Whole-body CD8+ T cell visualization before and during cancer immunotherapy: a phase 1/2 trial
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.
(2022) Nature Medicine, volume 28, issue 12, pp. 2601 - 2610
(Article)
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
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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 SUVmax 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, 89ZED88082A can characterize the complex dynamics of CD8+ T cells in the context of ICIs, and may inform immunotherapeutic treatments.
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Keywords: General Biochemistry,Genetics and Molecular Biology
ISSN: 1078-8956
Publisher: Nature Publishing Group
Note: Funding Information: E.G.E.V. reports funding paid to the institution for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, CytomX, Crescendo Biologics, G1 Therapeutics, GE Healthcare, Genentech, Regeneron, Roche, Servier, Synthon; fees paid to the institution for membership of the advisory board from Daiichi Sankyo, NSABP and Crescendo Biologics. S.F.O. reports research grants from Novartis, Celldex Therapeutics paid to the institution. W.T. reports fees paid to the institution for membership advisory boards from Merck Sharp Dohme and Bristol-Myers-Squibb. M.J. reports fees paid to the institution for membership of the advisory board from BMS, Merck, Novartis, Sanofi, AstraZeneca. J.A.G. reports research grants from Roche, AbbVie, Siemens, paid to the institution. S.M.S.B., M.Y., H.K., J.J., S.G., M.T.L., M.J.M., J.R.E., P.K.K., S.P.W. and A.U. are employees of Genentech Inc., member of the Roche group; M.Y., S.G., M.J.M., S.P.W. and A.U. are also stockholders of Genentech, Inc/Roche. B.M.F. was employee of Genentech, Inc. and stockholder of Roche at time of work described; currently employee and stockholder of Gilead Sciences, Inc. The other authors declare no competing interests. Funding Information: We thank R. Boellaard for assistance and support with PET analyses and L. Pot for clinical tracer production coordination. This study was funded by the Dutch Cancer Society grant POINTING (grant number 10034), PPP-allowance of the Dutch Ministry of Economic Affairs and Climate Policy and a research grant from Genentech, all made available to the University Medical Center Groningen. Publisher Copyright: © 2022, The Author(s).
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