Multiparametric MRI of early tumor response to immune checkpoint blockade in metastatic melanoma

Abstract

BackgroundImmune checkpoint inhibitors are now standard of care treatment for many cancers. Treatment failure in metastatic melanoma is often due to tumor heterogeneity, which is not easily captured by conventional CT or tumor biopsy. The aim of this prospective study was to investigate early microstructural and functional changes within melanoma metastases following immune checkpoint blockade using multiparametric MRI.MethodsFifteen treatment-naïve metastatic melanoma patients (total 27 measurable target lesions) were imaged at baseline and following 3 and 12 weeks of treatment on immune checkpoint inhibitors using: T2-weighted imaging, diffusion kurtosis imaging, and dynamic contrast-enhanced MRI. Treatment timepoint changes in tumor cellularity, vascularity, and heterogeneity within individual metastases were evaluated and correlated to the clinical outcome in each patient based on Response Evaluation Criteria in Solid Tumors V.1.1 at 1 year.ResultsDifferential tumor growth kinetics in response to immune checkpoint blockade were measured in individual metastases within the same patient, demonstrating significant intertumoral heterogeneity in some patients. Early detection of tumor cell death or cell loss measured by a significant increase in the apparent diffusivity (Dapp) (p<0.05) was observed in both responding and pseudoprogressive lesions after 3 weeks of treatment. Tumor heterogeneity, as measured by apparent diffusional kurtosis (Kapp), was consistently higher in the pseudoprogressive and true progressive lesions, compared with the responding lesions throughout the first 12 weeks of treatment. These preceded tumor regression and significant tumor vascularity changes (Ktrans, ve, and vp) detected after 12 weeks of immunotherapy (p<0.05).ConclusionsMultiparametric MRI demonstrated potential for early detection of successful response to immune checkpoint inhibitors in metastatic melanoma.

MRI techniques for immunotherapy monitoring

“… 55 In a separate study on treatment-naïve patients, a gradual decrease in K trans , v e , and v p was also detected in the responding and pseudoprogressive melanoma metastases over 12 weeks of pembrolizumab (anti-PD-1) monotherapy or combined ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy. 5 Nevertheless, a significant decrease in tumor vascular permeability was only detectable following a reduction in tumor volume and tumor cell loss, showing that vascular normalization occurs relatively late in response to immunotherapy and after cell death has begun. This contrasts with antiangiogenic therapy in human melanoma where the treatment effects are targeted directly towards the vascular network and are generally non-cytotoxic.…”

“… 47 There are a number of advanced DWI approaches which have been developed, including diffusion kurtosis imaging (DKI) for detecting tissue heterogeneity based on the non-Gaussian movement of water within the heterogeneous tumor microenvironment. 5 48 In summary, DWI may be a very versatile, although non-specific tool, to evaluate overall cellular alterations within tumors during immunotherapy.…”

“…Diffusion-weighted MRI techniques have been widely used to monitor response to cancer treatment in general, and more recently have been applied in immunotherapy trials. 5 49 50 For example, a recent study of patients with glioblastoma treated with a dendritic cell vaccine and standard-of-care therapy demonstrated a higher pretreatment tumor ADC in the responders compared with the non-responders. 49 There was a significant decrease in tumor ADC in the responders after 8 weeks of treatment which persisted during immunotherapy suggesting that leukocyte infiltration may have played a role, and this correlated significantly with longer progression-free survival.…”

“…Images reproduced with permission from Lau et al . 5 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.…”

Adapting Imaging Protocols for PET-CT and PET-MRI for Immunotherapy Monitoring

“…This position is further supported by recently published data on the role of multiparametric MRI (mpMRI) in the evaluation of immunotherapy responses. In particular, in a study investigating the ICIs responses of metastatic melanoma patients using mpMRI, several direct or calculated readouts were of prognostic value, namely diffusion/ADC, the derived cell-density, and DCE derivates (K trans , v e , and v c ) already after 3 weeks of treatment [ 37 ]. Moreover, DCE- and DWI-MRI have been shown to distinguish pseudoprogression from real progression in different tumor entities and brain metastatic disease under ICIs [ 38 , 39 ].…”