VANCE trial marks milestone in t cell therapy for solid tumors

The largest ever clinical trial of T cell therapy for solid tumors has ended, heralding a new era for precision T cell therapy. Led by a Singapore clinician-scientist, the multinational, phase III VANCE trial demonstrates that Singapore has the expertise and capabilities to run a large-scale global cell therapy trial. Results were published in the high impact factor journal, Annals on Oncology (JIF: 56.7), in October 2024.

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 - is a monumental task and achievement. 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 Toh Han Chong, VANCE trial lead and study first author, Senior Consultant, Division of Medical Oncology and Deputy Chief Executive Officer (Strategic Partnerships), National Cancer Centre Singapore (NCCS)

"This international T cell therapy trial driven by Singapore's biotech and the National Cancer Centre Singapore represents a significant milestone. The delivery of high-quality T cells at large scale has been a major barrier for extending the applications of these therapies. To have achieved this goal when T cell therapy was in its infancy makes this Singapore-led achievement even more commendable," said Professor Cliona Rooney, Baylor College of Medicine, Houston, Texas and one of the pioneers of T cell therapy.

What is 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 or from another person, growing or genetically modifying them in the laboratory, then reintroducing them into the body to fight cancer cells. The most well-known type of T cell therapy is CAR-T cell therapy, which has been approved for use by the US FDA since 2017 to treat blood cancers such as acute leukaemia, lymphoma and multiple myeloma.

Laying the foundation of the VANCE trial

Prof Toh and his team at the Laboratory of Cell Therapy and Cancer Vaccine at NCCS have been driving research to develop novel ways to treat Asian-endemic cancers for over 20 years. Nasopharyngeal carcinoma (NPC) is a common cancer in males in Singapore and Southern China with an incidence of 8.9 per 100,000 males and 25 per 100,000 males, respectively. Current mainstay treatment of early and locally advanced NPC is radiotherapy and chemoradiotherapy but once NPC spreads beyond the originating site, treatment is largely not curative with median survival currently at 21 to 29 months.

There have been efforts to find more effective treatments for advanced NPC. NPC is closely associated with the Epstein-Barr virus (EBV), making NPC a good candidate to treat with immunotherapy targeting EBV. Small studies have shown that EBV-specific cytotoxic T cell (EBV-CTL) therapy, a type of T cell therapy, produces clinical responses and clinical benefit in NPC patients.

Between 2008 to 2011, Prof Toh's team conceptualised and led a Phase II single arm clinical trial in patients with recurrent or metastatic NPC at NCCS with 35 patients with advanced stage 4 NPC. They were given 6 cycles of EBV-CTL therapy after platinum-based combination chemotherapy treatment and results showed that adding the T cell therapy after first line chemotherapy generated promising clinical benefits compared to historical trials with subjects who only received chemotherapy. In this study, the median survival was 29.9 months, compared to median survival then which was generally 11 to 12 months. One patient who achieved complete clearance of NPC disease survived for nearly 10 years.

Executing the VANCE trial

Following the promising NCCS Phase II trial of EBV-CTL therapy for NPC, the VANCE trial, a global, multi-centre, randomised, open-label Phase III clinical trial of T cell therapy was launched, with Prof Toh as the overall coordinating principal investigator. Collaborators were from international medical institutions such as Tan Tock Seng Hospital (TTSH), Universiti Malaya Medical Centre, King Chulalongkorn Memorial Hospital, National Taiwan University Hospital, Stanford School of Medicine, UCSF School of Medicine, Massachusetts General Hospital and Baylor College of Medicine.

A total of 330 patients were enrolled between July 2014 and January 2020 at 23 trial sites in Singapore, Malaysia, Thailand, Taiwan and the United States. Participants were randomly divided into two groups – one that received chemotherapy followed by EBV-CTL therapy, and one that received chemotherapy alone. Treatment for this group consisted of two stages: 4 cycles of chemotherapy (gemcitabine and carboplatin) and 6 cycles of EBV-CTL therapy (totalling over 1 billion precision targeting T cells for each patient) starting 2 to 4 weeks after the completion of chemotherapy treatment. The group receiving chemotherapy, alone, underwent 6 cycles of chemotherapy.

Trial outcomes uncover ways to refine T cell therapy

Of the 330 patients on the VANCE trial, 154 patients completed the study. Median overall survival for participants on the trial was 25 months for the chemotherapy and EBV-CTL therapy group and 24.9 months in the chemotherapy only group. Results demonstrated that chemotherapy and EBV-CTL therapy was safe to use but that there was no overall survival improvement for the entire cohort of patients. Notably, in a subset analysis of patients enrolled in the combined US, Singapore and Taiwan sites, patients in the chemotherapy and EBV-CTL therapy group had better progression free survival and overall survival compared to the chemotherapy only arm.

This points to the opportunity to refine the approach to generate positive outcomes. The next steps for the team will be to identify biomarkers in the patient characteristics including their own immune system and biomarkers in the EBV CTL therapy product to improve outcomes through improvement in cell therapy design.

"T cell therapies are not standardised but personalised and called a 'living therapy' as they comprise the body's T cells that are alive, which grow and expand in the body to kill cancer, sometimes for many years. Our trial results indicate that more efforts are needed to improve how T cell therapies are developed and administered to optimise treatment outcomes for patients, and we have now started on these studies," said Prof Toh.

A new era in precision T cell therapy

"Adapted cell therapy by re-educating T cells against viral surface proteins is an effective and safe treatment. To our knowledge, the VANCE trial is the largest completed T cell therapy trial in solid cancers and is a significant contribution to the field. The benefit to patients in an exploratory subgroup within the VANCE trial warrants further investigation and a comprehensive analysis of the Phase II EBV CTL trial may identify biomarkers to help this quest," said Principal Investigator for the VANCE trial at TTSH and study senior author, Assistant Professor Jens Samol, Senior Consultant, Medical Oncology, TTSH.

Efforts are now underway to harness the insights gleaned from this study into further investigations to benefit patients. The study team has started planning the VANCE trial biomarker studies, which aim to identify biomarkers in the patient's immune system and in EBV CTL therapy. A comprehensive analysis of the Phase II EBV CTL trial conducted at NCCS that identifies biomarkers will be presented at the European Society of Medical Oncology (ESMO) Asia Congress in Singapore from 6 to 8 December 2024. These results are crucial for validation that will precede the VANCE trial biomarker studies.