Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas.

Hirokazu Ogino,Nancy Ann Oberheim Bush,Michael R Olin,Joanna J Phillips,Anny Shai,Annette M Molinaro,Cynthia M Wong,Christopher L Moertel,Hideho Okada,Mitchel S Berger,Susan M Chang,Takahide Nejo,Kaori Okada,Atsuro Saijo,Yasuhiko Nishioka,Andrés M Salazar ,David R Gibson ,Jane Rabbitt ,Jennifer Clarke ,Shawn Hervey-Jumper ,Jennie Taylor ,Nicholas Butowski ,Payal Watchmaker ,Meghan Tedesco ,Philip V Theodosopoulos

doi:10.1172/jci151239

Abstract

BACKGROUNDLong-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODSWe conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor.RESULTSA total of 17 eligible patients were enrolled — 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident–like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination.CONCLUSIONThe regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT02549833.FUNDINGNIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.

Highlights

Gliomas are the most common primary malignant central nervous system (CNS) tumors [1]
Despite the unmet need for developing effective and safe therapy for World Health Organization (WHO) grade II low-grade glioma (LGG), immunotherapy has not been extensively investigated in this population [12]
By implementing a neoadjuvant design, we prospectively evaluated the impact of the GBM6-AD lysate vaccine with poly-ICLC in the peripheral blood and tumor microenvironment (TME)

Summary

Introduction

Gliomas are the most common primary malignant central nervous system (CNS) tumors [1]. As of 2016, they are classified according to histology and molecular characteristics as grade I-IV by the World Health Organization (WHO) [2] Among these clinically and molecularly diverse tumors, WHO grade II low-grade gliomas (LGGs), which include diffuse astrocytomas and oligodendrogliomas, are more common in young adults during the third and fourth decades of life. Secondary to their infiltrative nature, they are not curable with resection [3]. Single-cell RNA/TCR-sequencing detected CD8+ T-cell clones that expanded with effector phenotype and migrated into tumor microenvironment (TME) in response to neoadjuvant vaccination.

Methods

Results

Conclusion