title: T-cell receptor gene therapy in human melanoma-bearing immune-deficient mice: human but not mouse T cells recapitulate outcome of clinical studies.
abstract: Adoptive cell therapy using T-cell receptor (TCR)-engineered T cells is a clinically feasible and promising approach to target tumors, but is currently faced with compromised antitumor efficacies in patients. Here, we extensively validated immune-deficient mice to facilitate further development of the therapeutic potential of TCR-engineered T cells. Treatment of human melanoma-bearing SCID or NSG mice with high doses of human T cells transduced with an hgp100/HLA-A2-specific TCR did not result in antitumor responses irrespective of chemotherapeutic preconditioning. Imaging of human green fluorescent protein-labeled T cells demonstrated significant T-cell accumulation in intratumoral vasculature directly upon T-cell transfer, which was followed by loss of T cells within 72 hr. Peripheral persistence of human T cells was highly compromised and appeared related to T-cell differentiation. On the contrary, adoptive transfer (AT) of relatively low numbers of hgp100/HLA-A2 TCR-transduced mouse T cells resulted in rapid clearance of large established human melanomas. Unexpectedly and in contrast to reported studies with chimeric antibody receptor-engineered T cells, antitumor activity and homeostatic expansion of T cells were independent of TCR transgene as evidenced in two SCID strains and using two different human melanoma cell lines. Interestingly, the xeno-reactive melanoma response of mouse T cells appeared to be dictated by CD4(+) tumor-infiltrating lymphocytes and did not require in vitro T-cell activation, retroviral gene transfer, or subcutaneous interleukin-2 support. Taken together, AT of human but not mouse T cells in human melanoma-bearing immune-deficient mice is in close accordance with clinical studies.
authors.affiliation: Laboratory of Experimental Tumor Immunology, Department of Medical Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center , 3075 EA Rotterdam, The Netherlands.
authors.forename: Trudy
authors.initials: T
authors.lastname: Straetemans
authors.forename: Miriam
authors.initials: M
authors.lastname: Coccoris
authors.forename: Cor
authors.initials: C
authors.lastname: Berrevoets
authors.forename: Elike
authors.initials: E
authors.lastname: Treffers-Westerlaken
authors.forename: Csilla E V
authors.initials: CE
authors.lastname: Scholten
authors.forename: Debby
authors.initials: D
authors.lastname: Schipper
authors.forename: Timo L M
authors.initials: TL
authors.lastname: Ten Hagen
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D058951:gp100 Melanoma Antigen / Q000235:genetics* / Q000276:immunology
chemical_list: D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen; D049452:Green Fluorescent Proteins