CD8+ T-cell density imaging with 64Cu-labeled cys-diabody informs immunotherapy protocols

Purpose: Noninvasive and quantitative tracking of CD8+ T-cells by positron emission tomography (PET) has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cys-diabody, labeled with 64Cu, to assess the sensitivity of PET imaging of normal and diseased tissue. Experimental Design Radiolabeling of an anti-CD8 cys-diabody (169cDb) with 64Cu was developed. The accumulation of 64Cu-169cDb was evaluated with PET/CT imaging (0, 5, and 24 hours) and biodistribution (24 hours) in wild-type mouse strains (n = 8 per group studied with imaging and immunohistochemistry or flow cytometry) after intravenous administration. Tumor-infiltrating CD8+ T-cells in tumor bearing mice treated with CpG and aPD-1 were quantified and mapped (n = 6-8 per group studied with imaging and immunohistochemistry or flow cytometry). Results We demonstrate the ability of immunoPET to detect small differences in CD8+ T-cell distribution between mouse strains and across lymphoid tissues, including the intestinal tract of normal mice. In FVB mice bearing a syngeneic HER2-driven model of mammary adenocarcinoma (NDL), 64Cu-169cDb PET imaging accurately visualized and quantified changes in tumor-infiltrating CD8+ T-cells in response to immunotherapy. A reduction in the circulation time of the imaging probe followed the development of treatment-related liver and splenic hypertrophy and provided an indication of off-target effects associated with immunotherapy protocols. Conclusion 64Cu-169cDb imaging can spatially map the distribution of CD8+ T-cells in normal organs and tumors. ImmunoPET imaging of tumor-infiltrating cytotoxic CD8+ T-cells detected changes in T-cell density resulting from adjuvant and checkpoint immunotherapy protocols in our pre-clinical evaluation.

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