Monitoring the efficacy of adoptively transferred prostate cancer-targeted human T lymphocytes with PET and bioluminescence imaging.
Noninvasive imaging technologies have the potential to enhance the monitoring and improvement of adoptive therapy with tumor-targeted T lymphocytes. We established an imaging methodology for the assessment of spatial and temporal distributions of adoptively transferred genetically modified human T cells in vivo for treatment monitoring and prediction of tumor response in a systemic prostate cancer model.


METHODS
RM1 murine prostate carcinoma tumors transduced with human prostate-specific membrane antigen (hPSMA) and a Renilla luciferase reporter gene were established in SCID/beige mice. Human T lymphocytes were transduced with chimeric antigen receptors (CAR) specific for either hPSMA or human carcinoembryonic antigen (hCEA) and with a fusion reporter gene for herpes simplex virus type 1 thymidine kinase (HSV1tk) and green fluorescent protein, with or without click beetle red luciferase. The localization of adoptively transferred T cells in tumor-bearing mice was monitored with 2'-(18)F-fluoro-2'-deoxy-1-beta-d-arabinofuranosyl-5-ethyluracil ((18)F-FEAU) small-animal PET and bioluminescence imaging (BLI).


RESULTS
Cotransduction of CAR-expressing T cells with the reporter gene did not affect CAR-mediated cytotoxicity. BLI of Renilla and click beetle red luciferase expression enabled concurrent imaging of adoptively transferred T cells and systemic tumors in the same animal. hPSMA-specific T lymphocytes persisted longer than control hCEA-targeted T cells in lung hPSMA-positive tumors, as indicated by both PET and BLI. Precise quantification of T-cell distributions at tumor sites by PET revealed that delayed tumor progression was positively correlated with the levels of (18)F-FEAU accumulation in tumor foci in treated animals.


CONCLUSIONS
Quantitative noninvasive monitoring of genetically engineered human T lymphocytes by PET provides spatial and temporal information on T-cell trafficking and persistence. PET may be useful for predicting tumor response and for guiding adoptive T-cell therapy.
Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Konstantin
K
Dobrenkov
Malgorzata
M
Olszewska
Yury
Y
Likar
Larissa
L
Shenker
Gertrude
G
Gunset
Shangde
S
Cai
Nagavarakishore
N
Pillarsetty
Hedvig
H
Hricak
Michel
M
Sadelain
Vladimir
V
Ponomarev
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D017930:Genes, Reporter; D043425:Glutamate Carboxypeptidase II / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D051379:Mice; D016513:Mice, SCID; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000628:therapy*; D019275:Radiopharmaceuticals; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D015898:Tomography Scanners, X-Ray Computed; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
C508411:2'-fluoro-2'-deoxy-5-fluoroethyl-1-beta-D-arabinofuranosyl uracil; D000954:Antigens, Surface; D019275:Radiopharmaceuticals; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; D001086:Arabinofuranosyluracil; D013937:Thymidine Kinase; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II