Hepatitis C virus (HCV) is a major cause of acute hepatitis and chronic liver disease, including cirrhosis and hepatocellular carcinoma. Globally, an estimated 170 million persons are chronically infected with HCV, and 3 to 4 million persons are newly infected each year. The standard anti-viral therapy for HCV infection is interferon in combination with ribavarin, however, many patients fail to respond to this therapy. Clearly, more effective therapies for HCV infected patients are necessary.

There is evidence that the immune system can mediate clearance of HCV infection. Despite the fact that HCV reactive T ceils have been isolated which recognize more than fifty antigenic HCV epitopes, a majority of patients exposed to HCV develop chronic infection. The development of chronic infection is influenced, at least in part, by the tendency of the virus to rapidly mutate, leading to antigen escape variants. Moreover, it has been speculated that both low T cell avidity and an ineffective cytokine profile generated in response to infection may contribute to the development of chronic infection rather than viral clearance.

Dr. Michael Nishimura and colleagues at the University of Chicago have previously shown that HCV-positive liver transplant patients that received HLA-disparate liver allograffs have HCV-reactive T cells of host origin that are restricted by the donor HLA molecules. Initial studies of these T cells showed that they have relatively high affinity for their HCV epitope ligand. This work was extended, and the inventors subsequently cloned the T cell receptors from the HCV epitope reactive T cells and developed a vector to deliver the T cell receptor coding sequences to cells, e.g., Peripheral Blood Lymphocyte (PBL)-derived T cells or hematopoietic stem cells, ex vivo. The engineered autologous cells are returned to the HCV-infected patient to effect treatment of acute or chronic HCV infection or HCV-related malignancies. Unlike vaccine and peptide/MHC tetramer strategies, this approach does not rely on the patient's T cell receptor repertoire and/or precursor frequency. Moreover,  cells which natively express an HCV epitope-reactive T cell receptor can be engineered to express a second, recombinant T cell receptor which is reactive to a different HCV epitope, thereby diminishing the impact of HCV escape variants on chronic infection.

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