Engineering human tumor-specific cytotoxic T cells to function in a hypoxic environment

Hypoxia occurs in many tumors and reduces the effectiveness of radio- (a)nd 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- (i)nducible 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 hIL2 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 O-2 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 (TLs) 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.