MRI techniques for immunotherapy monitoring

Abstract

MRI is a widely available clinical tool for cancer diagnosis and treatment monitoring. MRI provides excellent soft tissue imaging, using a wide range of contrast mechanisms, and can non-invasively detect tissue metabolites. These approaches can be used to distinguish cancer from normal tissues, to stratify tumor aggressiveness, and to identify changes within both the tumor and its microenvironment in response to therapy. In this review, the role of MRI in immunotherapy monitoring will be discussed and how it could be utilized in the future to address some of the unique clinical questions that arise from immunotherapy. For example, MRI could play a role in identifying pseudoprogression, mixed response, T cell infiltration, cell tracking, and some of the characteristic immune-related adverse events associated with these agents. The factors to be considered when developing MRI imaging biomarkers for immunotherapy will be reviewed. Finally, the advantages and limitations of each approach will be discussed, as well as the challenges for future clinical translation into routine clinical care. Given the increasing use of immunotherapy in a wide range of cancers and the ability of MRI to detect the microstructural and functional changes associated with successful response to immunotherapy, the technique has great potential for more widespread and routine use in the future for these applications.

Keywords: Immunologic Techniques; Immunotherapy; Tumor Biomarkers.

Figure 1

Multiparametric MRI for monitoring cancer immunotherapy. (A) Schematic diagram of the multiparametric MRI approach used for investigating changes in tumor volume (T₂-weighted MRI), vascular permeability (DCE-MRI), tumor cellularity and heterogeneity (DKI) in patients with metastatic melanoma receiving immune checkpoint inhibitors. (B) Intertumoral differences in treatment response, vascular permeability, and cellularity were detected in a patient with metastatic melanoma during the first 12 weeks of treatment with nivolumab. Quantitative maps of tumor vascular permeability (K^trans ) and tumor cellularity (D_app ) were shown with corresponding changes in tumor volume measured on T₂-weighted MRI. Images reproduced with permission from Lau et al. D_app, apparent diffusivity; DCE, dynamic contrast-enhanced; DKI, diffusion kurtosis imaging; K^trans, the volume transfer constant from the blood plasma to the extravascular tumor interstitial space.

Figure 2

Imaging glucose metabolism with HP ¹³C-MRI. (A) An increased expression of glucose transporters, for example, GLUT1 and elevated glycolysis is seen in cells with higher energy demand, for example, cancer cells and activated T cells. (B) Several ¹³C-labeled imaging probes have been developed for evaluating different downstream processes of the glucose metabolism pathway. These include [1-¹³C]pyruvate for imaging the kinetics of pyruvate-to-lactate conversion, ¹³C-labeled bicarbonate (H¹³CO₃ ⁻) for detecting tumor pH in vivo, and increased production of [1,4-¹³C₂]malate from the administered [1,4-¹³C₂]fumarate as a surrogate biomarker of cell necrosis or tumor cell death in response to treatment. (C) HP ¹³C-MRI of a patient with prostate cancer showed a marked decrease in [1-¹³C]pyruvate to [1-¹³C]lactate conversion, with a corresponding reduction in tumor size, in the three bone metastases (left acetabular, left and right iliac lesions) between week 8 and 19 following pembrolizumab treatment. Images adapted and reproduced with permission from de Kouchkovsky et al. (A) and (B) are graphics created by the author (DL). ATP, adenosine triphosphate; NADH, reduced nicotinamide adenine dinucleotide; FADH, reduced flavin adenine dinucleotide; TCA, tricarboxylic acid; PC, pyruvate carboxylase ; PDH, pyruvate dehydrogenase.

Figure 3

MRI tracking of leukocytes and viral vector-mediated gene therapy. (A) Graphical overview of direct and indirect cell labeling approaches with superparamagnetic iron oxide (SPIO) nanoparticles, ¹⁹F-perfluorocarbons (PFC), and examples of MRI reporter genes. (B) A comparison between the negative contrast (decreased signal) obtained with SPIO versus the positive contrast (increased signal) obtained with ¹⁹F-PFC labeling of human dendritic cells. (C) Chemical exchange saturation transfer MRI of lysine-rich protein (LRP) concentration in rat glioma tumors before and at 8 hours following G47Δ oncolytic viral (OV) therapy showed higher signal on the magnetization transfer ratio asymmetry (MTR_asym) maps of tumors injected with G47Δ-LRP but not the empty vector. (D) T₂-weighted MRI showed signal loss or decreased T2 signal (orange arrow) at the popliteal lymph node near the footpad of a mouse at 48 hours following injection with dendritic cells expressing ferritin (FTH-DC). (A) is a graphic created by author (DL) using Biorender (publication licence AU24ELW1E5). Images in (B), (C) and (D) are reproduced with permission from Ahrens et al, Farrar et al, de Vries et al and Kim et al.

Figure 4

MRI of immune-related adverse events associated with immune checkpoint blockade. (A) T2 FLAIR imaging showed the simultaneous reduction of melanoma brain metastases and development of new diffuse inflammatory lesions (bright signal indicated by red arrow) in the brain, brain stem, and cerebellum of a patient who developed encephalomyelitis following two cycles of combined ipilimumab (ipi) and nivolumab (nivo). The inflammatory lesion in the brain was shown to resolve over time following temporary cessation of ICI treatment and 10 days of high-dose steroids. (B) T₁-weighted imaging revealed multiple marginal bony erosions (pink arrow) and synovial enhancement following intravenous gadolinium-based contrast administration at the metacarpophalangeal, proximal interphalangeal, and intercarpal joints (blue arrows), and tenosynovitis (pink arrows), in both hands of a patient with ICI-associated inflammatory arthritis. (C) Increased T1 and T2 relaxation times associated with myocardial inflammation and late gadolinium enhanced lesions (white arrow) indicating myocardial necrosis and fibrosis as a latent effect of ICI-associated myocarditis. Images reproduced with permission from Bjursten et al, Subedi et al, and Faron et al . FLAIR, fluid-attenuated inversion recovery; ICI, immune checkpoint inhibitors.