Generating potent Th1/Tc1 T cell adoptive immunotherapy doses using human IL-12: Harnessing the immunomodulatory potential of IL-12 without the in vivo-associated toxicity.
Interleukin (IL)-12 is a cytokine originally identified from medium conditioned by an Epstein-Barr virus transformed cell line. IL-12 has been shown to increase IFN-gamma secretion from NK and T cells, significantly enhance cytolytic activity in both of these cell types, and promote the development of Th1/Tc1 immune responses. These properties make IL-12 an attractive candidate for the development of various clinical protocols ranging from the treatment of viral diseases to tumor immunotherapy. The initial attempts to use IL-12 in the treatment of tumors demonstrated toxicity at potentially therapeutic doses. To circumvent the toxicity associated with IL-12 administration, the authors have developed an adoptive immunotherapy protocol that uses IL-12 for a brief period during ex vivo T cell activation. They show that IL-12 conditioning may be achieved without altering the growth characteristics of the in vitro expanding T cells. T cells generated in the presence of IL-12 show a shift to a Th1/Tc1 dominant phenotype. The resultant cells are more potent killers in vitro and in vivo as assessed by CTL assays and tumor regression. The ability to harness the potent Th1/Tc1 generating potential of IL-12 while avoiding its associated in vivo toxicity has the potential to benefit a large number of clinical trial protocols using adoptive transfer of T cells specific for tumors, viruses, or intracellular pathogens.
Emtage
Peter C R
PC
Division of Hematology-Oncology, Harvard Medical School, beth Israel Deaconesss Medical Center, Boston, Massachusetts, USA.
Clarke
Danielle
D
Gonzalo-Daganzo
Rosa
R
Junghans
Richard P
RP
Gonzalo-Dagonzo
Rosa
R
D019264:Adoptive Transfer; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018664:Interleukin-12 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000502:physiology; D014407:Tumor Cells, Cultured
D018664:Interleukin-12