are still right at the top of the iceberg, but immunotherapy has the potential to save many more lives."
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