In Vivo PET Tracking of ⁸⁹Zr-Labeled Vγ9Vδ2 T Cells to Mouse Xenograft Breast Tumors Activated with Liposomal Alendronate

TY - JOUR

T1 - In Vivo PET Tracking of 89Zr-Labeled Vγ9Vδ2 T Cells to Mouse Xenograft Breast Tumors Activated with Liposomal Alendronate

AU - Man, Francis

AU - Lim, Lindsay

AU - Volpe, Alessia

AU - Gabizon, Alberto

AU - Shmeeda, Hilary

AU - Draper, Benjamin

AU - Parente-Pereira, Ana C.

AU - Maher, John

AU - Blower, Philip J.

AU - Fruhwirth, Gilbert O.

AU - T.M. de Rosales, Rafael

N1 - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2019/1/2

Y1 - 2019/1/2

N2 - Gammadelta T (γδ-T) cells are strong candidates for adoptive immunotherapy in oncology due to their cytotoxicity, ease of expansion and favorable safety profile. The development of γδ-T-cell therapies would benefit from non-invasive cell tracking methods and increased targeting to tumor sites. Here we report the use of [89Zr]Zr(oxinate)4 to track Vγ9Vδ2 T cells in vivo by positron emission tomography (PET). In vitro, we showed that 89Zr-labeled Vγ9Vδ2 T cells retained their viability, proliferative capacity and anti-cancer cytotoxicity with minimal DNA damage for amounts of 89Zr ≤20 mBq/cell. Using a mouse xenograft model of human breast cancer, 89Zr-labeled γδ T cells were tracked by PET imaging over 1 week. To increase tumor antigen expression, the mice were pre-treated with PEGylated liposomal alendronate. Liposomal alendronate, but not placebo liposomes or non-liposomal alendronate, significantly increased the 89Zr signal in the tumors, suggesting increased homing of γδ-T cells to the tumors. γδ-T-cell trafficking to tumors occurred within 48 h of administration. The presence of γδ-T cells in tumors, liver and spleen was confirmed by histology. Our results demonstrate the suitability of [89Zr]Zr(oxinate)4 as a cell labeling agent for therapeutic T cells and the potential benefits of liposomal bisphosphonate treatment before γδ-T cell administration.

AB - Gammadelta T (γδ-T) cells are strong candidates for adoptive immunotherapy in oncology due to their cytotoxicity, ease of expansion and favorable safety profile. The development of γδ-T-cell therapies would benefit from non-invasive cell tracking methods and increased targeting to tumor sites. Here we report the use of [89Zr]Zr(oxinate)4 to track Vγ9Vδ2 T cells in vivo by positron emission tomography (PET). In vitro, we showed that 89Zr-labeled Vγ9Vδ2 T cells retained their viability, proliferative capacity and anti-cancer cytotoxicity with minimal DNA damage for amounts of 89Zr ≤20 mBq/cell. Using a mouse xenograft model of human breast cancer, 89Zr-labeled γδ T cells were tracked by PET imaging over 1 week. To increase tumor antigen expression, the mice were pre-treated with PEGylated liposomal alendronate. Liposomal alendronate, but not placebo liposomes or non-liposomal alendronate, significantly increased the 89Zr signal in the tumors, suggesting increased homing of γδ-T cells to the tumors. γδ-T-cell trafficking to tumors occurred within 48 h of administration. The presence of γδ-T cells in tumors, liver and spleen was confirmed by histology. Our results demonstrate the suitability of [89Zr]Zr(oxinate)4 as a cell labeling agent for therapeutic T cells and the potential benefits of liposomal bisphosphonate treatment before γδ-T cell administration.

KW - bisphosphonate

KW - cancer immunotherapy

KW - cell immunotherapy

KW - cell tracking

KW - liposome

KW - nanomedicine

KW - PET

KW - zirconium-89

UR - http://www.scopus.com/inward/record.url?scp=85056272403&partnerID=8YFLogxK

U2 - 10.1016/j.ymthe.2018.10.006

DO - 10.1016/j.ymthe.2018.10.006

M3 - Article

C2 - 30429045

AN - SCOPUS:85056272403

SN - 1525-0016

VL - 27

SP - 219

EP - 229

JO - Molecular Therapy

JF - Molecular Therapy

IS - 1

ER -