i24News Interview

Professor Michael Levitt

Israeli firm NeoTX tries to treat cancer by ‘tricking’ immune system

Three Nobel Prize winners and an immigrant ‘trick’ the immune system to fight the disease on its own

By Maayan Jaffe-Hoffman / 31 Oct 2022 

Three Nobel Prize winners and an immigrant to Israel from Chicago are developing a drug that stimulates a patient’s immune system
so that it can fight cancer on its own.
“We forget we have powerful immune systems and sometimes we need a nudge to get them going,” says NeoTX chief advisor and
Nobel Prize laureate Prof. Michael Levitt. He was awarded the 2013 Nobel Prize in Chemistry for the development of computer
simulations of biological molecules. Levitt joined NeoTX last spring when it acquired InterX, a company that was using quantum mechanics to discover and design therapeutic molecules based on his work.
Two other Nobel Prize winners – Prof. Roger Kornberg, who serves as chairman of the board, and Prof. Arieh Warshel, an Israeli American biochemist – are also actively involved.
NeoTX’s technology is basically a “coating” of the cancerous tumor with bacteria, which stimulates the immune system to attack
it when it enters the body. Early results from Phase I and Phase II trials of its drug naptumomab estafenatox (NAP) show when combined with more traditional cancer therapies – such as chemotherapy – show a promising response.
“Cancer drugs can be very helpful, but they are all subject to resistance,” explains NeoTX CEO Asher Nathan. “For most patients, they only work for a certain amount of time and then the cancer breaks through…. We think the key for patients is to have responses that are going to last longer. What we are doing is not so much trying to cure cancer, but to get the immune system back on track so it can kill the cancer on its own.”

He says that on average, people develop five pre-cancer cells a day, but they don’t develop cancer because the body fights and kills these cells. “We are all getting cancer and all getting cured by our immune system,” Nathan says.
The challenge is that sometimes cancer cells can “hide themselves” from the body’s immune system so that it does not recognize them as a threat. Other times, they can influence the immune system not to kill the cancer cells or even use the immune system to thrive or multiply. NAP binds genetically engineered bacterial components to  the tumor surface “fooling the immune system to thinking it is being attacked by bacteria and triggering a strong antibacterial immune response,” Nathan says.
In June, the company launched a Phase II trial in the US focused on patients with nonsmall cell lung cancer (NSCLC) who have been previously treated with chemotherapy and checkpoint inhibitors.  NAP is being administered with docetaxel, a widely used cytotoxic
chemotherapeutic agent that is a standard of care for people with  NSCLC. The safety of NAP in combination with docetaxel was previously shown in a small Phase I trial in the US, also involving  patients with NSCLC. In that trial, one patient lived for 11 years  which is much longer than would have been expected with docetaxel alone. “Patients who enroll in Phase I trials like this one are generally out of options and they know they are at the end. So, when a patient survives, it is like a miracle,” Nathan says. “This one patient was expected to live two or three more months at most. But he took the drug and after six months he was able to stop taking any drug and live cancer free. It’s not something you see everyday.”

‘We have amazing bodies’
Although Nathan says he does not want to get people’s hopes up and he would not yet tout NAP as a “new cancer breakthrough” or something that is “going to eliminate cancer,” he is confident the drug represents “a shot at working and a lot of promise.”
The company is in the midst of a new funding round and Nathan  says he hopes to use the money to launch more clinical trials and develop more drugs if the Phase II results come back as he hopes by the summer of 2023. Levitt says that the world went into a panic when COVID-19 struck and there was a frenzy of pharma companies searching for vaccines and other cures. However, “there is no doubt that cancer causes much more death by any measure than the pandemic caused” and is a much more complicated disease. Therefore, he sees his work with NeoTX as something for the long term.
“If you look back 50 years, when someone would get diagnosed with cancer they would start preparing for their funeral,” he tells the Report. “Now, you can recover from cancer. We have made great progress.” But he says that the world is ready for the next revolution in cancer treatment. “I think what is novel with NeoTX is that they  treat cancer by getting the body to fight the cancer better,” Levitt says.
He adds that people lived for two million years without modern medicine. Science and technology has enabled people to live longer. “NeoTX reminds us that we have amazing bodies and our bodies have amazing defense mechanisms. Tapping into these is a great idea,” he says.
When can patients potentially get access to NAP if it works?
“Very soon,” says Nathan. “If the Phase II results look good, then  we hope to go into a registered Phase III trial that will take about two years. Then, by 2026 or 2027 the drug could be approved.”

