The Story Behind an Israeli Immunologist's Cancer-fighting Breakthrough

Meet Zelig Eshhar, the scientist who paved the way for a chimeric cancer therapy

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Prof. Zelig Eshhar.
Prof. Zelig Eshhar.Credit: Tomer Appelbaum
Smadar Reisfeld
Smadar Reisfeld
Smadar Reisfeld
Smadar Reisfeld

Prof. Zelig Eshhar has a hybrid name. When he was born, his parents called him Zelig Lipka, but he didn’t like the shtetl-like sound of that. He wanted to be a genuine Israeli. Not wishing to do away, however, with “Zelig” – he was named for a revered uncle, who was murdered by Arabs at Sarafand (today Tzrifin army base) – he decided to change only his surname. His father had told him that lipka was the name of a tree in Polish, so he opened a Hebrew lexicon of local flora to a random page and encountered eshhar (buckthorn tree). It then turned out that the leaves of both the eshhar and the lipka are grayish green, and since then he’s been Zelig Eshhar, a Diaspora-Israeli hybrid, a riveting fusion.

Similarly, it was a hybrid – this one conceived in his brain and realized in his lab – that landed him the Israel Prize in Life Sciences (in 2015), and recently thrust his name into reports about the sale of Kite Pharma, a biopharmaceutical company, for $11.9 billion. The prodigious sum was paid by Gilead Sciences for cancer treatment based on a technology developed in Eshhar’s lab that involves hybridization of two components of the immune system – the T cell and an antibody – to create the “chimeric antigen receptor,” which can target and destroy cancer cells.

The effectiveness of the treatment, in experiments done to date, has been remarkable: Some 94 percent of those suffering from acute lymphoblastic leukemia – a specific type of blood cancer – for example, went into full remission, even after all other treatments had failed. That’s an extraordinary achievement.

Feeling the organism

A pall of sadness hung over my conversation with Eshhar. Despite his scientific, medical and economic success, the 76-year-old Eshhar is not a happy person these days. For months, he has been mourning his partner, Lihi Semel, who died of cancer in March. He still lives in her beautiful home in Tel Aviv’s resurgent Neve Tzedek neighborhood. He shows me the pictures she collected, the high stack of books that still stands next to her side of the bed, and the view of the city from their balcony that she loved: the rooftops, the sea and the crescent moon atop the minaret of Hassan Bek Mosque.

“Maybe I should be over it by now,” he says, “but every corner here is filled with her, and she complemented me in so many ways. The absence is large and gaping.”

Eshhar grew up in Rehovot, where his playground was the sandstone hills of what was then a village and where he became acquainted with the world of bees at an early age. “The agriculture teacher in primary school brought us a beehive,” Eshhar recalls. “I watched the bees’ activity – I wasn’t afraid of being stung. I learned all about them: how they gather pollen, how they store the honey and what happens in the process of their turning from egg into adult. Later, when my Nahal [military] unit joined Kibbutz Yad Mordechai, I became an expert beekeeper.”

One day, he recalls, someone from the Weizmann Institute of Science, in Rehovot, came to the kibbutz and gave a talk on molecular biology. "DNA, RNA, ribosomes. My jaw dropped. Immediately I wanted to translate all the wonders I’d come to know into molecules. I enrolled for an undergraduate degree at the [Hebrew University of Jerusalem’s] Faculty of Agriculture in Rehovot, and there I got to know the world of molecules."

One can’t help but notice that Eshhar’s scientific biography parallels that of the history of immune system science to an uncanny degree. Indeed, he sometimes seems to be a kind of Forrest Gump, a person who somehow finds himself in the right place at the right time and appears at all the key junctions of that particular history. As his doctoral adviser at Weizmann, he chose Prof. Michael Sela, a 1959 Israel Prize laureate and later one of the developers of Copaxone, a drug for treating relapse-related multiple sclerosis, which brought Israel’s Teva Pharmaceuticals, worldwide fame and prosperity.

“It was there that I learned about T cells,” Eshhar relates. “Broadly speaking, they are immune system cells that have the ability to differentiate between ‘self’ and ‘alien’ – that is, between the body’s own cells and invasive cells from outside. They do so by means of a receptor that sits on the T cell and binds with molecules of the foreign invader. The binding activates the T cell’s killer mechanism, which eradicates the alien cell. Eradication occurs, for example, when a virus invades a body cell. Because the virus alters the surface of the infected cell, the T cells identify it as a foreign element and annihilate it.

