NEW YORK –Although their autologous Epstein-Barr virus (EBV)-targeted cell therapy failed to improve overall survival in patients with advanced EBV-positive nasopharyngeal cancer (NPC), researchers at the National Cancer Centre Singapore are focusing on their accomplishment: the study was, to date, the largest autologous cell therapy trial completed in a solid tumor indication.
"The amount of logistics, manufacturing, quality control, distribution channels ... this was kind of like the Amazon.com of T-cell therapy," said Toh Han Chong, the deputy director of the National Cancer Centre Singapore and one of the lead authors on the study, which was dubbed VANCE.
The Phase III VANCE trial was designed to compare outcomes from first-line treatment with bespoke EBV-specific cytotoxic T lymphocytes, or EBV-CTL, plus chemotherapy to chemotherapy alone in patients with EBV-positive locally recurrent or metastatic nasopharyngeal cancer (NPC).
The study, which was published in the Annals of Oncology last month, spanned 23 sites in five countries: Singapore, the United States, Malaysia, Thailand, and Taiwan.
Because the autologous cell therapy is patient specific, this meant the harvested cells and finished product required global transportation in both directions. This was a particular feat when it came to the study sites in various parts of the US, across the world from the central manufacturing site in Malaysia.
"We had to collect the blood from the patients, get it to a satellite location, spin down the blood to get the peripheral blood mononuclear cells, and then, from there, ship the blood to Malaysia where the 'kitchen' is where we make the cells," Toh said. "They were traveling all the way across the world."
Other autologous cell therapy manufacturers have had to grapple with such logistics, too. But in many cases, these manufacturers have established their facilities in more centrally located regions, like Europe. In the case of commercial products from major cell therapy drugmakers like Novartis and Gilead, Toh noted they've also had access to far more financial resources.
The VANCE trial relied on funding from a biotech startup, called Tessa Therapeutics, that Toh and colleagues started. It, though, has since folded.
The lack of overall survival benefit in the sweeping trial, Toh suspects, is one of the reasons Tessa had to shut its doors. The trial also wrapped up during the COVID-19 pandemic, then struggled with the overall dearth of funding during a period in 2022 to 2023 that many investors now call the "biotech winter."
"It was just hard to fundraise," he said. "A lot of companies closed down during this time."
Now that Tessa is no longer standing, Toh said the rights to EBV-CTL are in the midst of negotiations, though he couldn't comment further.
Whoever ends up with the rights to the cell therapy next, Toh believes the treatment's lack of overall survival benefit in the VANCE trial won't mean its end. While the overall population of patients didn't live any longer with EBV-CTL plus chemotherapy than they did with chemo alone, there were certain subgroups of patients who did benefit.
"There will surely be biomarkers to look at," he said.
Making sense of VANCE outcomes
According to Toh, EBV-CTL had demonstrated promising activity in NPC patients before entering the vast Phase III trial. In an earlier Phase II trial, combining the treatment with chemotherapy led to a 71.4 percent response rate across 35 patients, with three complete responses.
"Our study achieved one of the best survival outcomes in patients with advanced NPC, setting the stage for a future randomized study of chemotherapy with and without EBV-CTL," wrote Toh and his colleagues back in 2014, when the Phase II trial was published in the journal Molecular Therapy. The researchers chose to study their treatment in NPC, as the cancer is often associated with EBV and has few available treatment options.
"When you take the blood from the patients, you infect that with a general strain of the EBV virus," Toh explained of the treatment. "And then once you have that immortalized into a cell line that just keeps reproducing, you layer that with T cells from the patients, and then you include interleukin-2, and just keep expanding and growing. It's kind of like cooking a broth."
In the process of cooking up this metaphorical 'broth,' he explained, the cells become activated CD8 and CD4 T cells. "And those cells will recognize the proteins of EBV."
According to Toh, one of the benefits of targeting EBV is that the virus contains numerous proteins. "It's not like a CAR T-cell therapy where it's going against one protein like CD19," he said. "It's really going against an alphabet soup of proteins. It's what we call polyclonally activated."
With encouragement, excitement, and early-stage biotech funding from the now-defunct Tessa, the treatment entered the vast Phase III VANCE trial in July 2014.
