Cancer patients who have no other options come to Prof. Izhak Haviv, a Bar-Ilan University biologist, who often succeeds in prolonging their lives and improving their quality of life. He tells "Globes" about the personalized vaccines for cancer patients on which he is working, explains how he learned to like millionaires, and criticizes the Israeli government's approach to the field, "Israel's national medical recordkeeping isn't as impressive as we're led to believe"
He recounts, "One night, close to midnight, as often happened, I left the house of a patient whom I had no way of helping. I stood in despair outside the door and asked myself, What for? Why do I give up quality time with my family? Why do I wear myself out like this, spend all my time in such sad surroundings, if things are moving so slowly anyway? But then I got a phone call from the husband of another patient of mine, who said, 'Just a few months ago when you first met us at her bedside she couldn't even lift her head. Now we just returned from a hiking trip with the kids in the Black Forest.' He gave me back all my enthusiasm and hope."
It isn't a doctor who said these things, but a biologist - Professor Izhak Haviv, expert on cancer genomics and personalized medicine at the new medical school in the Galilee and at Bar-Ilan University. Over the years the boundaries between his specialty and that of medical oncology have blurred, making him an unusual kind of biologist - one who is in direct contact with patients, usually those for whom no other therapy options have been found. "I've been in this field for 18 years, I've had 180 students, and of these only five have yet to prolong the life of at least one person thanks to the research they carried out," he summarizes his achievements to date.
Biologist straddling the line
"There's a conflict between oncology genetics research, where over the past few years a huge amount of knowledge has been amassed on what cancer is in terms of changes in DNA sequence, and therapeutic practice, which has a 70-year history," explains Haviv regarding both the uniqueness and the difficulty of his job. "While oncology drugs fit the risk-benefit balance and help cancer patients, they are essentially poisonous and cause significant morbidity. The optimal indications for drugs were developed on the basis of what's referred to as evidence-based medicine - putting together data from many different people and choosing the treatment that fits as many of them as possible. But when you look at a DNA sequence you find that even if on the face of it, two people are sick with the same kind of cancer, there are no two identical cases ever. So these two approaches, personalized and evidence-based, are on a collision course, and I'm straddling the line between them - originally a biologist, but really part of the support team of the oncologist who wants to make decisions based on cutting-edge research as well as his own experience."
Today cancer is known to be a disease caused by genetic changes undergone in malignant cell's genome, in contrast to the patient's regular cells, and the type of change tells us a great deal about the way in which the disease should be treated. But "in the vast majority of cases genomics-based medicine doesn't fulfill its promise," Haviv admits, explaining that the human genome has 3 billion base pairs, that is, "letters" that make up the genome sequence, and science has already identified 36 million of these base pairs as sites where mutations could potentially cause cancer. On 13 thousand of these 36 million base pairs there is clinical information, i.e., something can be known about the type of cancer liable to be caused by a mutation in them and about the mechanism by which it would happen. "But we only really understand 500 mutations, that is, we know how to treat such a cancer case. These 500 mutations exist in about 5% of patients. For the other 95% there are more ambiguous findings - you know what the change is in that patient, but you don't know what medication would be appropriate or whether it's a questionable prediction. My goal is to get us to a situation where we have information on more than 13 thousand base pairs." The main missing information is on the phenotype, i.e., the clinical vulnerability of each case, predicted or dictated by the presence of a mutation or combination of mutations.
Nor are the 500 mutations that scientists do understand, tested for each patient. "The better hospitals offer patients the opportunity to test and make decisions based on 6 of the 13,000 base pairs," says Haviv. "Exceptionally high-quality care includes testing of 500 base pairs. If you happen to be a celebrity patient or very wealthy, at hospitals like Memorial Sloan Kettering, they'll test all 13 thousand base pairs."
Today's research efforts in the sphere of genome sequencing are being carried out as "umbrella projects" in which patients are referred to clinical trials for various drugs, depending on the results of their genetic testing; algorithms are used to assess the degree of success and to identify links between successful drugs and different genetic traits. "In my view, this method is too slow and expensive, especially given the high cost of regulating these kinds of trials. Israel definitely doesn't have the resources to conduct such trials," says Haviv.
But we have another advantage: consistent and information-intensive medical records - since every Israeli has a single identification number and Israelis are loyal to their HMOs over long periods.
"Well, that's what they say."
That's not how it really is?
"Israeli medical record-keeping is less complete and of lower quality than we like to think.
"The state tries to market it as a competitive advantage in the digital health field, but record-keeping will need a lot of additional information before it can truly be competitive."