Curing cancer is no small feat: Israel’s NeoTX is still up for the challenge.

The startup’s CEO sits down with Geektime for an exclusive interview about how he and his team at NeoTX are changing the biopharmaceutical industry

By Alissa Abrahami / 3 Aug 2022 

Israeli startup NeoTX is a biopharmaceutical company that focuses on research and development in the field of oncology. Founded in 2015, NeoTX developed a Tumor Targeted Superantigen (TTS) platform technology which was inspired by the fact that the immune system is much better at killing bacteria than cancer cells. The TTS has two components: a TAA (Tumor Associated Antigen) which is a molecule that attaches to cancer cells and a Superantigen Peptide which can activate a controlled, natural, antibacterial immune response. What the TTS does, gis it coats the tumour with a superantigen (bacteria) and lets the body’s immune system do the work; the immune system attacks the bacteria and subsequently the tumour it surrounds. This ultimately converts a weak antitumoral immune response to a strong, antibacterial one, and has even worked in patients who are not responding to their standard immunotherapy treatment. TTS technology has the potential to challenge the effectiveness of other cancer treatments such as chemotherapy and CAR-T cell therapy, as the advantage of TTS that is not seen in chemotherapy, is that the immune system is used to attack cancerous tumours that develop alongside the disease and provides an active response to the development of the tumour.

We sat down with Asher Nathan, one of NeoTX’s co-founders, and CEO, to better understand the journey that brought him and NeoTX to where they are today.

Nathan is a Chicagoan who moved to Israel many years ago. He started his career at the University of Illinois where he received a BSc in chemistry and biology. He then continued his studies at The Hebrew University of Jerusalem. Since completing his education, he has had an impressive track record in the field of biotechnology; he was Managing Director at Paramount Biocapital, drug development and investment firm; founded IntelliGenne and EvoRx, two biotech companies; and served as a Managing Partner at Zoticon Bioventures, a company he co-founded. His career has led him to gain extensive experience in biotechnology, business strategy and development, and entrepreneurship. Moreover, he has authored over 25 patents in the biotechnology field.

Fighting the big fight

Though Nathan has dabbled in other specialties within biotech, he has gravitated toward oncology: “Oncology has always been closest to my heart. I love the challenge. I compare it to the lure of a casino. What we are setting out to do looks easy – kill the out-of-control cancer cells without killing the healthy cells– yet no matter what you throw at them, they appear more intelligent and evolve resistance faster than we can develop new drugs.” It is this challenge that drives Nathan every day. He has two strategies for running NeoTX and that is to think differently and think big. He explained to us that to overcome such a daunting task, such as killing cancer cells, you need to have a different approach than all the other biotech companies striving to achieve the same thing. “It is nearly impossible to have a unique drug in immune oncology. It is a very crowded space as there are at least a handful of companies for every new approach. Most Companies are OK with having competition because it gives them the impression there is safety in numbers, but we have a different approach: we have managed to be the only oncology company – that I am aware of– based on superantigen technology. So, in that, it is evident that we are not afraid to swim alone in the deep waters without a lifeguard because we know whatever sunken treasures we find belong solely to us; we have found a different approach that is worth fighting for.”

On his second strategy– thinking big– Nathan explained that as an oncology company with unique technology for cancer immunotherapy, NeoTX has world-renowned drug development capabilities but lacks drug discovery competency. So, their challenge is to bring the two together: drug discovery with breakthrough technology and drug development. “By putting the two together, we have a much bigger dream: an integrated company with assets and technologies that can drive innovation into the next decade and can make us a leading company for oncology treatment.”

“When I wake up every day, I tell myself to believe in the team and product and to lead the company by example. That is what gets us through each day, which has its own challenges, triumphs, and failures. But from these experiences, we learn, and we make improvements for next time.” He went on by saying that he knows from first-hand experience how challenging it is to hit the ground running on a startup, especially in biotech, with a lack of capital and data working in a constant loop against you. But when doubts fill your thoughts, you just have to think of your purpose: “Although it’s fun to see promising ideas get funded, it is far more satisfying to be part of the action and feel the thrill of seeing patients spared certain death because of something you are doing. When you see a patient with intractable cancer whose tumour is proliferating, which typically means he should have had less than 3 months to live, respond so well to the treatment from our technology, that after 2 years, he is still cancer free, you understand that what you are doing– the struggle to make this startup a success– is well worth it.”

