학술논문
Whole-body CD8+T cell visualization before and during cancer immunotherapy: a phase 1/2 trial
Document Type
Article
Author
Kist de Ruijter, Laura; van de Donk, Pim P.; Hooiveld-Noeken, Jahlisa S.; Giesen, Danique; Elias, Sjoerd G.; Lub-de Hooge, Marjolijn N.; Oosting, Sjoukje F.; Jalving, Mathilde; Timens, Wim; Brouwers, Adrienne H.; Kwee, Thomas C.; Gietema, Jourik A.; Fehrmann, Rudolf S. N.; Fine, Bernard M.; Sanabria Bohórquez, Sandra M.; Yadav, Mahesh; Koeppen, Hartmut; Jing, Jing; Guelman, Sebastian; Lin, Mark T.; Mamounas, Michael J.; Eastham, Jeffrey Ryan; Kimes, Patrick K.; Williams, Simon P.; Ungewickell, Alexander; de Groot, Derk J. A.; de Vries, Elisabeth G. E.
Source
Nature Medicine; 20220101, Issue: Preprints p1-10, 10p
Subject
Language
ISSN
10788956; 1546170X
Abstract
Immune checkpoint inhibitors (ICIs), by reinvigorating CD8+T cell mediated immunity, have revolutionized cancer therapy. Yet, the systemic CD8+T cell distribution, a potential biomarker of ICI response, remains poorly characterized. We assessed safety, imaging dose and timing, pharmacokinetics and immunogenicity of zirconium-89-labeled, CD8-specific, one-armed antibody positron emission tomography tracer 89ZED88082A in patients with solid tumors before and ~30 days after starting ICI therapy (NCT04029181). No tracer-related side effects occurred. Positron emission tomography imaging with 10 mg antibody revealed 89ZED88082A uptake in normal lymphoid tissues, and tumor lesions across the body varying within and between patients two days after tracer injection (n= 38, median patient maximum standard uptake value (SUVmax) 5.2, IQI 4.0–7.4). Higher SUVmaxwas associated with mismatch repair deficiency and longer overall survival. Uptake was higher in lesions with stromal/inflamed than desert immunophenotype. Tissue radioactivity was localized to areas with immunohistochemically confirmed CD8 expression. Re-imaging patients on treatment showed no change in average (geometric mean) tumor tracer uptake compared to baseline, but individual lesions showed diverse changes independent of tumor response. The imaging data suggest enormous heterogeneity in CD8+T cell distribution and pharmacodynamics within and between patients. In conclusion, 89ZED88082A can characterize the complex dynamics of CD8+T cells in the context of ICIs, and may inform immunotherapeutic treatments.