Largest Singapore-led T-cell trial on solid tumours marks new era for precision immunotherapy

SINGAPORE - The completion of the largest-ever immunotherapy clinical trial on solid tumours such as nasopharyngeal cancer (NPC) is paving the way for a new era in precision immunotherapy for the future in cancer care.

This is despite the study having ended without an overall survival benefit – the gold standard primary end point in cancer clinical trials – which provides confirmed evidence that a given treatment extends life.

Called Vance, the global, multinational, randomised phase three trial, led by Singapore clinician-scientist Toh Han Chong, is the largest completed trial on T-cell therapy on any solid tumour.

“We are proud of the fact that it was the world’s largest... I think it really is a testament to the remarkable work done by my colleagues, especially in a biotech company. These were the actual people making the T-cells in Singapore, so it’s kind of a made-in-Singapore triumph,” said Professor Toh, who is also deputy chief executive officer of strategic partnerships at the National Cancer Centre Singapore (NCCS).

Solid tumours are abnormal masses of tissue formed in specific organs such as the breasts, brain and upper part of the throat, or nasopharynx.

The Vance study looked at cancer of the nasopharynx since Prof Toh and his team at NCCS have been driving research to develop novel ways to treat Asian-endemic cancers.

NPC is common in males in Singapore and southern China, with an incidence of 8.9 per 100,000 males and 25 per 100,000 males, respectively.

Well-known NPC sufferers include Malaysian badminton star and three-time Olympic silver medallist Lee Chong Wei and South Korean actor Kim Woo-bin.

The current mainstay treatment of early and locally advanced NPC is radiotherapy and chemoradiotherapy, but once it spreads beyond the originating site, treatment is largely not curative, with the median survival currently at 21 to 29 months.

NPC is also closely associated with the Epstein-Barr virus (EBV), making NPC a good candidate to treat with immunotherapy targeting the virus.

EBV is common and highly contagious, spreading through bodily fluids, especially saliva. Some cases lead to mononucleosis, or the kissing disease, and rare cases lead to cancer. Several small studies have shown that EBV-specific T-cell therapy produces clinical responses and benefit in NPC patients.

The Vance study enrolled 330 NPC patients between July 2014 and end-January 2020 at 23 sites in five places: Singapore, Malaysia, Thailand, Taiwan and the United States.

Participants were randomly divided into two groups – in one group, patients received only six cycles of chemotherapy each, while in the other group, patients received four cycles of chemotherapy and six cycles of EBV T-cell therapy, totalling over one billion precision-targeting T-cells each, two to four weeks after completing chemotherapy.

The trial did not turn out a significant overall survival benefit for all its participants. However, it found in an analysis of patients enrolled at the US, Singapore and Taiwan sites that those who received both chemotherapy and T-cell therapy did better compared with the chemotherapy-only group.

This means the insights gleaned from this study can be harnessed into further trials to benefit more patients, and the teams have started planning the Vance trial biomarker studies to identify biomarkers in the patient’s immune system and in T-cell therapy.

T-cell therapy is a type of immunotherapy that harnesses the body’s immune cells to fight cancer. It is developed by extracting cancer-recognising T-cells from a person’s own blood, growing or genetically modifying them in the laboratory, then reintroducing them into the body to fight cancer cells.

Prof Toh, who has been training in the field of T-cells for about 25 years, said T-cell therapy “is both frightening and remarkable”.

“When you infuse seven T-cells in a patient, within weeks and months, they can increase a thousandfold... One of the most amazing things about T-cells is that after 10 years, they are still fighting. I’ll give you an example. If you were to send soldiers into war and 10 years later, you bring helicopters to extract them, they are still alive and they still have bullets. That is the remarkable thing about T-cell therapy that very few people know about,” he said.

Between 2008 and 2011, Prof Toh’s team conceptualised and led a phase two single-arm clinical trial with 35 patients with advanced stage four NPC, giving them six cycles of EBV T-cell therapy after chemotherapy treatment.

The results showed that adding the T-cell therapy after first-line chemotherapy generated promising clinical benefits compared with historical trials with subjects who had received only chemotherapy. One patient who was completely cleared of NPC survived for nearly 10 years.

Following the promising NCCS phase two trial, Vance was launched.

“It was like not starting with three kittens but buying three tigers instead. So it was as if we got three tigers sitting in an apartment somewhere. It was a massive operation, involving many centres, but we did it anyway. So we started with the phase three trial,” Prof Toh said.

Unlike the well-known chimeric antigen receptor (Car) T-cell, which has artificial proteins bound to help the immune cells track down and destroy the cancer cells, he said the T-cells that his team gave to the Vance patients were “polyclonal, activated multi-targeting T-cells, which hit several parts of the cancer”. 

Blood was collected from patients and white cells extracted manually to create T-cells that were generated repeatedly for the Vance phase three trial.

Assistant Professor Jens Samol, an oncologist at Tan Tock Seng Hospital (TTSH) and principal investigator for the Vance trial at TTSH, said: “Think of these T-cells as re-educated T-cells and what the lab did, essentially, was to take the patient’s own T-cells, separated them from the rest of the blood and other immune cells, and then re-educated them against some protein on the virus surface and returned them so they would target the actual cancerous protein.”

Using the analogy of national service, Prof Toh said the T-cells are like recruits who are trained for between two and three months before going out into the field.

“These ‘re-educated’ T-cells are not engineered but trained as it was critical in the study that the subjects do not suffer side effects,” he said.

“The planning, establishment and execution of the Vance trial, including the large-scale manufacturing, storage, shipment and delivery of high-quality T-cells as treatments to patients’ bedsides across the world, was a monumental task and achievement,” Prof Toh added.

“This is testament to the expertise across disciplines and institutions involved, showcasing Singapore’s ability to accomplish very complex cell therapy at the highest level.”

Professor Samol said: “The benefit to patients in the subgroup within the Vance trial warranted further investigation, and a comprehensive analysis of phase two might identify biomarkers to help this quest.”

Efforts are now under way to harness the insights gleaned from the study into further investigations to benefit more NPC patients.