Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice

Dhanalakshmi Chinnasamy, Zhiya Yu, Sid P. Kerkar, Ling Zhang, Richard A. Morgan, Nicholas P. Restifo, Steven A. Rosenberg

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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). Experimental Design: 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.

Original languageEnglish (US)
Pages (from-to)1672-1683
Number of pages12
JournalClinical Cancer Research
Volume18
Issue number6
DOIs
StatePublished - Mar 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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