No place like Israel

When we asked Nathan about his experiences here in Israel, as an entrepreneur and scientist, he gave a beautiful anecdote that sums up the spirit of Israel as the Startup Nation. He told us about a time during the COVID-19 pandemic when one of their partnered hospitals’ labs shut down. “When a patient in a trial receives our experimental drug, we need to take their blood and analyze it right away. During the peak of the pandemic, there was an instance where we unexpectedly couldn’t send it to the hospital we normally work with, so we were frantically trying to find a solution. We were able to find another unrelated hospital with a lab willing to volunteer to do the testing and a taxi driver who was patient enough to fetch it from the hospital and drive it to that lab which was in a completely different city. Such a chain of events would happen anywhere else in the world and is a true testament to our great nation.”

NeoTX was founded in 2015 by Asher Nathan (CEO), Ramona Lloyd Ph.D. (VP Regulatory), Marcel Rozencweig MD (President, Former Chief Medical Officer), Roger Kornberg Ph.D. (Chairman of the Board, Former Chief Scientist) and Robert Harow (Chief Financial Officer, Chief Operating Officer). To date, they have raised over $80 million. They are headquartered in Rehovot, Israel, with 50 employees worldwide.

Credit: GeekTime

New cancer treatment fools the immune system to attack

NeoTX, whose team includes several Nobel laureates, is testing a cancer-fighting approach that uses bacteria to bait the immune system into an attack.

By Brian Blum JULY 5, 2022, 12:40 PM

Immunotherapy holds perhaps the greatest promise for fighting cancer in the 21^st century. Rather than bombarding the body with toxic chemicals, as in chemotherapy, immunotherapy utilizes the immune system to neutralize malignant tumors.

The only problem: It only works in about 20 percent of patients with solid tumors.

The reason is straightforward, but still represents a vexing roadblock for cancer researchers: Tumors are not an infection coming from outside but an internal malfunction of the body’s own cells, which begin to replicate out of control.

“Cancer looks like us. It’s hard for the immune system to identify,” explains Dr. Asher Nathan, CEO of NeoTX, a Rehovot-based startup developing a novel way of knocking out tumors – by coating them in bacteria.

“Unlike with cancer, our bodies are finely tuned to attack bacteria,” Nathan says. “Bacteria is a billion years old. Our immune systems have had a long time to figure out how to effectively neutralize bacterial infections. That’s why you don’t wake up in the morning with a cold and think, ‘I’m going to die.’”

Cancer, of course, is a very different story. Compared with bacteria, “cancerous tumors are like the new kid on the block,” Nathan notes.

NeoTX is not Nathan’s first foray into medical technology; after immigrating to Israel 40 years ago from Chicago, he founded IntelliGene and EvoRX, two biotech companies formed around technologies he invented.

For NeoTX, Nathan identified and licensed a drug developed by the Swedish company Active Biotech called naptumomab estafenatox (NAP).

NAP is composed of two proteins: a genetically modified “superantigen” and an antibody that latches onto a tumor via a molecule called 5T4 found primarily on tumors.

A superantigen is a bacterial derivative that elicits a strong antibacterial immune response. NeoTX calls its technology “Tumor-Targeted Superantigen” or TTS.

Once NAP’s 5T4 antibody has attached itself to a tumor, the superantigen “reprograms” the immune system to mount an antibacterial response against the bacteria as well as the tumor.

“The concept behind this drug is, let’s coat the tumor with a bacterial molecule so that the immune system will go into ‘Defcon 1’ and attack the tumor as if it’s bacteria,” Nathan says.

The secret weapon

Once the immune system knows what to look for, it sends in the body’s secret weapon: killer T-cells.

The T-cells identify the bacteria-coated tumors, then start to create an army of cells primed to attack any superantigens they find. Nathan recommends the video below to see how T-cells work; they “grope around like a blind robot” and after hitting a superantigen, punch a hole in the cell … then insert a molecule that causes the cell to explode.”

It’s a fine balance. When fighting a bacterial infection, “the body can go crazy,” Nathan notes. “You can get a high fever that exhausts the immune system. That’s how the bacteria continue to fight. We genetically engineered our superantigen to be safer. It doesn’t generate as strong a response, but it still creates a very powerful immune reaction.”

Targeting bacteria is smart for another reason: Part of how tumors succeed in evading the body’s defenses is by releasing chemicals that weaken the immune response.