The trial enrolled 330 patients, 164 of whom were assigned to treatment with chemotherapy and EBV-CTL and 166 of whom were assigned to treatment with chemotherapy alone.
After a median follow up of 45.6 months for patients on the combination and 51.8 months for patients receiving chemo alone, the overall survival outcomes were not significantly different. The patients receiving chemotherapy plus EBV-CTL lived for a median 25 months, and the patients receiving chemotherapy alone lived for a median 24.9 months.
The progression-free survival outcomes were not significantly different, either. Patients receiving chemotherapy plus EBV-CTL lived for a median 7.9 months without disease progression or death, versus 8.6 months for patients who received chemotherapy alone.
The safety profile, according to Toh, was a noteworthy improvement over what's typically seen with autologous cell therapies. Only one patient in the trial experienced a grade 2 serious adverse event — a fever — related to EBV-CTL.
"It's worth mentioning that there were almost zero side effects," Toh said. "When you give someone a CAR T, you can get cytokine release syndrome, you can get iCANs that hits the brain ... but with [EBV-CTL], some people even said a COVID-19 vaccine had more side effects."
To be sure, the combined chemotherapy caused its fair share of side effects, but Toh pointed out that chemotherapy side effects tend to be manageable for oncologists and patients.
Site-specific subgroups
Interestingly, when the researchers looked only at patients treated at centers in the US, Singapore, and Taiwan, they did see a benefit of adding the cell therapy.
The median overall survival for patients in these three regions was 48.5 months on the combination, versus 32.5 months on chemo alone. The progression-free survival for patients treated with the EBV-CTL combination in these three regions was 10.8 months, versus a median of 8.5 months for patients treated with chemo alone.
In the wake of the VANCE study outcomes, one of the focuses for Toh and his colleagues has been trying to explain these site-specific benefits relative to the overall lack of EBV-CTL benefit.
With the help of statisticians at Singapore's National Cancer Centre, researchers have mostly ruled out one of their initial theories, that subsequent treatment with immune checkpoint inhibitor therapy may have contributed to better overall survival in the control group. And while it's possible the differences in specialized experience treating patients with autologous therapies at centers in Singapore, Taiwan, and the US may have contributed to improved outcomes in these regions relative to Malaysia and Thailand, this type of influence would be difficult, if not impossible, to study or prove.
Other explanations could include patient biomarkers or differences in the bespoke products themselves. Toh and his colleagues are studying both possibilities.
"We are looking at specific biomarkers in the patients, and then we are looking at specific biomarkers in the T-cell product itself," Toh said. He said he was unable to share the specific biomarker he and his colleagues are studying, as the analyses haven't yet been published.
If the research were to shed light on a specific group of biomarker-defined patients who benefit from EBV-CTL therapy, drugmakers with deep pockets may be able to repeat a Phase III trial exclusively enrolling patients with these biomarkers to validate the benefit.
"If you are at a big company like Novartis or Iovance, you would do that," Toh said. "But Tessa doesn't exist anymore. We would have to go back to the drawing board." Toh said he and his colleagues would need to seek funding sources with what he called "financial firepower." This wouldn't be impossible, but it might be more challenging without the biotech financing model. Toh and his colleagues will need to cross that bridge when they get there, if indeed a clear subgroup comes to light.
Global scale
In the meantime, they're celebrating what the sheer size and reach of their trial will signal to the rest of the solid tumor cell therapy field: that it's possible to study bespoke therapies like these on a truly global scale, at all sorts of sites with deep differences in resources.
Sites in the VANCE trial included experienced, top-tier cell therapy treatment centers at institutions like Massachusetts General Hospital and Stanford University. But they also treated patients at remote sites in locations like northern Thailand, on the Cambodian border.
"Patients came on horseback and sat on the floor," Toh said. "These patients arrived at the doorstep of these centers with huge burdens of disease."
Even the drugmakers behind commercially available autologous cell therapies often struggle to administer their therapies in remote community settings in the US due to the logistics and expertise required.
"Almost everybody got their T-cells," Toh said. "You have to give credit for the ability to organize and manufacture and ship these cells all the way from California to Kuala Lumpur."