1. ¹Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Methodist Hospital, Houston, Texas, USA
2. ²Department of Pathology, Texas Children's Hospital, Houston, Texas, USA
3. ³Breast Cancer Center, Baylor College of Medicine, Houston, Texas, USA
4. ⁴Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Hematology/Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA

Correspondence: Patricia Yotnda, Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Room N1120, Houston, Texas 77030, USA. E-mail: pyotnda@bcm.tmc.edu

Received 18 July 2007; Accepted 28 November 2007; Published online 29 January 2008.

Abstract

Hypoxia occurs in many tumors and reduces the effectiveness of radio- and chemotherapy. Hypoxia also impedes immune responses to tumors, reducing T lymphocyte production of cytokines such as interleukin-2 (IL-2) and interferon gamma, as well as the survival and proliferation of these cells. We constructed a lentiviral vector encoding a bidirectional hypoxia-inducible responsive element (HRE) derived from human vascular endothelial growth factor, which drives the hIL-2 gene and a marker gene. We used a model of human B cell lymphoma to show that tumor-specific T cells modified with this vector upregulate hIL-2 expression when oxygen tension is low in vitro and in vivo. The consequence of this effect is to increase T-cell survival and proliferation whilst sustaining effector function, even in O₂ concentrations as low as 1%. The phenotype of the transduced cells is unchanged, as is their ability to migrate to tumor. HRE-IL-2-modified cytotoxic T lymphocytes (CTLs) produce faster and more complete tumor regression than parental CTLs and increase overall survival. Hypoxia-resistant T cells may thus be of value in the treatment of human tumors in which areas of hypoxia may otherwise account for resistance to this therapeutic strategy.