Detecting Early Response to Immune Checkpoint Blockade by Multimodal Molecular Imaging

Abstract

Immune checkpoint inhibitors have become a standard therapy for several cancers; however, the response is inconsistent and a method for non-invasive assessment has not been established to date. To investigate the capability of multi-modal imaging to evaluate treatment response to immune checkpoint blockade therapy, we employed hyperpolarized 13C MRI on tumor bearing mice using [1-13C] pyruvate and [1,4-13C2] fumarate to detect early changes in tumor glycolysis and necrosis, respectively. Following PD-L1 Ab + CTLA-4 Ab dual immune checkpoint blockade (ICB) therapy, dynamic contrast enhanced (DCE) MRI was used to determine the treatment effect on intratumor perfusion/permeability. Mice bearing MC38 colon adenocarcinoma and B16.F10 melanoma were used as sensitive and less sensitive models, respectively to immune checkpoint dual blockade of PD-L1 and CTLA-4. Glycolytic flux significantly decreased upon treatment in the less ICB sensitive B16.F10 model but remained essentially unchanged in MC38 tumors. Imaging [1,4-13C] fumarate conversion to [1,4-13C] malate showed a significant increase in necrosis in the treatment group for the ICB sensitive MC38 tumor (p = 0.0003), with essentially no change in ICB sensitive B16.F10 tumors. Histological assessment showed increased necrotic tissue with enhanced lymphocyte infiltration in the MC38 treatment group, suggesting immunogenic tumor cell death. Dynamic contrast enhanced MRI showed significantly increased perfusion/permeability of Gd-DTPA in MC38 treated tumor, while a similar trend but statistically non-significant change was observed in B16.F10 treated tumor. These results provide imaging biomarkers to detect early response to cancer immunotherapy, allowing qualitative assessment of tumors treated with immune checkpoint blockade therapy.