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

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.

• Authors: Dhanalakshmi Chinnasamy, Zhiya Yu, Sid P Kerkar, Ling Zhang, Richard A Morgan, Nicholas P Restifo, Steven A Rosenberg
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 6 Pg. 1672-83 (Mar 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22291136 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Receptors, Antigen, T-Cell
• Recombinant Proteins
• Interleukin-12
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Animals
• Feasibility Studies
• Female
• Humans
• Immunotherapy, Adoptive (methods)
• Interleukin-12 (administration & dosage, genetics, metabolism)
• Melanoma, Experimental (therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neoplasms (blood supply, therapy)
• Receptors, Antigen, T-Cell (immunology)
• Recombinant Proteins (metabolism)
• T-Lymphocytes (immunology)
• Transduction, Genetic
• Vascular Endothelial Growth Factor Receptor-2 (immunology)