Of mice and avatars
To bypass the cost of conducting trials on large numbers of people, Haviv studies a different person each time, but in depth. "We take the tissue of a single patient and keep it alive, as a kind of avatar of that patient's cancer. We start applying therapies to this tissue and see which treatment is more effective. In this way we figure out what might help the patient, and as a researcher I gradually piece together the connection between a given mutation and a successful treatment."
It sounds somewhat like the treatment offered by Prof. David Sidransky of Champions Oncology.
"Champions grafts the tumors into immune-deficient mice, but their business model is different from ours. We study selected patients in order to understand the relationship between their cancer's unique genetic sequence and the drug.
"The drugs that we test are generally biological drugs that act on the mechanisms that are specifically controlled by various genes. The goal is that the next time a patient with this kind of mutation comes to us, we'll know how to treat him. That's research. By contrast, Sidransky offers a medical service to a specific wealthy person - finding him, empirically, the drug that is appropriate for him. He'll test, on his mice, biological drugs, chemotherapy, and combinations of both, until he gets a result that seems suitable for that patient, and he uses it more for treatment purposes than for research purposes. The company's business model is still kind of weak, since tailoring the therapy with the aid of your mouse avatar doesn't provide additional knowledge that's significant enough to justify the cost of this operation. But whether or not it's his main intention, he's definitely advancing research.
"Big companies like Pfizer, Novartis and AstraZeneca are conducting experiments similar to ours on specific tumor tissues, and determining their faulty genetic sequences. We cooperate with them and they cooperate among themselves. Novartis is a huge company with a laboratory that has 100 patient-derived tumor xenograft models; we're small but we have 700."
One of the greatest triumphs in the oncology field in recent years has been the removal of natural blocks, which are in the way for the patients' natural immune systems to attack tumors. Because we collect both the patient's tumor, as well as immune cells, Haviv's laboratory is active in this sphere as well. "We were the first to show that when a patient's tumor has more mutations, then that's actually when it responds most strongly to immunotherapy, that is, to drugs that reverse immune system suppression and induce antitumor responses, fight the tumor. The logic is clear-cut: when the tumor acquires a mutation, it presents it on the surface of the cell. This increases the chance that the immune system will identify it as "not-self." For example, most smokers have high mutation load. The mutations cause various problems and can also cause cancer, but they also appear foreign to the immune system, and thus are vulnerable to such drugs."
So in that sense it's better to be a smoker?
"If you've already developed lung cancer as a smoker, then you have a better chance of benefiting from treatment with a drug like Keytruda, than someone who gets lung cancer without being a smoker. Smokers can, sometimes (20%) survive for five years with Keytruda, compared with two years for lung cancer patients who didn't smoke. Of course, it's better not to smoke and reduce your chance of getting lung cancer, heart disease or emphysema."
Haviv takes personalized in vitro medical research even one step further. "We realized that our avatar is just tissue and doesn't reflect the entire body, that is, the immune system. So now we're growing the patient's specific immune system within a mouse lacking an immune system, and also grafting the patient's specific tumor into it." Later, the experiment will be conducted not on a mouse but on the patient's tissue.
How do you grow a human immune system in a mouse?
"Part of the immune system's development takes place in an organ that is hidden until age two - the thymus. A researcher in my laboratory, who works in regenerative medicine, restores our patient's cells to the stem cell state and grows a new thymus from them - an organ that no longer exists in the patient, and transplants it into the mouse so that the mouse will produce the patient's immune system."
Personalized vaccines
But Haviv's most groundbreaking research has to do with personalized vaccines. "Let's say a patient comes to us who underwent the costly whole genome sequencing, and no treatment was found for him/her. We look at all other base pairs which code for protein change (60 million base pairs) and ask whether one of them is mutated in this patient's cancer. If so, we ask whether, among those unique mutations, there's one that the immune system can identify. Usually in this kind of situation we find that the immune system is able to discern unique mutations in the tumor, but only one cell out of, say, the 50,000 immune system cells manages to identify the mutation. What we then do is synthesize protein derivatives that resemble those mutations and expose the patient's white blood cells to them. In this way we enable a much larger percentage of the immune system cells to learn to respond to those mutations and, ultimately, to the tumor cells. This is how we awaken a fatal immune response to the tumor."
Today Haviv is already planning treatment using this method - first with a single patient, someone with a brain tumor who is being cared for at Ichilov and is expected to receive the treatment soon. A similar form of therapy has been given only once before, says Haviv, by Prof. Steven Rosenberg (NIH), one of the inventors of the experimental CAR-T cancer therapy.
