Detection of immune responses after immunotherapy in glioblastoma using PET and MRI

Abstract

Contrast-enhanced MRI is typically used to follow treatment response and progression in patients with glioblastoma (GBM). However, differentiating tumor progression from pseudoprogression remains a clinical dilemma largely unmitigated by current advances in imaging techniques. Noninvasive imaging techniques capable of distinguishing these two conditions could play an important role in the clinical management of patients with GBM and other brain malignancies. We hypothesized that PET probes for deoxycytidine kinase (dCK) could be used to differentiate immune inflammatory responses from other sources of contrast-enhancement on MRI. Orthotopic malignant gliomas were established in syngeneic immunocompetent mice and then treated with dendritic cell (DC) vaccination and/or PD-1 mAb blockade. Mice were then imaged with [18F]-FAC PET/CT and MRI with i.v. contrast. The ratio of contrast enhancement on MRI to normalized PET probe uptake, which we term the immunotherapeutic response index, delineated specific regions of immune inflammatory activity. On postmortem examination, FACS-based enumeration of intracranial tumor-infiltrating lymphocytes directly correlated with quantitative [18F]-FAC PET probe uptake. Three patients with GBM undergoing treatment with tumor lysate-pulsed DC vaccination and PD-1 mAb blockade were also imaged before and after therapy using MRI and a clinical PET probe for dCK. Unlike in mice, [18F]-FAC is rapidly catabolized in humans; thus, we used another dCK PET probe, [18F]-clofarabine ([18F]-CFA), that may be more clinically relevant. Enhanced [18F]-CFA PET probe accumulation was identified in tumor and secondary lymphoid organs after immunotherapy. Our findings identify a noninvasive modality capable of imaging the host antitumor immune response against intracranial tumors.

Temporal and spatial modulation of the immune response of the murine Gl261 glioma tumor microenvironment

“…In the orthotopic Gl261 model the combination of i.v. contrast MRI and [ 18 F]-2-fluoro-d-(arabinofuranosyl) cytosine PET/CT enabled the distinction of regions of high immune inflammatory activity/infiltration in animals treated with DC vaccine and/or anti-programmed cell death-1 mAb (27), closing the gap between preclinical models and clinical treatment/monitoring.…”

Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod

“…Other PET probes are also under investigation. A recent study demonstrated the feasibility of PET probes targeting deoxycytidine kinase to evaluate immune cell aggregation in gliomas [48]. While this technique requires further evaluation in a clinical setting, amino acid PET is currently available to patients and has shown the ability to differentiate between pseudoprogression and GBM recurrence [49].…”

Current Landscape and Emerging Fields of PET Imaging in Patients with Brain Tumors

“…Recently, it has been shown that a radiolabeled [ 89 Zr]IAB22M2C has the potential to visualize CD8 + T-cell-enriched tumor tissue [168]. The assessment of immune cells infiltrating tumors has also been investigated with PET using radiolabeled clofarabine (2-chloro-2 -deoxy-2 -[ 18 F]fluoro-9-b-D-arabinofuranosyl-adenine; [ 18 F]CFA) [169]. [ 18 F]CFA is a substrate for the enzyme deoxy-cytidine kinase, which is overexpressed in immune cells such as CD8 + T-cells [169].…”