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

Jai Seo, Richard Tavaré, Lisa M. Mahakian, Matthew T. Silvestrini, Sarah Tam, Elizabeth S. Ingham, Felix B. Salazar, Alexander D Borowsky, Anna M. Wu, Katherine W. Ferrara

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Abstract

Purpose: Noninvasive and quantitative tracking of CD8+ T cells by PET has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cysdiabody, labeled with 64Cu, to assess the sensitivity of PET imaging of normal and diseased tissue. Experimental Design: Radiolabeling of an anti-CD8 cysdiabody (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/group studied with imaging and IHC 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/group studied with imaging and IHC 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. Conclusions: 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 preclinical evaluation.

Original languageEnglish (US)
Pages (from-to)4976-4987
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number20
DOIs
StatePublished - Oct 15 2018

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Immunotherapy
Cell Count
T-Lymphocytes
Neoplasms
Flow Cytometry
Lymphoid Tissue
Intravenous Administration
Hypertrophy
Adenocarcinoma
Breast
Research Design
Liver

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Seo, J., Tavaré, R., Mahakian, L. M., Silvestrini, M. T., Tam, S., Ingham, E. S., ... Ferrara, K. W. (2018). CD8+ T-cell density imaging with 64Cu-labeled cys-diabody informs immunotherapy protocols. Clinical Cancer Research, 24(20), 4976-4987. https://doi.org/10.1158/1078-0432.CCR-18-0261

CD8+ T-cell density imaging with 64Cu-labeled cys-diabody informs immunotherapy protocols. / Seo, Jai; Tavaré, Richard; Mahakian, Lisa M.; Silvestrini, Matthew T.; Tam, Sarah; Ingham, Elizabeth S.; Salazar, Felix B.; Borowsky, Alexander D; Wu, Anna M.; Ferrara, Katherine W.

In: Clinical Cancer Research, Vol. 24, No. 20, 15.10.2018, p. 4976-4987.

Research output: Contribution to journalArticle

Seo, J, Tavaré, R, Mahakian, LM, Silvestrini, MT, Tam, S, Ingham, ES, Salazar, FB, Borowsky, AD, Wu, AM & Ferrara, KW 2018, 'CD8+ T-cell density imaging with 64Cu-labeled cys-diabody informs immunotherapy protocols', Clinical Cancer Research, vol. 24, no. 20, pp. 4976-4987. https://doi.org/10.1158/1078-0432.CCR-18-0261
Seo, Jai ; Tavaré, Richard ; Mahakian, Lisa M. ; Silvestrini, Matthew T. ; Tam, Sarah ; Ingham, Elizabeth S. ; Salazar, Felix B. ; Borowsky, Alexander D ; Wu, Anna M. ; Ferrara, Katherine W. / CD8+ T-cell density imaging with 64Cu-labeled cys-diabody informs immunotherapy protocols. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 20. pp. 4976-4987.
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abstract = "Purpose: Noninvasive and quantitative tracking of CD8+ T cells by PET has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cysdiabody, labeled with 64Cu, to assess the sensitivity of PET imaging of normal and diseased tissue. Experimental Design: Radiolabeling of an anti-CD8 cysdiabody (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/group studied with imaging and IHC 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/group studied with imaging and IHC 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. Conclusions: 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 preclinical evaluation.",
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AU - Seo, Jai

AU - Tavaré, Richard

AU - Mahakian, Lisa M.

AU - Silvestrini, Matthew T.

AU - Tam, Sarah

AU - Ingham, Elizabeth S.

AU - Salazar, Felix B.

AU - Borowsky, Alexander D

AU - Wu, Anna M.

AU - Ferrara, Katherine W.

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N2 - Purpose: Noninvasive and quantitative tracking of CD8+ T cells by PET has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cysdiabody, labeled with 64Cu, to assess the sensitivity of PET imaging of normal and diseased tissue. Experimental Design: Radiolabeling of an anti-CD8 cysdiabody (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/group studied with imaging and IHC 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/group studied with imaging and IHC 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. Conclusions: 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 preclinical evaluation.

AB - Purpose: Noninvasive and quantitative tracking of CD8+ T cells by PET has emerged as a potential technique to gauge response to immunotherapy. We apply an anti-CD8 cysdiabody, labeled with 64Cu, to assess the sensitivity of PET imaging of normal and diseased tissue. Experimental Design: Radiolabeling of an anti-CD8 cysdiabody (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/group studied with imaging and IHC 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/group studied with imaging and IHC 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. Conclusions: 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 preclinical evaluation.

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