Work

Selective T-Cell Immunotherapy for B-Cell Lymphoma Under Hypoxia

Year: 2009

Type: article

Abstract: Many tumors harbor chronic and intermittent hypoxic cellular niches giving a survival advantage to malignant cells including cancer stem cells. To achieve a successful immunotherapeutic response, T cells must overcome physiological challenges specific to the tumor microenvironment such as hypoxia. To exploit the hypoxic tumor microenvironment, we introduce a new approach that exploits hypoxia as a condition for T-cell activation. In addition, this approach may be used to limit off-target effects to normal cells expressing antigen under normoxia. We demonstrate that a chimeric antigen receptor (CAR), which is specific for CD19, expressed on malignant and normal B cells, can be conditionally expressed in a strictly oxygen-sensitive manner. Using the Sleeping Beauty transposon/transposase system, we can achieve stable, persistent CAR transgene expression from DNA plasmids without the expense and complexity of retroviral production. Cell surface expression of our CAR is high at 1% O2 and not detectable at 20% O2. This oxygen-sensitive CAR is designed to deactivate when T cells circulate out of hypoxic tumor microenvironments to minimize deleterious off-target effects in vivo. When supplemented with one or more survival factors and/or homing receptors, this approach to CAR expression has the advantage of transforming hypoxia from an adverse factor to a T-cell triggering mechanism. This is expected to be of broad interest as investigators implement T-cell immunotherapy to eliminate tumors from the hypoxic niche as well as develop approaches that limit T-cell targeting within desired microenvironments thereby decreasing the possibility of inadvertent targeting of normal tissues.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2008.12.218