Utility of [99mTc]Tc-tilmanocept, an immunosuppressive macrophage functional imaging agent in melanoma patients receiving checkpoint inhibitor treatment: a feasibility study

Abstract

Background: Immunotherapy is a mainstay in the treatment of patients with advanced melanoma. Yet, resistance mechanisms exist, and tumour-associated macrophages (TAMs), particularly the M2-like phenotype, are associated with poorer outcomes, with CD206 serving as their specific marker. We present the first human SPECT/CT study to visualize CD206 + TAMs in patients undergoing immunotherapy and compare the findings to clinical outcomes (NCT04663126).

Material and methods: This prospective diagnostic open-label, non-randomized, feasibility study aimed to visualize CD206 + cells including M2-like TAM in target lesions (T-Lesion) of melanoma patients treated with immunotherapy using [^99mTc]Tc-Tilmanocept imaging. Patients had dynamic, whole-body planar and SPECT/CT acquisitions at 1- and 3-h after injection of 350 MBq ± 10% [^99mTc]Tc-Tilmanocept. SUV_{max/peak/mean}, MTV and TLA were measured on SPECT/CT imaging in T-Lesion with ratios to healthy tissues to compare with baseline [¹⁸F]FDG PET/CT imaging, multispectral immunofluorescence staining findings on lesions' biopsies, tumour response at three months and follow-up.

Results: Five patients were recruited. T-Lesion uptake on [^99mTc]Tc-Tilmanocept imaging remained stable at 1- and 3-h post-injection with strong and significant correlations with baseline [¹⁸F]FDG PET/CT. SUV_max T-Lesion/ SUV_mean fat-tissue ratio on [^99mTc]Tc-Tilmanocept SPECT/CT at 1-h was significantly associated with tumour response at three months (p = 0.005), total cells densities for macrophages and CD8 + cells on multispectral immunofluorescence staining and poorer outcomes during the follow-up (p = 0.026).

Conclusion: These preliminary pilot data provide the first-in-human proof of concept that CD206-based functional imaging showed measurable signal in tumour lesions in patients with advanced melanoma. If validated it might be useful in reflecting tumour immune status, hence help predicting tumour response to ICI.

Keywords: CD206 imaging; Immune checkpoint inhibitors; Prediction of response; Quantitative SPECT/CT; [99mTc]Tc-Tilmanocept.

Fig. 1:

73-year woman with stage IIIC melanoma of the left calf melanoma and subcutaneous lesions: a) coronal views of PET image, CT image and fused [¹⁸F]FDG PET/CT image b) axial slices showing on top row fused [^99mTc]Tc-Tilmanocept SPECT/CT images at 1-h and CT images on bottom row c) coronal slices showing CT images with arrows pointing to subcutaneous lesions and fused [^99mTc]Tc-Tilmanocept SPECT/CT images at 1-h

Fig. 2:

80-year woman with stage IV melanoma with unknown primary with multiple metastatic lesion: a and d) Maximum intensity projections [¹⁸F]FDG PET images for the first scan and second scan at three months, respectively; b) transaxial slices showing PET, low-dose CT and fused PET/CT images of the first [¹⁸F]FDG PET/CT scan, and c) transaxial slices showing PET, low-dose CT and fused PET/CT images of the second [¹⁸F]FDG PET/CT scan with a partial metabolic response

Figures 3

Multispectral immunofluorescence staining images in red CD8 staining, in green PD1 staining, in yellow CD163 staining, in pink CD206 staining, in light pink SOX10 staining, and in blue DAPI staining: a) 73-year woman with stage IIIC melanoma of the left calf melanoma with high immune cells infiltration “inflamed” and b) 77-year man with stage IV melanoma with two primary melanoma locations (left infraorbital and presternal) with low immune cells infiltration “excluded”

Figures 4

Graphics showing the differences in a) SUV_max values and b) ratio between SUV_max target lesion/ SUV_mean fat-tissue on [^99mTc]Tc-Tilmanocept SPECT/CT at 1-h between lesions in patients that presented with poor outcomes (in green) during the follow-up after the second [¹⁸F]FDG PET/CT scan and those that did not have disease recurrence or disease progression (in blue)