title: Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice.
abstract: OBJECTIVE
  We investigated the feasibility of delivering the proinflammatory cytokine interleukin (IL)-12 into tumor using T cells genetically engineered to express a chimeric antigen receptor (CAR) against the VEGF receptor-2 (VEGFR-2).
  
  
  METHODS
  Two different strains of mice bearing five different established subcutaneous tumors were treated with syngeneic T cells cotransduced with an anti-VEGFR-2 CAR and a constitutively expressed single-chain murine IL-12 or an inducible IL-12 gene after host lymphodepletion. Tumor regression, survival of mice, and persistence of the transferred cells were evaluated.
  
  
  RESULTS
  Adoptive transfer of syngeneic T cells cotransduced with an anti-VEGFR-2 CAR and a constitutively expressing single-chain IL-12 resulted in the regression of five different established tumors of different histologies without the need for IL-2 administration. T cells transduced with either anti-VEGFR-2 CAR or single-chain IL-12 alone did not alter the tumor growth indicating that both of them had to be expressed in the same cell to mediate tumor regression. Anti-VEGFR-2 CAR and IL-12-cotransduced T cells infiltrated the tumors, expanded, and persisted for prolonged periods. The antitumor effect did not require the presence of host T and B cells but was dependent on host IL-12R-expressing cells. The anti-VEGFR-2 CAR changed the immunosuppressive tumor environment by altering/reducing both the systemic and the intratumoral CD11b(+)Gr1(+) myeloid suppressor cell subsets that expressed VEGFR-2.
  
  
  CONCLUSIONS
  These results suggest that targeted delivery of IL-12 into the tumor environment with T cells redirected against VEGFR-2 is a promising approach for treating patients with a variety of solid tumor types.
authors.affiliation: National Cancer Institute, Clinical Research Center, Bethesda, MD, USA.
authors.forename: Dhanalakshmi
authors.initials: D
authors.lastname: Chinnasamy
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Sid P
authors.initials: SP
authors.lastname: Kerkar
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D018664:Interleukin-12; D040301:Vascular Endothelial Growth Factor Receptor-2