Immune System Drugs Melt Tumors In New Study, Leading A Cancer Revolution
The 49-year-old woman had had three melanoma growths removed from her skin, but now the disease was spreading further. A several-centimeter-sized growth under her left breast went deep into her chest wall. Some of the tissue in the tumor was dying because of lack of blood flow.
Doctors at Memorial Sloan Kettering Cancer Center offered her an experimental combination of two drugs: Opdivo and Yervoy, both manufactured by Bristol-Myers Squibb, both among a vanguard of new medicines that boost the immune system to attack tumors. Three weeks later she came back for her second dose.
“She didn’t say anything and when I examined her, I said, ‘Wait a minute!’” says Paul Chapman, the doctor who was treating her. “She said, ‘Yeah, it kind of just dissolved.’”
Where the tumor was before was, literally, a hole – a wound doctors hope will heal with time. Chapman took some fluid from it, and found there were no melanoma cells there. “I’ve been in immunotherapy for a long time, and we’ve talked and fantasized about reactions like this, but I’ve never seen anything this quickly,” he says. He skipped her next dose, and gave her two more before she stopped treatment because of the diarrhea the drug combination was causing. She has no detectable melanoma – amazing for a disease that has long been considered close to untreatable.
The story, published as a case report this morning in the New England Journal of Medicine, alongside a 142-patient study that tested the combination of Opdivo and Yervoy against Yervoy alone. The results show that the anonymous woman’s case was anything but a fluke, as the combination of the two drugs had unprecedented cancer-fighting potency, but also caused toxicity: 50% of patients had side effects that were severe or life-threatening. But an amazing 22% of patients – 16 of them – had what’s called a complete response. As with Chapman’s patient, all their cancer seemed to melt away.
“To me it’s a really graphic demonstration that the immune system is sitting there, waiting,” says Jedd Wolchok, Director, Ludwig Collaborative Laboratory at Memorial Sloan Kettering and lead author of the new study. “And there are immune cells which are fully prepared to get rid of these tumors. But they are being held in check.”
These new drugs release the body’s own weapons: killer white blood cells called T cells. And that approach is one of several bringing a huge amount of excitement to the field of cancer research, one that can be palpably felt here at the annual meeting of the American Association for Cancer Research in Philadelphia, where researchers are unveiling advances large and small. They are priming the immune system not only with drugs but also with genetically engineered cells and viruses. And they are using powerful genetic sequencing technologies not only to classify tumors and pick drugs, but to create blood tests that will allow doctors to monitor cancer in real time, catching it early and knowing rapidly which medicines will prove effective.
Analysts at Piper Jaffray were swept up in the excitement. “We are attending the AACR cancer meeting in Philadelphia, and are awestruck by the speed at which the oncology field is evolving,” they wrote. The combination of immune-boosting and genetic tools, they argue, could in 20 years make the market for cancer treatment as big as all of health care is now: half a trillion dollars a year.
That could, in part, be the wishful thinking of Wall Streeters who don’t want the current biotech boom (the Nasdaq iShares Biotechnology Index is up 116% in two years) to end. In fact, part of the worry about all these new technologies is their cost: the combination of Opdivo and Yervoy could have a wholesale cost of $270,000 if the patient stays on Opdivo for a full year. How we’re going to pay for all this innovation remains a big question. Other immune therapies that use a patient’s own genetically modified cells could cost even more.
But the innovation is real. Here’s a roundup:
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The combination of Opdivo and Yervoy had stunning efficacy. Yesterday, Merck announced that its Keytruda, a PD-1 blocker much like Opdivo, beat Yervoy as a melanoma treatment. In both trials, Yervoy caused tumors in about 11% of patients to shrink. Keytruda caused tumors in 33% of patients to shrink. The Opdivo-Yervoy combination caused tumor shrinkage in 66% of patients. It’s not clear how long patients live on the new treatment – the study hasn’t gone on long enough – but it’s much longer than the average 4.4-month survival on Yervoy alone.
Doctors will debate whether this treatment should be used for all melanoma patients or whether the side effects mean patients should try Keytruda or Opdivo alone first. But Wolchok says the standard treatment he offers melanoma patients is an expanded access clinical trial providing the combination. A larger trial testing the combo is expected in a few months. Bristol-Myers Squibb would not say when it will ask the Food and Drug Administration to approve the new therapy.
