Multimodal Molecular Imaging Detects Early Responses to Immune Checkpoint Blockade

Abstract

Immune checkpoint blockade (ICB) has become a standard therapy for several cancers, however, the response to ICB is inconsistent and a method for noninvasive assessment has not been established to date. To investigate the capability of multimodal imaging to evaluate treatment response to ICB therapy, hyperpolarized ¹³C MRI using [1-¹³C] pyruvate and [1,4-¹³C2] fumarate and dynamic contrast enhanced (DCE) MRI was evaluated to detect early changes in tumor glycolysis, necrosis, and intratumor perfusion/permeability, respectively. Mouse tumor models served as platforms for high (MC38 colon adenocarcinoma) and low (B16-F10 melanoma) sensitivity to dual ICB of PD-L1 and CTLA4. Glycolytic flux significantly decreased following treatment only in the less sensitive B16-F10 tumors. Imaging [1,4-¹³C2] fumarate conversion to [1,4-¹³C2] malate showed a significant increase in necrotic cell death following treatment in the ICB-sensitive MC38 tumors, with essentially no change in B16-F10 tumors. DCE-MRI showed significantly increased perfusion/permeability in MC38-treated tumors, whereas a similar, but statistically nonsignificant, trend was observed in B16-F10 tumors. When tumor volume was also taken into consideration, each imaging biomarker was linearly correlated with future survival in both models. These results suggest that hyperpolarized ¹³C MRI and DCE MRI may serve as useful noninvasive imaging markers to detect early response to ICB therapy. SIGNIFICANCE: Hyperpolarized ¹³C MRI and dynamic contrast enhanced MRI in murine tumor models provide useful insight into evaluating early response to immune checkpoint blockade therapy.See related commentary by Cullen and Keshari, p. 3444.