The VANCE trial, the largest clinical trial of T cell therapy for solid tumors to date, has concluded, signaling a new era for precision T cell therapy. The multinational, Phase III trial, led by a Singaporean clinician-scientist, highlights Singapore's capabilities in conducting large-scale global cell therapy trials. The results were published in Annals of Oncology in October 2024.
Professor Toh Han Chong, lead investigator of the VANCE trial and Senior Consultant at the National Cancer Center Singapore (NCCS), emphasized the monumental effort involved in the trial's execution, including the manufacturing, storage, and delivery of high-quality T cells to patients worldwide. He noted that this achievement underscores Singapore's ability to manage complex cell therapies at the highest level.
T Cell Therapy and the VANCE Trial
T cell therapy is an immunotherapy approach that uses the body's immune cells to combat cancer. It involves extracting cancer-recognizing T cells, expanding or modifying them in the lab, and reintroducing them to target cancer cells. CAR-T cell therapy, a well-known type of T cell therapy, has been FDA-approved for blood cancers since 2017.
Professor Toh's team at NCCS has been researching novel treatments for Asian-endemic cancers for over two decades. Nasopharyngeal carcinoma (NPC), prevalent in Singapore and Southern China, served as a focal point. While radiotherapy and chemoradiotherapy are standard treatments for early-stage NPC, advanced NPC has limited curative options, with median survival ranging from 21 to 29 months.
NPC's association with the Epstein-Barr virus (EBV) makes it a suitable target for EBV-specific cytotoxic T cell (EBV-CTL) therapy. Previous small studies indicated that EBV-CTL therapy could yield clinical benefits in NPC patients. A Phase II trial at NCCS, conducted between 2008 and 2011, demonstrated that EBV-CTL therapy after platinum-based chemotherapy improved median survival to 29.9 months, compared to the historical 11 to 12 months with chemotherapy alone.
VANCE Trial Design and Execution
Building on the Phase II trial's promise, the VANCE trial was launched as a global, multi-center, randomized, open-label Phase III clinical trial. It involved collaborators from various international institutions. Between July 2014 and January 2020, 330 patients were enrolled across 23 trial sites in Singapore, Malaysia, Thailand, Taiwan, and the United States. Participants were randomized to receive either chemotherapy followed by EBV-CTL therapy or chemotherapy alone.
The treatment regimen included four cycles of chemotherapy (gemcitabine and carboplatin) followed by six cycles of EBV-CTL therapy, totaling over 1 billion T cells per patient. The control group received six cycles of chemotherapy alone.
VANCE Trial Outcomes and Future Directions
Of the 330 patients, 154 completed the study. The median overall survival was 25 months in the chemotherapy and EBV-CTL therapy group and 24.9 months in the chemotherapy-only group. While the combination therapy was deemed safe, it did not significantly improve overall survival for the entire cohort.
However, a subset analysis of patients from the US, Singapore, and Taiwan sites showed improved progression-free survival and overall survival in the chemotherapy and EBV-CTL therapy group. This suggests potential for refining the approach to achieve positive outcomes. Future research will focus on identifying biomarkers in patient characteristics and the EBV-CTL therapy product to enhance cell therapy design.
Professor Toh emphasized the personalized nature of T cell therapies, describing them as "living therapies" that expand in the body to kill cancer cells. He noted that the trial results highlight the need to improve T cell therapy development and administration to optimize patient outcomes.
Assistant Professor Jens Samol, Principal Investigator for the VANCE trial at TTSH, highlighted the trial's significance as the largest completed T cell therapy trial in solid cancers. He noted that the benefit observed in a subgroup warrants further investigation and that a comprehensive analysis of the Phase II EBV CTL trial may reveal biomarkers to guide this quest.
Efforts are underway to leverage the insights from the VANCE trial for further investigations. The study team is planning biomarker studies to identify relevant factors in the patient's immune system and in EBV-CTL therapy. A comprehensive analysis of the Phase II EBV CTL trial conducted at NCCS will be presented at the European Society of Medical Oncology (ESMO) Asia Congress in Singapore from December 6-8, 2024. These results are crucial for validating the VANCE trial biomarker studies.