Meanwhile, advances have come so fast that they’re hard to catalogue. Merck and Bristol have both announced positive results for Keytruda and Opdivo in non-small cell lung cancer, and Keytruda has shown benefit in mesothelioma, the rare cancer that can be caused by asbestos. In an early trial, a similar AstraZeneca drug caused tumors to shrink in 19% of patients with the hard-to-treat triple-negative form of breast cancer.
Some of the most dramatic stories in immunotherapy have come from the field of CAR-T, in which a protein chimeric antigen receptor (CAR) is used to modify a white blood cell (or T-cell) so that it attacks tumors. This has led to stories of patients with blood cancer where tumors literally melt away through an immune response that, like the complete responses seen with the Opdivo-Yervoy combination, could actually be dangerous. (You can hear one such story here.) The excitement around these cells has resulted in the formation of a number of biotechnology startups, including Juno Therapeutics and Kite Pharma.
But so far CARTs have only worked in blood cancer, which is in many ways an easier target. Today, researchers at the University of Pennsylvania, who are working with Novartis, presented data on a CART that targets mesothelin, a protein on the surface of many tumor cells, in two patients with serous ovarian cancer, two with epithelial mesothelioma, and one with pancreatic cancer.
The good news is that nothing particularly terrible happened when the cells were infused (although these patients were sick, and developed conditions including sepsis, fluid in the lung, and anemia). There were no cases of the cytokine release syndrome – the extreme, potentially deadly immune response that occurred in some blood cancer patients.
The CART cells seemed to go to where the tumors were, including in the fluid around the heart, without causing damage and inflammation. It’s still too early, though, to know whether the CART cells are damaging the tumors. All researchers could say was that four of the patients had remained stable – there are no melting tumors this time.
Michel Sadelain, a researcher at Memorial Sloan Kettering and one of the co-founders of Juno Therapeutics, was hopeful but cautious. “With advanced stable disease at four weeks, it’s encouraging but you can’t over-interpret that,” he said. Still, he holds out hope for meso-CARTs, which JUNO is developing to. “If the toxicities are manageable I believe it’s going to be something big,” he says.
Researchers also presented data on using T-cells to treat a rare condition called Epstein-Barr Virus-associated lymphoproliferative disorder. This disease occurs when the virus that causes mononucleosis causes a kind of secondary cancer in patients after a transplant, often a bone marrow transplant. This is a rare disease, but perfect for cell therapy: white blood cells are great at attacking cells infected with viruses, and the patients don’t have immune systems. Using T-cells donated from other patients, researchers were able to reduce or eliminate the cancer cells in 63% of patients. The treatment has received breakthrough designation from the Food and Drug Administration, but has not yet been licensed by a drug company. Atara Biotherapeutics has an exclusive option to license it.
A blood test for cancer?
Another big idea is what’s called a liquid biopsy, in which free bits of cancer DNA are detected via a blood test. Here at AACR, researchers from the Department of Radiation Sciences at Umeå University in Sweden used the technique to determine when patients with lung cancer would stop responding to Xalkori, a Pfizer lung cancer drug. But the implications of the test are much bigger.
Last year at the Forbes Healthcare Summit in New York, Richard Klausner, the chief medical officer of DNA sequencing leader Illumina and the former head of the National Cancer Institute, gave an early look at the promise of this technology.
“There’s a phenomena that we now know that tumors put out, at very early stages, their DNA into the circulation,” Klausner said. “We can now measure that with incredible precision. I think one of the biggest breakthroughs we can see in cancer in the next few years is this possibility that there could be a blood test or a urine test that detects early stage cancer.”
Many of these advances could be years away from the market. And doctors’ ardor is predicated partly on how grim things have been in the past. Even in the Opdivo-Yervoy study, 126 of 142 patients did not see their cancer vanish entirely. And even with the best studies of CART therapy in leukemia, two or three out of every ten patients are not helped, and are likely to die. But in the world of cancer research, where it often seemed that arduous research was only adding mere months to patients lives, this counts as reason for hope.
“We are in the middle of a revolution,” said Louis Weiner, of Georgetown University, at an AACR press conference about the immunotherapies. “I don’t think that is hyperbolic. Those are the kinds of observations that we’ve rarely seen in our business. What really makes it exciting is that it is not just one disease.”
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Source: Forbes Health