In recent years, cancer research and treatment centers have been awash with a wave of new, exciting developments, under the umbrella of “immunotherapy,” in other words, harnessing the immune system to eliminate cancerous growths. For the first time, metastatic tumors shrink and retract for a few years at a time, sometimes they even disappear, and the side effects of the drugs are much less severe.
Recent developments are based on the following insight: within each of us, there is constant cancerous activity underway - cells undergo mutations in the body, and begin multiplying uncontrollably. For most of us, most of the time, the immune system identifies these cells and destroys them, but, sometimes, a growth or a cancerous cell manages to beat out the immune system - it is able to hide from the immune system, suppress it, overcome messages it receives telling it to self-destruct, or it simply grows too quickly for the immune system to kill it. These are the growths that become dangerous. The immune system does not know how to beat them from within, and we don’t know how to beat them from without.
The notion that the key to treating cancer lies in an understanding of what cancer does to the immune system arose already a few hundred years ago, but researchers are only now beginning to unlock the riddle. The basic idea is genius, because the immune system is the most suitable entity to destroy cancer. It is capable of reaching each and every metastasis in the body, every cell, something that no chemotherapy, or antibody, or radiation will ever be able to do, to say nothing of surgery. Moreover, it knows how to quickly adapt its methods to the mutations in the cancerous cells. If we needed to create a medicine in the laboratory to combat every possible cancerous mutation, we would not be able to. The immune system does this with relative ease.
What is happening today in the field of immunotherapy can be described as a life or death battle between two forces: the human immune system, boosted by the human brain and science, against cancerous growths that try and outwit the immune system in any way possible. As the immune system grows more sophisticated, the cancer finds new ways to evade it -- much like the ongoing wars between hackers and information security companies.
Before diving into this battle, we wanted to clarify what this thing called “cancer” is - is it a malfunction in the body? An additional organ? Cancer researcher Dr. Gal Markel has more difficulty than we would expect responding: “It is a part of the body that has turned into a traitor and developed advanced self-preservation tools - as though it were a being of its own, or at least an organ, but it is a part us, of our own flesh,” he says, “It appears that it has a will to survive, at least to the same extent other living beings have such a will, but it does not live outside of the body, or separately from the body. It is entirely made up of our cells, and in the end, it kills its ‘host,’ so it is neither so smart, nor such a survivalist.”
The technology that was almost overlooked
One of the most important discoveries in the field of immunotherapy is the primary mechanism by which a cancer cell manages to evade the immune system. Researchers discovered that immune system cells have an “immune checkpoint,” a sort of brake system, the activation of which prevents the immune system from taking action. Most cancer cells do not know how to operate these “brakes,” and thus the immune system takes them out easily, but every once in a while, a cancerous cell is created which secretes material that harms one of the brakes, and suppresses the immune system surrounding the growth.
The fundamental idea behind these new medicines is as follows: instead of attacking the cancerous growth, we interrupt its activities against the immune system. In other words, we interrupt its ability to “hit the brakes,” thereby reawakening the immune system, so it can once again identify the enemy, and destroy it.
Bristol-Myers Squibb (BMS) was the first company to release a drug in this field. BMS VP Oncology Global Clinical Research Renzo Canetta explains how this technology was almost overlooked. Canetta says that this is all possible thanks only to the alertness and curiosity of the scientists, and the alertness of the patients. “We are accustomed to gauging the success of a treatment by the fact that a cancerous growth shrinks, but only in a small portion of the patients to whom we gave the drug, in which we so believed, did the growth shrink,” Canetta said, “In some of them, we actually saw that it grew. We told those patients: ‘We are sorry, we have nothing to give you,’ but, lo and behold, after a while, we saw the patient again, who said, ‘Listen, it’s weird, I feel better.’ We immediately changed our protocols to not send home patients whose tumors didn’t shrink, but who felt better, and in a more in-depth investigation we discovered that the tumors in fact grew because they were full of [immune system] T-cells. The tumor grew because there was a life or death battle underway between the cancer cells and the immune system cells that had succeeded in penetrating the tumor. Previously, they had been unable to do this.”
In the end, the tumors did shrink. Ten years have passes since the experimental treatment, and a few patients who were treated this way are still living. Though the results were not positive for all the patients, this is still a ray of hope. All the patients who were treated at that time were terminal. Most had melanoma, with brain, liver, and lung metastases. Canetta says 25% of them held on for many years, “and among those who survive two years, we did not see nearly any cancer return.”