Baruj Benacerraf, left, shakes hands with King Carl Gustaf of Sweden in Stockholm, Sweden, Dec. 1980.Credit: AP Photo/Tobbe Gustavsson

“As my research subject, I chose to investigate the structure of the T cell’s receptor,” he continues. “It was totally basic science; I had no concept or pretension that a day would come when that knowledge would serve me in devising a treatment for cancer. For my post-doctorate [in 1973-76], I wanted to go to a laboratory in New York, but Sela told me, ‘You’re a young person with three children. New York is no place to raise children. Go to Boston. I have a friend there who will take you in.’ On the spot Sela made a phone call, and so I arrived at Harvard, at the laboratory of Prof. Baruj Benacerraf, who later – in 1980 – was awarded the Nobel Prize [in Physiology or Medicine] for his research about T cells. It was under Benacerraf, a Jew whose parents were of Moroccan and Algerian origin, and who had immigrated to the United States, that I became interested in cancer.”

How are T cells connected with cancer?

Eshhar: “As I explained, T cells identify foreign cells that have invaded the body. It turns out that they also consider body cells that have become cancerous to be foreign, and attack them. Unfortunately, the mechanism by which the T cell receptor identifies foreign molecules on cancerous cells and binds with them is not very efficient, so cancer cells occasionally evade them and develop in the body. Benacerraf discovered a distinctive molecule that characterizes the cancerous cells, and he wanted to get a handle on it. That was my task, and I gained recognition when I succeeded, because no one had done it previously. As a molecule person, I had an intuition about the essence of the material we were looking for, and it worked.”

Intuition plays a part in science.

“Of course. One of the books that influenced me is ‘A Feeling for the Organism,’ a biography [by Evelyn Fox Keller, of geneticist] Barbara McClintock, recipient of the 1983 Nobel Prize [in Physiology or Medicine]. It’s a marvelous title, fusing science and emotion, and I identified deeply with it. Everything I did afterward always related to feeling and involvement, even the study of molecules.”

Dr. Barbara McClintock in 1947.Credit: Smithsonian Institution Archives

In his last year at Harvard, Eshhar heard about a newly developed technology having to do with other cells of the immune system – B cells, which produce antibodies. In contrast to T cells, whose receptors identify the target as alien in a general manner only, antibodies identify enemy targets specifically. For example, when a bacterium penetrates the blood, the immune system starts to produce an array of antibodies to counter it, each of which identifies a specific molecule and homes in on it. Together they neutralize the bacterium.

Eshhar: “The new method created a hybrid between two cells: a cell that produces a specific antibody and a cancer cell that divides ceaselessly. What resulted was a cell that continuously produces a specific antibody. It’s like building a factory that, instead of conventional rockets, manufactures a guided missile that can zero in on a particular target.”

‘Best of both worlds’

Grasping the potential of the technology, Eshhar, on his way to Israel from the U.S. after completing his post-doctoral studies, made a detour to Cambridge, England – with his and the container holding their belongings – where Cesar Milstein, one of the developers of the method. Milstein, however, told him that there was no room for him in his lab.

Excuse me, but didn’t you call or write first to find out if you could work in the lab?

“No! I was impassioned, and I was certain we would work something out.”

Things worked out, although differently. Eshhar returned to the Weizmann Institute and went – alone – to Switzerland for a few months to study the method from its other co-developer, Georges Kohler. The stubbornness paid off. The new method became one of the great breakthroughs in the history of scientific and medical research, and Milstein and Kohler received the Nobel Prize for it in 1984. Eshhar started to manufacture antibodies that specifically targeted molecules that are distinctive to cancer cells. However, apart from the fact that they were able to locate the cells, they displayed no special aggressiveness toward them.

Cesar Milstein in 1987. Credit: Ted Blackbrow / ANL / REX / Shut

Then came the flash of inspiration. “I said to myself,” Eshhar recalls, “why not take the best of both worlds? In principle, a T cell is capable of eradicating a cancerous cell, thanks to its killer mechanism, but it’s not good at identifying the target. An antibody, in contrast, is an expert in identifying targets but it has no killer mechanism. What if the capabilities are combined? We’ll create a hybrid, a chimera – the monster in Greek mythology that had the head of a lion, the body of a goat and the tail of a dragon or snake. On the one hand, it will have the antibody’s excellent binding ability, and on the other, the T cell’s killer ability. We named the chimera the ‘T-body,’ a kind of verbal hybrid of antibody and T cell.”

How did you create the chimera?