“Anything we do nearby the tumor becomes problematic,” Nathan says. But with NAP, “the tumor-killing T-cells are created far from the immune-suppressed tumor site.” Only then do they begin their journey to seek out and destroy the tumors.

Moreover, when the immune system encounters a superantigen bound to a tumor, it modifies the suppressive micro-environment around the tumor so that the body’s natural defenses are better able to kill it.

“This creates a natural, holistic and profound immune response,” Nathan says.

Reboots the immune system

But the best may be yet to come.

“When we’ve tested this drug in animals, we find that even when you try to reintroduce cancers into, say, a mouse that’s been cured by the technology, it doesn’t stick,” Nathan says.

“None of the mice that were ‘rechallenged’ got cancer again. The drug ‘wakes up’ the immune system – at least in mice – and we don’t need any more drug.”

Nathan likens it to the reboot function on a computer. “The drug reboots the immune system so it can do what it natively needs to do – remove the suppressive environment and kill as many tumor cells as possible. Then, the T-cells can go after more targets.”

NeoTX’s bacterial coating approach is currently in a Phase I trial in Israel and, based on encouraging results, has begun a Phase 2 trial in the United States with 30 patients.

One patient has non-small cell lung cancer that had metastasized to the liver. “That’s a death sentence, usually within four months,” Nathan says. The patient received NeoTX’s drug over a decade ago (prior to it being licensed from Active Biotech). “She lived for 11 years and died of something else, not her cancer.”

NAP plays particularly well with checkpoint inhibitors, another type of cancer treatment that aims to tamp down “checkpoints” created by the cancer that essentially trick the T-cells into thinking the tumor is a friend.

“It’s like a secret handshake in a college fraternity,” Nathan quips.

If the handshake were inhibited, so to speak, the T-cells would see the tumor for what it is – very much not a friend – and could attack. Combining NAP with a checkpoint inhibitor “allows our drug to kill more tumor cells,” Nathan says.

AstraZeneca collaboration

Pharma giant AstraZeneca is collaborating with NeoTX on the former’s own checkpoint inhibitor technology. The hope is that patients who don’t normally respond will have greater success in beating back their cancers.

Developing and commercializing any new drug can take up to 15 years and many millions of dollars. NeoTX has raised around $80 million so far. Nathan is optimistic that if NAP passes Phase 2 and 3 trials, it could hit the market as early as 2027.

While the technology has so far been tested on solid lung, esophageal and urethral cancer tumors, patients with blood cancer such as lymphoma and leukemia could benefit, too – in particular those who are candidates for CAR-T, a promising treatment that involves removing T-cells from a patient, engineering them for maximum killing ability in a lab, then reinjecting them.

CAR-T, a form of immunotherapy, tends to work well for blood cancers but poorly for solid tumors. That’s another aim for NeoTX – to provide a pharmaceutical complement that will allow CAR-T to be effective outside the blood cancer domain.

Immunotherapy has become a crowded field. “If you look at all the companies that are trying to elicit an immune system response, there are probably 1,000 out there. But for the specific mechanism we’re trying, it’s zero,” Nathan notes.

“One of our investors said to us, ‘You’re either geniuses or you’re crazy.’ I replied, ‘What makes you think it’s one or the other?’”

NeoTX has no shortage of geniuses. Roger Kornberg, the 2006 winner of the Nobel Prize in chemistry, is the company’s chief scientist (as well as a long-time collaborator with Nathan in his previous endeavors).

Michael Levitt and Arieh Warshel, who shared a Nobel in chemistry in 2013, are advisers. Dr. Marcel Rozencweig, a medical oncologist and 18-year veteran of pharma company Bristol Myers Squibb, where he was head of global oncology, is NeoTX’s president.

Recently, the head of global clinical oncology at Bayer pharmaceuticals, Dr. Scott Fields, joined NeoTX as chief medical officer.

“It is extremely rare that someone as high up as Scott Fields would leave pharma to work in such a small company,” Nathan tells ISRAEL21c. “It is even more rare that he would come to a company based in Israel.”

Cancer, sadly, isn’t going away anytime soon. “The average person develops around five cancerous or pre-cancerous cells a day,” Nathan notes.

“Our bodies are very efficient at killing, such that most people don’t get a new cancer every day. Our drug could level the playing field so the body can do what it’s meant to.”

Credit: Israel21c

NeoTX Therapeutics in the JPost:

https://www.jpost.com/health-and-wellness/article-701906