BMS’s first drug, Yervoy, is approved for the treatment of melanoma, and it operates against the immune checkpoint CTLA4. After a year of treatment, 46% of patients are still alive, almost double what was expected for them. After two years, 24% of the patients are still alive. In a follow-up study that included all the patients that were treated with the drug in this study and others, it was found that 22% of patients survived at least three years. This product is, in effect, the only one that has been on the market for more than a year. In the third quarter, the drug had revenue totaling $350 million, which translates into more than a billion dollars a year. Yervoy is sold to US consumers for $120,000. In Israel, it is covered by the health funds for melanoma patients.
The main drawback to this drug is its side effects. Side-effects include an array of auto-immune symptoms, in which the immune system attacks the body. These side-effects occur because the “brakes” have been removed from the immune system, so the immune system becomes overactive in other parts of the body as well. It can be suppressed with steroids or other medicines, but then the patient becomes vulnerable to infectious diseases.
The next generation of immunotherapy drugs is already looking much better in this respect. Bristol-Myers Squibb and Merck both have advanced drugs that operate against an immune checkpoint called PD1. Merck’s Keytruda and BMS’s Opdivo were registered for marketing only in recent months (Keytruda has already been approved in the US and is priced at $150,000 a year, Opdivo has been approved in Japan, and is awaiting approval in the US), and it is too early as of yet to estimate how much revenue they will bring, however, in light of their results, it seems likely that they will be adopted as quickly as the pioneering drug was. There is also an Israeli company that uses this mechanism, CureTech, but its drug is in much earlier stages of development.
Based on studies that have been carried out until now, it seems that the family of PD1 drugs is less toxic than the previous generation of drugs, and the results are exciting: In a BMS trial, for example, 41% of patients survived three years. A combination of PD1 drugs and the previous generation of drugs reached a survival rate of 80% for two years. These are results than make oncologists dance, together with their patients.
According to Canetta, the drug is suitable for many types of cancer, “Due to our activity in this field, BMS has decided to completely abandon its activity in the field of chemotherapy, and not to develop new chemotherapy drugs, despite the fact that, in the past, we had much success in this area.”
The secret is in the mix
Canetta’s words bring us to the next generation of Immunotherapy. Now, researchers are already asking: If the drug is so effective, why doesn’t it work for all patients, and why doesn’t it always have results of 100% remission in patients for whom it is effective? The answer may lie in the fact that immunotherapy drugs work better when they are combined.
It appears that the cancer initiates an array of defense mechanisms against the immune system. Various tumors can activate different immune checkpoints; the same tumor can activate multiple immune checkpoints, and so forth. The good news is that it appears that there are countless immune checkpoints. How many are there? No one really knows. Currently, international pharmaceutical companies are working on four or five different immune checkpoints and on combinations thereof. Israeli immunotherapy company cCam, which was born at the Ella Institute of Melanoma, and which is headed by Dr. Gal Markel (who is also the chief scientist of the Ella Institute), has discovered a new immune checkpoint, CEACAM1, and will soon begin clinical trials of a drug that gets involved in the manipulation that the cancer carries out on it. Investors include: Roche International, OrbiMed and Pontifax, and Mori Arkin. Markel believes that there are 10-15 such immune checkpoints in the immune system, and that combined drugs are the key to success.
But Israeli company Compugen Ltd. (Nasdaq: CGEN; TASE: CGEN) claims to have discovered eleven new immune checkpoint proteins, with the potential to regulate immune system activity, and already has preliminary lab evidence of the efficacy of six of them. Compugen developed a systematic process for the discovery of new immune checkpoints, and today has one of the broadest pipelines in the world for immune checkpoint protein drugs. Over 15 years, the company developed an advanced computational platform for the identification of proteins and genes, but it was unable to translate the discoveries into commercial successes, and was therefore regarded during those years as a scientifically fascinating company, but lacking a clear objective - in short, a disappointment. Then, company CEO Dr. Anat Cohen-Dayag understood that the detection abilities that the company had developed over the years could be used also to detect new immune checkpoints, and, for that, pharmaceutical companies would be willing to pay.
In 2013, Compugen signed an agreement with Bayer in which Bayer bought a license to develop drug targeting two of the new immune checkpoints that Compugen had discovered for $10 million paid upon signing, and more than $530 million to be paid at milestones, as well as royalties from future payments.
