When T Spells Trouble For Cancer

The world’s largest clinical trial of T-cells for cancer is being conducted by a Singapore-based biotech company, Tessa Therapeutics. Sim Shuzhen finds out more.

AsianScientist (Nov. 3, 2017) – In December 2015, former US President Jimmy Carter announced that he was cancer-free, following treatment with the immunotherapy drug Keytruda (pembrolizumab). His recovery from an aggressive form of melanoma triggered a deluge of patient requests for the drug, which works by unleashing the immune system against tumor cells.

The promise of cancer immunotherapy—and the hype surrounding the field, thanks to high-profile success stories like ex-President Carter’s—has generated a wave of excitement not just within the medical community, but also in industry circles. In 2016, half of all deals to cancer treatment startups went to companies developing immunotherapies, a study by research firm CB Insights found.

But the field suffered a setback in July 2016, when a closely watched chimeric antigen receptor T-cell (CAR-T) therapy trial run by Seattle-based Juno Therapeutics was halted after three patients died from cerebral edema, or swelling in the brain. While CAR-T therapies remain promising and continue to be actively investigated, the incident nevertheless raised important questions about their future and long-term safety.

There are alternatives on the horizon: In what is currently the world’s largest T-cell therapy clinical trial for cancer, Singapore biotech Tessa Therapeutics is testing a new type of treatment that takes advantage of the immune cells’ ability to mount a potent and targeted antiviral response. Targeted at nasopharyngeal cancer (NPC), the phase 3 trial could potentially yield the first-ever T-cell therapy for a solid tumor.

Going antiviral

Some cancers are associated with infection by specific viruses, which are thought to drive the genetic changes that eventually lead to tumor formation. NPC, which affects the region behind the nose and above the back of the throat, is one such cancer—it’s linked to Epstein-Barr virus (EBV), a common and typically asymptomatic infection.

While such tumors give themselves away by displaying ‘non-self’ virus-derived proteins on their surfaces, these often escape the notice of T-cells—the immune system’s professional assassins. Tessa’s strategy creates T-cells which can detect and home in on these proteins, and carry out their assassin’s duty.

To achieve this, the company isolates T-cells from patient blood and ‘trains’ them by stimulating them with EBV-derived protein fragments. Now primed to recognize EBV-positive tumor cells, these virus-specific T-cells (VSTs) are then infused back into the patient.

Dr. John Connolly, Tessa’s chief scientific officer and a principal investigator at Singapore’s Institute of Molecular and Cell Biology, has spent most of his academic career trying to understand why some patients but not others respond to immunotherapy, in the hope of using that information to improve treatments, he told Asian Scientist Magazine.

“The results were so dramatic that we knew we were on to something.”

Tessa arose out of a phase 2 clinical trial Connolly conducted with oncologist Dr. Toh Han Chong, now Tessa’s chief medical officer, at Singapore’s National Cancer Centre. (Toh previously studied under Dr. Malcolm Brenner, who invented the VST technology, at the Baylor College of Medicine in Texas.) Sixty-three percent of the patients in that trial survived for two years post-treatment, one of the best outcomes reported thus far for advanced-stage NPC.

“The results were so dramatic that we knew we were on to something. We began discussing ways in which such a promising treatment could be funded through the next stage of development, and eventually be commercialized,” said Connolly.

While existing T-cell therapies have worked well against leukemia and other blood cancers, they haven’t been as effective against solid tumors, such as those seen in lung or liver cancer, or in NPC. These tend to be less molecularly uniform, and are also trickier for T-cells to penetrate.

But VSTs have a number of qualities that make them especially effective, said Connolly. For one, they are good at infiltrating solid tumors; for another, they have a long immunological memory and can self-renew, thus maintaining their killing abilities for years after infusion.

Better design, with data

The NPC phase 3 trial currently underway involves some 300 patients across 29 centers in Singapore, Malaysia, Taiwan, Thailand and the US. Scaling up to this from a single-center phase 2 trial was a huge logistical challenge, said Mr. Andrew Khoo, Tessa’s cofounder and chief executive officer. Since cell therapy is relatively new, the company had to work out quality control standards with regulators in each country, as well as provide training to physicians at each site.

The road from academia to a phase 3 clinical trial has been a huge learning experience for Connolly as well.

“Before we started on this journey, I hadn’t appreciated just how much the right team can accomplish,” he said. “While the scientific idea is a critical spark to get things going, the real value comes from the efforts of a dedicated multidisciplinary team.”

Connolly hopes that the trial, in addition to assessing how effective Tessa’s treatment is, will also provide insights into why some patients, but not others, respond to T-cell therapy.