What's the difference between your approach and that of CAR-T?
"We find mutations that the immune system identifies naturally, but at insufficiently high intensity, and we enhance this natural phenomenon through exposure. By contrast, the CAR-T method genetically engineers the immune system cells to attack the tumor by latching onto the cancer cell through a protein that is overexpressed on the cancer cell's surface. The risk is that they might also target and destroy normal cells. It's not a problem if the normal cells targeted aren't crucial, and that's actually what happens with the first type of cancer dealt with by the leading CAR-T company, Kite (a particular kind of leukemia), but it could potentially hurt the chances of expanding the technology to new areas. We're working with Prof. Zelig Eshhar of the Weizmann Institute (he's another of the CAR-T inventors) to produce a CAR-T that can better distinguish between normal and cancerous cells."
How do you decide which patient to include in a trial?
Generally we get patients who currently have no treatment options. Most of these are patients who go from treatment to treatment, and each time we manage to prolong their lives a little. We ask doctors to refer patients who suit our current areas of interest: two-drug combinations, personalized vaccines, smart CAR-T, and improved genetic testing. My vision is that we'll be able to test 3 billion base pairs and tailor drugs based both on the mutant base pairs and on the healthy genetics of each patient, thereby tailoring the drugs to all of the cancers and all of the patients."
Money's the name of the game According to Haviv, one of the problems is that patients come to him in an "impoverished" state, meaning that even if, on paper, there is a therapy that suits the unique mutations of their tumor, they won't necessarily be able to handle it. By "impoverished" he is referring mainly to their physical status: patients arrive in situations where malignant tissue has developed at the expense of healthy tissue, and the body no longer has enough functional health to survive, even if all of the cancerous cells are killed. But the patients definitely do also arrive impoverished financially.
"Today, about half of the healthcare basket is cancer drugs, and it's still not enough," says Haviv. Using the woman who toured the Black Forest as an example, he describes how patients who need unapproved drugs have to embark on a process that, in his words, borders on smuggling. "A foreign doctor has to, essentially, 'see' the patient, that is, the patient's file, and authorize her to purchase the drug abroad, and someone has to go with the patient's I.D. card to a pharmacy abroad, buy it and transport it to Israel. And then this lovely woman's enthusiastic spouse discovers that if he wants to keep her alive he has to spend 70 thousand dollars a month. And this isn't some tycoon who could finance treatments for all of Israel's cancer patients just from what he owes to the banks. What do you do now?"
In that particular instance, Haviv went personally to Health Minister Yaakov Litzman and asked him to allow the drug to be imported legally, obviating the need for costly middleman activity. It worked. "Last year the drug was actually added to the basket," he says. "The new generation drugs provide a different quality of life. Not only do you feel better than with chemotherapy, but you're also not going to the hospital every few days. Life doesn't revolve around the disease. The cost is huge, but the payoff is prolonging life in a way that enables you to really live."
The patient mentioned above eventually developed resistance to the therapy and died. "That's the reality we're talking about, for good or ill. Partial recovery and a return to normal functioning for a while, then the disease recurs, and there's disappointment. The temporary nature of the success and the financial cost - both have far-reaching consequences," says Haviv.
Sometimes, life is prolonged beyond expectations and there are patients who have been going from one trial to the next for over a decade. "My first patient for whom a certain drug seemed appropriate was in Australia, but back then, there was no such indication in medical guidelines, i.e., it couldn't be given in the country legally," he relates. "She happened to be married to a billionaire. I said to him, "Let's call it a trial, we'll add another nine people who will receive the drug and the whole thing will cost you a million dollars." He said to me, What's a million dollars? This is my wife. He funded the trial and seven patients responded well and benefited. His wife actually didn't respond well and we moved her to a different trial. Through one thing and another she's made it 12 years so far."
It's cases such as these that have endeared millionaires to Haviv. "It's not always a bad thing that hospitals are on friendly terms with the rich. We're always talking about how wealthy people advance their own interests in hospitals, but we forget that it also works the other way. Hospital directors do what they can within the rules of ethics, but sometimes saving lives justifies crony capitalism.
"It's actually people who made their money creatively who get creative and bypass conventions when a family member gets cancer. They become almost like students in my lab, they learn everything I'm doing and manage me. They get on my case and spur me on more than any professional journal's deadline. They identify bottlenecks in my research and solve them, because they're good managers. In general, Jews don't give up. We're still a people that doesn't take no for an answer."
Published by Globes [online], Israel business news - www.globes-online.com - on February 23, 2017
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