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

Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy

“…Thus, CT- and MRI-based immune-related response criteria (irRC) and immunotherapy RECIST (iRECIST) standards have been developed to improve the discrimination between true disease progression and pseudoprogression for patients treated with immunotherapy ( 6 , 8 , 9 ). However, such anatomical imaging–based evaluation criteria cannot provide early response assessment and cannot confirm disease progression until at least 4 weeks after onset of immunotherapy, which may be beyond the period when treatment strategies can be effectively adjusted ( 10 , 11 ).…”

MRI techniques for immunotherapy monitoring

“…In a separate study, a multiparametric imaging approach using DCE-MRI, hyperpolarized [1- 13 C]pyruvate and [1,4- 13 C 2 ]fumarate MRI was used to simultaneously detect early changes in tumor vascular permeability and perfusion, glycolysis, and necrotic cell death in response to combined anti-CTLA-4 and anti-PD-L1 therapy. 86 Following successful response to treatment, a significant increase in [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]fumarate to [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]malate conversion indicating tumor cell death, and tumor vascular permeability and perfusion (as measured by K trans ) was detected in MC38 colorectal tumors. These changes were not significant in the less treatment-sensitive B16-F10 melanoma.…”

Multi‐band echo‐planar spectroscopic imaging of hyperpolarized 13C probes in a compact preclinical PET/MR scanner

“…We have designed, implemented, and tested a substantially optimized pulse sequence for rapid and efficient HP 13 C metabolic imaging on a new commercial preclinical PET/MR scanner system. There are relatively few prior reports on HP 13 C MRI studies on this platform, [10][11][12] all based on "broadband" EPSI or chemical shift imaging approaches. Our multi-band EPSI-based approach enables more efficient sampling of HP 13 C metabolite dynamics.…”

“…The use of flyback readouts and excitation pulse waveforms, with their tolerance for potential gradient imperfections, provides a robust entry point for these studies. First 13 C reports on this platform appeared only in the past 2 years 10–12 . We present results from HP 13 C metabolic imaging using the new multi‐band EPSI sequence in comparison with conventional “broadband” EPSI, as well as simultaneous 18 F‐fluorodeoxyglucose PET (FDG‐PET) data.…”

“…First 13 C reports on this platform appeared only in the past 2 years. [10][11][12] We present results from HP 13 C metabolic imaging using the new multi-band EPSI sequence in comparison with conventional "broadband" EPSI, as well as simultaneous 18 F-fluorodeoxyglucose PET (FDG-PET) data.…”