Whole-body CD8+ T cell visualization before and during cancer immunotherapy: a phase 1/2 trial

• Published in: Nature medicine Vol. 28; no. 12; pp. 2601 - 2610
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2022; Nature Publishing Group
• Subjects: 692/699/67/1059/2325; 692/699/67/2321; 692/699/67/580; Antibodies; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer immunotherapy; Cancer Research; CD8 antigen; CD8-Positive T-Lymphocytes; Emissions; Heterogeneity; Humans; Immune checkpoint inhibitors; Immune response; Immune system; Immunoconjugates; Immunogenicity; Immunotherapy; Immunotherapy - adverse effects; Immunotherapy - methods; Infectious Diseases; Inflammation; Lesions; Lymphocytes; Lymphocytes T; Lymphoid tissue; Medical imaging; Metabolic Diseases; Mismatch repair; Molecular Medicine; Neoplasms - diagnostic imaging; Neoplasms - drug therapy; Neurosciences; Pharmacodynamics; Pharmacokinetics; Pharmacology; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Radioactivity; Side effects; Solid tumors; Tomography; Tumors; Visualization; Zirconium; Zirconium isotopes
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-022-02084-8

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 89 ZED88082A 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 89 ZED88082A 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 (SUV max ) 5.2, IQI 4.0–7.4). Higher SUV max was 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, 89 ZED88082A can characterize the complex dynamics of CD8 + T cells in the context of ICIs, and may inform immunotherapeutic treatments. A CD8-specific, one-armed antibody positron emission tomography tracer enables the visualization of the immune response in patients with solid tumors before and after starting immunotherapy.