“This is a big deal for us. I think that understanding the mechanisms of resistance is even more important than understanding the mechanisms of action,” he said. “We are fortunate enough to be running the world’s largest T-cell therapy trial for cancer. This gives us access to an enormous number of patient samples to analyze, and to try and get deeper into why some patients don’t respond. We can then rationally design our therapies based on that.”

Immunotherapy essentially involves jumpstarting the immune response; while this can be extremely effective against cancer, it can also be very dangerous. Treatments such as checkpoint inhibitors and cytokines are known to cause extremely toxic side effects, which can be lethal in some cases.

“We are fortunate enough to be running the world’s largest T-cell therapy trial for cancer.”

By comparison, Tessa’s therapies have thus far not elicited any significant adverse reactions, and Connolly has made it a research priority to understand why. He thinks it’s possible that other methods of stimulating and expanding T-cells do so in a more random manner, resulting in a T-cell population that induces a potent but less focused immune response. By contrast, the VST platform could produce more uniform populations that trigger a response which is highly specific to the tumor.

“I think there is a fundamental quality of these VSTs that is different from T-cell populations you get by using other methods,” he says. Understanding this difference, he thinks, will help the field design safer T-cell therapies.

CARs and combinations

Tessa isn’t stopping at NPC. The company is also programming VSTs to initiate an immune response against cancers that are not virally associated. Its treatment for liver and lung cancer, for example, combines the VST platform with CAR-T technology; VSTs are further engineered to carry a CAR that targets GPC3, a protein found on the surface of liver and lung tumors.

“I think combinations are going to be the ultimate success in this field. But you can’t just stick chemotherapy A and chemotherapy B together and hope that they will work.”

In addition, Tessa is exploring the use of VSTs or CAR VSTs in combination with other types of therapies. One strategy, soon to enter phase 1 trials for head and neck cancer, couples CAR VSTs with an oncolytic virus that preferentially infects tumor cells and kills them by bursting them open. The dying cells release molecules which further stimulate the CAR VSTs, enhancing their killing potential.

“I think combinations are going to be the ultimate success in this field,” said Connolly. “But you can’t just stick chemotherapy A and chemotherapy B together and hope that they will work. We have to go back to first principles, ask what the appropriate immune response is, and then select the appropriate combination that will recreate that destructive cycle.”

VSTs could also be used in combination with antibody-based therapies such as checkpoint inhibitors, which target molecules that normally help put the brakes on the immune response. Blocking these molecules ramps up the immune response, enhancing the VSTs’ killing ability.

In March 2017, Tessa acquired Euchloe Bio, a biotech company originally spun out of the Singapore Immunology Network, that specializes in therapeutic antibodies for cancer. Euchloe’s protein engineering platforms and expertise, says Connolly, will not only allow Tessa to develop antibody-based combination therapies in-house; it will also help the company design better, more effective CARs, as well as improve its VST manufacturing process.

“We see ourselves pushing forward a suite of different therapies that can be used in combination, all of which are connected by a fundamental thread and build upon each other,” said Khoo. “Technologies and acquisitions need to be very methodically thought out.”

Tempered optimism

The NPC phase 3 trial is also unique in that Tessa’s treatment is being tested as a first-line therapy. “This is one of the few first-line phase 3 trials out there for solid tumors, so we will be defining the standard of care,” said Connolly.

Given that most patients receiving experimental therapies are already in the late stages of disease, how does Tessa define success?

“I think everybody’s ultimate goal is a cure, and I’m proud to say that we absolutely want to cure these patients,” said Connolly. “But we are realistic in our capability to do that. We hope to get durable responses in more of our patients, until eventually you have something which would be called a functional cure.”

In the more immediate and medium term, said Khoo, the company is focused on prolonging overall survival and improving quality of life with minimal side effects. Getting closer to a cure, Connolly reiterates, will take more research to understand why some patients respond well to treatment and others do not.

“I’m extremely enthusiastic about the potential of our therapies, but I want to emphasize that we have to understand the mechanisms behind it,” Connolly said. “Rushing to market will not get you anywhere. You have to start with a real foundational scientific understanding of why people do and don’t respond, in order to design new and better treatments.”

This article was first published in the July 2017 print version of Asian Scientist Magazine. Click here to subscribe to Asian Scientist Magazine in print.


Copyright: Asian Scientist Magazine.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

Shuzhen received a PhD degree from the Johns Hopkins Bloomberg School of Public Health, USA, where she studied the immune response of mosquito vectors to dengue virus.

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