New Article Alert! New Findings on Personalized Vaccine and Pembrolizumab for Liver Cancer Treatment

New Findings on Personalized Vaccine and Pembrolizumab for Liver Cancer Treatment

Authors: Mark Yarchoan, Edward J. Gane, Thomas U. Marron, Renzo Perales-Linares, Jian Yan, Neil Cooch, Daniel H. Shu, Elana J. Fertig, Luciane T. Kagohara, Gabor Bartha, Josette Northcott, John Lyle, Sarah Rochestie, Joann Peters, Jason T. Connor, Elizabeth M. Jaffee, Ildiko Csiki, David B. Weiner, Alfredo Perales-Puchalt and Niranjan Y. Sardesai

Published in Nature Medicine,  07 April 2024

Introduction

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and a leading cause of cancer-related death worldwide. Despite recent advancements in systemic therapy, the 5-year survival rate for advanced HCC remains below 10%. Immune checkpoint inhibitors (ICIs) targeting PD-1 have modest efficacy as monotherapy, with response rates of only 12-18%. New personalized immunotherapies that induce tumour-specific T-cell responses may have the potential to sensitize these typically immune-resistant tumours to ICI therapy.

Study Overview

Design: A phase 1/2 trial evaluating the efficacy of GNOS-PV02, a DNA plasmid vaccine encoding up to 40 patient-specific neoantigens, in conjunction with pembrolizumab in advanced HCC patients.

Endpoints: Safety, immunogenicity, and treatment efficacy, with advanced techniques like ELISpot assays and T-cell receptor sequencing to assess immune response.

 Key Highlights

• Innovation in HCC Treatment: The study addresses HCC’s resistance to immunotherapy(12-18% objective response rate), showcasing a pioneering approach with a personalized therapeutic cancer vaccine (PTCV).
• Safety and Efficacy: Demonstrating a favourable safety profile and significant clinical activity, the treatment marks a step forward in HCC therapy.
• Immunogenicity and Mechanism: Evidence of potent, tumor-specific T-cell responses elucidates the vaccine’s mechanism, providing insights into its clinical benefits.

What We Learned

• The combination of personalized therapeutic cancer vaccines with pembrolizumab can significantly enhance the immune response against HCC by targeting neoantigens specific to the patient’s tumour.
• A direct correlation between vaccine-induced neoantigen specificity and clinical outcomes emphasizes the value of personalized treatment strategies.
• Comprehensive immunological profiling affirms the vaccine’s capability to activate effective T-cell responses, highlighting its potential as a component of HCC treatment regimens.

Key Takeaways

• Clinical Impact: The observed 30.6% objective response rate, including 8.3% complete responses,  surpasses historical controls for pembrolizumab monotherapy(ORR 16.9%), indicating the vaccine’s added value.
• Safety Profile: The combination therapy was safe and well-tolerated, with no dose-limiting toxicities or treatment-related grade ≥3 adverse events, suggesting its suitability for advanced HCC patients.
• Future Directions: The correlation between the number of targeted neoantigens and clinical response underscores the importance of personalized vaccine design, warranting further exploration in larger trials.

This study provides evidence that a personalized neoantigen vaccine can enhance responses to PD-1 inhibitor therapy in advanced HCC, a tumour type typically resistant to immunotherapy. The induction of neoantigen-specific T cell responses, coupled with the increased tumour infiltration of cytolytic T cell clones, supports the proposed mechanism of action. While the small sample size and single-arm design limit the ability to attribute efficacy to the PTCV definitively, the results warrant further investigation in larger, randomized trials. Addressing tumour heterogeneity and evolving neoantigen profiles through longitudinal sampling and rapidly iterated vaccines may be critical to overcoming acquired resistance.

Summary by Amalya Sargsyan, MD

Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial