Available Technology

Transplant and Autoimmune Therapy Using T-Cells Expressing Programmed Death Ligand-1 (PD-L1)

Transplant complications (graft rejection and graft-versus-host disease) and autoimmune diseases are primarily caused by T cell immune responses against normal host tissue or transplanted tissues. These disorders can lead to serious complications and may be chronic, debilitating, and fatal. Current treatment for these disorders is oftentimes not effective, and is typically associated with significant side effects, including global immune suppression, which increases the rate of infection and cancer. Hence, there is a need for new technologies to more specifically suppress the immune system for treatment of these diseases.

Programmed death (PD) ligand 1 (PD-L1) is an immune molecule present on regulatory T cells (Tregs), other suppressor cell populations, and tumor cells; the function of PD-L1 is to suppress the function of pathogenic T cells that express the PD1 receptor. Therefore, it has been hypothesized that the transfer of T cells that are enriched for PD-L1 expression might represent an effective method to suppress autoimmunity or transplant complications. Adoptive T cell therapy using Tregs is one such approach; however, this approach is limited due to the relative rarity of Tregs and their tendency to possess differentiation plasticity towards pathogenic T cell subsets such as the Th17 subset. Ex vivo co-stimulated and expanded effector T cells can be generated in sufficient numbers for cell therapy; however, such cells are not enriched for PD-L1 expression.

The current technology overcomes these limitations through transduction of co-stimulated T cells with a lentiviral expression vector that dictates T cell expression of PD-L1. In this method, the co-stimulated T cells acquire the immunosuppressant characteristics of Treg cells. The PD-L1 gene expression construct co-expresses a cell surface molecule (i.e., CD19 or CD34) that allows enrichment of the gene-modified T cells to high purity. Also the construct co-expresses another gene, TMPK, which acts as a safety cell fate switch because the TMPK can specifically activate the cytotoxic prodrug, AZT. By incorporation of this TMPK/AZT cell fate safety switch, the current technology will allow for PD-L1 therapeutic delivery, with subsequent elimination of the therapeutic cells in the event of toxicity.

Patent Abstract: 

Transplant complications (graft rejection and graft-versus-host disease) and autoimmune diseases are primarily caused by T cell immune responses against normal host tissue or transplanted tissues. These disorders can lead to serious complications and may be chronic, debilitating, and fatal. Current treatment for these disorders is oftentimes not effective, and is typically associated with significant side effects, including global immune suppression, which increases the rate of infection and cancer. Hence, there is a need for new technologies to more specifically suppress the immune system for treatment of these diseases.

Programmed death (PD) ligand 1 (PD-L1) is an immune molecule present on regulatory T cells (Tregs), other suppressor cell populations, and tumor cells; the function of PD-L1 is to suppress the function of pathogenic T cells that express the PD1 receptor. Therefore, it has been hypothesized that the transfer of T cells that are enriched for PD-L1 expression might represent an effective method to suppress autoimmunity or transplant complications. Adoptive T cell therapy using Tregs is one such approach; however, this approach is limited due to the relative rarity of Tregs and their tendency to possess differentiation plasticity towards pathogenic T cell subsets such as the Th17 subset. Ex vivo co-stimulated and expanded effector T cells can be generated in sufficient numbers for cell therapy; however, such cells are not enriched for PD-L1 expression.

The current technology overcomes these limitations through transduction of co-stimulated T cells with a lentiviral expression vector that dictates T cell expression of PD-L1. In this method, the co-stimulated T cells acquire the immunosuppressant characteristics of Treg cells. The PD-L1 gene expression construct co-expresses a cell surface molecule (i.e., CD19 or CD34) that allows enrichment of the gene-modified T cells to high purity. Also the construct co-expresses another gene, TMPK, which acts as a safety cell fate switch because the TMPK can specifically activate the cytotoxic prodrug, AZT. By incorporation of this TMPK/AZT cell fate safety switch, the current technology will allow for PD-L1 therapeutic delivery, with subsequent elimination of the therapeutic cells in the event of toxicity.

Benefits 
Relative to other proposed cell therapies such as Treg therapy, co-stimulated T cells expressing the gene construct can be manufactured in clinically relevant numbers, possess a defined mechanism of action, and can be specifically modulated (eliminated) in vivo. -The proposed immuno-gene therapy would prove advantageous to current immune suppressive therapies, which cause many side effects.
Inventors: 

Daniel Fowler

Patent Number: 
61261,081 PCT Application No. PCTUS2010056450 U
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