title: T-cell receptor gene therapy of established tumors in a murine melanoma model.
abstract: Adoptive cell transfer therapy using tumor-infiltrating lymphocytes for patients with metastatic melanoma has demonstrated significant objective response rates. One major limitation of these current therapies is the frequent inability to isolate tumor-reactive lymphocytes for treatment. Genetic engineering of peripheral blood lymphocytes with retroviral vectors encoding tumor antigen-specific T-cell receptors (TCRs) bypasses this restriction. To evaluate the efficacy of TCR gene therapy, a murine treatment model was developed. A retroviral vector was constructed encoding the pmel-1 TCR genes targeting the B16 melanoma antigen, gp100. Transduction of C57BL/6 lymphocytes resulted in efficient pmel-1 TCR expression. Lymphocytes transduced with this retrovirus specifically recognized gp100-pulsed target cells as measured by interferon-gamma secretion assays. Upon transfer into B16 tumor-bearing mice, the genetically engineered lymphocytes significantly slowed tumor development. The effectiveness of tumor treatment was directly correlated with the number of TCR-engineered T cells administered. These results demonstrated that TCR gene therapy targeting a native tumor antigen significantly delayed the growth of established tumors. When C57BL/6 lymphocytes were added to antigen-reactive pmel-1 T cells, a reduction in the ability of pmel-1 T cell to treat B16 melanomas was seen, suggesting that untransduced cells may be deleterious to TCR gene therapy. This model may be a powerful tool for evaluating future TCR gene transfer-based strategies.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Abad
authors.forename: Claudia
authors.initials: C
authors.lastname: Wrzensinski
authors.forename: Willem
authors.initials: W
authors.lastname: Overwijk
authors.forename: Moniek A
authors.initials: MA
authors.lastname: De Witte
authors.forename: Annelies
authors.initials: A
authors.lastname: Jorritsma
authors.forename: Cary
authors.initials: C
authors.lastname: Hsu
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.forename: Cyrille J
authors.initials: CJ
authors.lastname: Cohen
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014162:Transfection; D058951:gp100 Melanoma Antigen
chemical_list: D008562:Membrane Glycoproteins; C548642:Pmel protein, mouse; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma