Tumor-targeted, systemic delivery of therapeutic viral vectors using hitchhiking on antigen-specific T cells.
Antigen-specific T cells circulate freely and accumulate specifically at sites of antigen expression. To enhance the survival and targeting of systemically delivered viral vectors, we exploited the observation that retroviral particles adhere nonspecifically, or 'hitchhike,' to the surface of T cells. Adoptive transfer of antigen-specific T cells, loaded with viruses encoding interleukin (IL)-12 or Herpes Simplex Virus thymidine kinase (HSVtk), cured established metastatic disease where adoptive T-cell transfer alone was not effective. Productive hand off correlated with local heparanase expression either from malignant tumor cells and/or as a result of T-cell activation by antigen, providing high levels of selectivity for viral transfer to metastatic tumors in vivo. Protection, concentration and targeting of viruses by adsorption to cell carriers represent a new technique for systemic delivery of vectors, in fully immunocompetent hosts, for a variety of diseases in which delivery of genes may be therapeutically beneficial.
Cole
Caroline
C
Molecular Medicine Program, Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota 55905, USA.
Qiao
Jian
J
Kottke
Timothy
T
Diaz
Rosa Maria
RM
Ahmed
Atique
A
Sanchez-Perez
Luis
L
Brunn
Gregory
G
Thompson
Jill
J
Chester
John
J
Vile
Richard G
RG
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D009928:Organ Specificity; D012190:Retroviridae / Q000235:genetics / Q000502:physiology; D012680:Sensitivity and Specificity