“By genetic engineering of the gene. In my doctoral dissertation, we decoded the structure of the T receptor. We knew then that the receptor is a protein, one end of which protrudes outside the T cell, while the other is embedded within the cell. We knew also that this outer region is what identifies the molecules on the surface of the foreign cell, and that the binding action arouses the inner region, which activates the killer mechanism. Accordingly, we took the gene for the receptor and replaced the area responsible for the binding with the antibody’s binding area. We introduced that chimeric gene into the T cell and got a chimeric receptor, whose external side binds to the cancerous molecule as strongly as an antibody, and whose inner side activates the killing mechanism that eradicates the cancerous cell. The chimeric gene was assembled by Prof. Gidi Gross, who at the time was a brilliant doctoral student of mine, and Tova Waks, my marvelous technician.”

Dr. Steven Rosenberg.Credit: National Cancer Institute

Dr. Steven Rosenberg, in whose lab at the U.S. National Cancer Institute Eshhar spent a sabbatical, was the first to dare to make use of the chimeric gene in clinical experiments, initially on laboratory mice and afterward on terminal leukemia patients.

Your doctoral supervisor is an Israel Prize laureate, you did your post-doc with a scientist who would later receive the Nobel Prize and you did advanced research with another scientist who was also later awarded the Nobel. Is there any chance that you will receive the prize, too?

“I went to all those places simply because they were the best in the field, and the fact that the scientists received the Nobel Prize is only proof of that,” he laughs. “As for me? I don’t know.”

It’s hard to know whether he is playing the naif, or if he really is unaware that his candidacy was submitted to the prize committee this year. In any event, for the time being, the treatments are being categorized as experimental, not yet an approved, and they are appallingly expensive. The main reason for the high price is the necessity of taking T cells from the patient, in order to inject the chimeric gene into them and transform them into efficient hybrids, before reintroducing them into the patient’s body. This manipulation cannot be carried out with the T cells of just anyone, because they will attack the patient’s healthy cells.

“That is why we are now trying to create a ‘universal donor’ – a generic cell that will be available ‘off the shelf’ for general usage,” Eshhar says. “The idea is to take any T cell, remove its original receptor, which identifies foreign cells, and thereby emasculate its ability to attack the patient’s cells.”

Still, after we’ve talked about ideas, how about a word on material concerns?

“For my whole professional life I was grant-impoverished. Requests I submitted for funding research were rejected, so I constantly registered patents in order to use the money from the royalties to work on my ideas. One patent, for example, is related to drugs. After I was already able to produce specific antibodies to deal with defined targets, I heard about a United Nations initiative, sponsored by Princess Diana, that offered huge grants for studies dealing with the war against drug abuse. The idea I had was to prepare specific antibodies to identify drugs, which we did for opium.

“We proposed the idea to a Swedish company, which responded enthusiastically, and on its basis developed a sensor that is used today in Southeast Asia to detect drugs that are being smuggled. The sensor can be inserted in an air conditioner at a border crossing, because all the air in the room passes through the air conditioner, and when the antibody apprehends the molecules of the drug’s scent, the sensor emits a signal that they are present.

“Of course I am happy about royalties and profits,” Eshhar continues, “but the truly great profit is the fact that my idea is saving people’s lives. I know it sounds like a cliché, but I’ve dedicated myself to that goal. Occasionally, when I happen to meet someone whose life was saved by the treatment – such as at events sponsored by the Israel Cancer Association – I am struck dumb with emotion for some time. There’s nothing greater than that.”

What’s next?

“Extensive research is being done on the hybrid. The Kite Pharma company took the hybrid idea in order to use it for treating cancer patients, and another company, based in France, took exactly the same idea, and with the aid of the same technology, is trying to develop treatment for autoimmune diseases. In these diseases, cells of the immune system attack the organs of the body itself – for example, the intestine, in Crohn’s disease – and their ongoing activity produces an inflammation of the organ. The hybrid cell in this case is constructed from a different T cell, a regulatory one, whose task in a healthy body is actually to reduce the immune reaction. The chimeric receptor introduced into this T cell is made from an antibody that recognizes a particular component of the inflammation, and when it binds with it, it activates the abating regulatory cell.”

Prof. Zelig Eshhar.Credit: Tomer Appelbaum

Just before concluding, after many hours of conversation, I ask Eshhar a self-evident, almost banal question, not really expecting a serious response: “And after all this, do you have any sort of conclusion regarding what you’ve done?” But in fact he does have a response, both serious and trenchant, which he offers without hesitation: “That you don’t have to believe in God in order to do good deeds.” How did God come into this?

Are you involved in a dialogue with someone about God?

He’s quiet for a moment; this is obviously a painful subject. “I am not very fond of religion,” he says finally, “but I love my grandchildren with all my soul. Years ago, one of my daughters became religiously observant, and afterward, when she got divorced, I became very involved in raising her small children. I have a hard time with the rigidity of the ultra-Orthodox world, with the automatic thinking and arbitrary prohibitions.”

Do you talk to them about science?

“Not much. Sometimes I challenge them with questions, but gently. I’m not sure it will be welcomed by their mother, so I refrain. They’re marvelous, and I love them more than anything, but when they’re taught that everything begins and ends with the Torah, it’s a reduction I find difficult. Zelig, for whom I’m named, wasn’t just a Jew, but also an ardent Zionist who immigrated to this country and brought his whole family here. So I find myself pleased with the High Court of Justice ruling that obligates the Haredim [to perform military service], because it means that my grandchildren will be drafted, will contribute to the state and maybe also be Israelis.

“And when I ask my little granddaughter, who’s just entered the first grade, what school is like, and she replies that it’s a good school, because they learn a lot of Torah, I want to tell her: ‘You don’t need to learn Torah in order to fulfill precepts. You can be generous and humane, help and heal, even if you learn science and literature.’ But I don’t say a thing.”

Double trouble

Prof. Gidi Gross.Credit: Courtesy of the Open University

Not long after my conversation with Prof. Eshhar, the media reported that his former student, Gideon Gross, was suing him for royalties that Eshhar received from Kite Pharma and allegedly did not share with him. Gross, Eshhar’s doctoral student , developed the idea of the hybrid receptor under his supervision. The receptor was registered as a patent whose inventors are: Eshhar, Gross and two other scientists who were less involved in the development. Because all the inventors worked at the Weizmann Institute, it paid to register the patent and was also its chief owner. Subsequently, additional fees were required to preserve the patent rights. However, the institute, which didn’t believe in the item’s economic potential, did not pay those fees but allowed the inventors to pay out of their pockets and thereby to become the patent’s chief owners.

On the basis of the patent, Eshhar formed a company, which a few years ago sold the rights to the use of the technology to Kite Pharma in return for royalties. Eshhar and his partners to the patent expected to reap a fine profit once the medication was approved for use. However, according to TheMarker, Gross claims that Eshhar concealed from him stock options that he received from Kite Pharma, of which his share would be $5.8 million.

Eshhar, at his lawyers’ instruction, will not comment on the suit. His confidants and students, though, are happy to express an opinion, albeit anonymously.

“Eshhar is the last person you can accuse of greed,” one of these sources says. “In my view, he isn’t even aware of all the accountancy and the royalties he gets – the work is done by professionals. He’s not occupied with that.”

Another confidant adds, “Not only do I not have any doubt that there was no intention to conceal and defraud, but when Eshhar registered the patent, he added Gross and Tova Waks [the lab manager], even though he wasn’t obligated to do so. Moreover, when the Weizmann Institute decided to forgo ownership of the patent, each of the scientists was supposed to buy his share with his own money, but Eshhar paid for everyone.”

Gross, too, doesn’t want to comment. “Still,” I ask him, “not long before the suit was filed, you told the media that glory and money are of no interest to you and you maintained that no wrong had been done to you. What happened?”

“Nothing happened,” he replies. “The most important thing is science, but I’m not a dumbbell who doesn’t protect his basic rights. Sorry if I’ve disappointed anyone when it turned out that I have two feet on the ground.”

I tell Gross that Eshhar spoke of him with tremendous esteem in the interview. He said, for example, that he tried to lure Gross to Ichilov Hospital in Tel Aviv, but that to his regret Gross prefers to remain in his town in the north of the country. This comment clearly moves Gross.

“Eshhar was my mentor and I really wouldn’t want to say anything against him,” he says, adding, “Sometimes all kinds of people with all kinds of interests operate around people, and a person isn’t always aware of them or able to neutralize them.”

These, in fact, are exactly the words that are voiced by Eshhar’s circle. “Someone meddled, stirred things up and stoked the fire,” the confidants aver. And however strange it may sound, there is sorrow, even amazement, on both sides: Both sides, Eshhar and Gross, describe a situation in which they are observing lawyers who have suddenly appeared in the arena – watching their moves, their language, their way of thinking – without fully understanding what’s happened.

It’s as if the hybrid has turned on its creators.



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