Resolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1

Yue Lu,Alphonsus H C Ng,Rohit Thakur,Timothy F Cloughesy,James R Heath,Robert M Prins,Jennifer A Wargo,Beth A Helmink,Richard G Everson,Michael T Tetzlaff,Frances E Chow

doi:10.1038/s41467-021-24293-4

Abstract

The response of patients with recurrent glioblastoma multiforme to neoadjuvant immune checkpoint blockade has been challenging to interpret due to the inter-patient and intra-tumor heterogeneity. We report on a comparative analysis of tumor tissues collected from patients with recurrent glioblastoma and high-risk melanoma, both treated with neoadjuvant checkpoint blockade. We develop a framework that uses multiplex spatial protein profiling, machine learning-based image analysis, and data-driven computational models to investigate the pathophysiological and molecular factors within the tumor microenvironment that influence treatment response. Using melanoma to guide the interpretation of glioblastoma analyses, we interrogate the protein expression in microscopic compartments of tumors, and determine the correlates of cytotoxic CD8+ T cells, tumor growth, treatment response, and immune cell-cell interaction. This work reveals similarities shared between glioblastoma and melanoma, immunosuppressive factors that are unique to the glioblastoma microenvironment, and potential co-targets for enhancing the efficacy of neoadjuvant immune checkpoint blockade.

Highlights

The response of patients with recurrent glioblastoma multiforme to neoadjuvant immune checkpoint blockade has been challenging to interpret due to the inter-patient and intratumor heterogeneity
In a recent multi-institution clinical trial (NCT02852655), we showed that patients with recurrent Glioblastoma multiforme (GBM), who were randomized to receive neoadjuvant pembrolizumab with continued post-surgical adjuvant therapy, had significantly extended overall survival (OS) compared to patients who were randomized to receive post-surgical adjuvant pembro alone[10]
To study the pathophysiological and molecular factors of therapy response at a higher resolution, we examined tumor samples collected from follow-on patients with recurrent GBM, who received anti-PD1 off label ± 5 days before surgical resection (Fig. 1a, top and Supplementary Table 1)

Summary

Introduction

The response of patients with recurrent glioblastoma multiforme to neoadjuvant immune checkpoint blockade has been challenging to interpret due to the inter-patient and intratumor heterogeneity. We report on a comparative analysis of tumor tissues collected from patients with recurrent glioblastoma and high-risk melanoma, both treated with neoadjuvant checkpoint blockade. Using melanoma to guide the interpretation of glioblastoma analyses, we interrogate the protein expression in microscopic compartments of tumors, and determine the correlates of cytotoxic CD8+ T cells, tumor growth, treatment response, and immune cell-cell interaction. Immune correlates of response were identified, suggesting that an optimized treatment regimen of neoadjuvant checkpoint blockade may yield strong patient benefit with reduced toxicity in high-risk melanoma. We report on an in-depth, spatially resolved comparative analysis of tissues collected from patients with recurrent GBM and high-risk melanoma, both treated with neoadjuvant immune checkpoint blockade (ICB) (Fig. 1a). We present a framework to uncover pathophysiological and molecular features that determine the effectiveness of immunotherapies

Methods

Results

Conclusion