We can already count 16 “immune checkpoint” drugs in the pipelines of pharmaceutical companies around the world, in various stages of testing. Almost all the drugs are first tested on melanoma patients, however, it seems that they will be suitable for other types of cancer as well. Davidoff Cancer Center Thoracic Cancer Unit Senior Medical Oncologist Prof. Nir Peled said, “We see already today, in the experimental treatments that are being carried out in our center, significant lengthening of life. People we thought would survive for two months are surviving for more than a year.”
Dr. Cohen-Dayag: “Today, we dare to talk about ‘curing cancer.’ That is the goal.”
Not so skeptical anymore
The field of immunotherapy includes much more than just attacking T-cells at immune checkpoints. Other companies are also working in creative ways to harness the immune system to fight cancerous growths.
One of the more interesting technologies in this field is “TIL” - TIL cells are specific immune system cells that succeeded in naturally penetrating a cancerous growth, but don’t manage to kill them, because they are not strong enough or are not active enough. In cell therapy, they remove a metastasis from a patient, remove the penetrating T-cells from it, and improve them in the laboratory. In parallel, they kill the patient’s immune system (similar to what is done in a bone-marrow transplant) and implant the new, improved T-cells.
When they just started the trial, everyone was, predictably, very skeptical. US National Institute of Health (NIH) Center for Cancer Research Surgery Branch Chief Prof. Steve Rosenberg demonstrated success in his lab, but it was not possible to replicate the results elsewhere. Many eyebrows were raised, until the results were replicated in another lab - at the Ella Institute at Tel Hashomer hospital.
Markel was very excited about the TIL technology: “We treated 100 patients for whom all previous treatments had failed, and 35% improved significantly,” he says. “The disease retreated partially to completely, and in roughly 10% for the patients, the cancer disappeared. We have a patient who has been living on this drug for seven and a half years already. Even patients whose cancer only goes into partial remission still gain long periods of normal life.”
The technology that is considered the next generation of TIL is CAR - a combination of Weizmann Institute Prof. Zelig Eshhar’s idea and Rosenberg’s work. In this method, using genetic engineering, a specific antibody that knows how to identify the cancerous growth is combined with a T-cell that knows how to kill it, and, together, they set out to destroy the growth. This technology is a little simpler than TIL, because there is no need to extract cells from the cancerous growth.
CAR has impressive results in treating blood-related cancers, such as leukemia and lymphoma: “In the clinical trials that have taken place to date, this product leads to a perfect reaction, total disappearance of the growth for years, also in people who previously tried ten drugs with no success. Some form of significant reaction is detected in 90% of patients,” says Markel. With other types of cancer, the technology is less effective, however, Markel believes that the development of new CAR molecules will lead to the effective treatment of a broader range of cancers. CAR products are currently in Phase II clinical trials, and may reach market as soon as 2016-2017.
Givatayim Mall CEO: “I’ve been thinking in the short-term for five years already.”
Givatayim Mall CEO Shmuel Bin, who received TIL treatment at the Ella Institute, has already lived five years longer than was predicted before immunotherapy. Today, he receives no treatment, and does not suffer from any side-effects either, but the trauma is still with him. “It was like a horror film,” he says, “I went to chemotherapy, and the first round was unbearable. I felt like I left there completely neutralized. I couldn’t talk to anyone.” Bin says he refused to undergo chemotherapy again, and he was told: “It’s your choice, but in that case you have four to eight months to live.”
After two additional rounds of chemotherapy, and an experimental treatment called Interleukin, Bin was told “there’s nothing more to do.” Then, he was offered the experimental TIL treatment. “They surgically removed a metastasis from my lung, and then I underwent intensive chemotherapy that destroyed my immune system. I was in complete isolation, because any fly could have killed me. They put back the modified immune cells with additional immune-boosting materials, and there were very difficult side-effects, but in the first CT scan, they saw that the metastasis was shrinking. Since then, they have all shrunk, and the vast majority of them have disappeared, without any additional treatment. I now celebrate my birthday on March 1, the date I was released from the hospital, because that is when I was reborn. Now, all my plans are short-term. Once, I was a strategist, with very long-term plans, but no one controls his own fate, and today, I am much more aware of this. You must try and enjoy every moment.”
Published by Globes [online], Israel business news - www.globes-online.com - on November 27, 2014
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