[HTML][HTML] A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus

S Koh, N Shimasaki, R Suwanarusk, ZZ Ho… - … Therapy-Nucleic Acids, 2013 - cell.com
S Koh, N Shimasaki, R Suwanarusk, ZZ Ho, A Chia, N Banu, SW Howland, ASM Ong…
Molecular Therapy-Nucleic Acids, 2013cell.com
Hepatocellular carcinoma (HCC) cells often have hepatitis B virus (HBV)-DNA integration
and can be targeted by HBV-specific T cells. The use of viral vectors to introduce exogenous
HBV-specific T-cell receptors (TCR) on T cells to redirect their specificity is complex and
expensive to implement in clinical trials. Moreover, it raises safety concerns related to
insertional mutagenesis and potential toxicity of long-lived HBV-specific T cells in patients
with persistent infection. To develop a more practical and safer approach to cell therapy of …
Hepatocellular carcinoma (HCC) cells often have hepatitis B virus (HBV)-DNA integration and can be targeted by HBV-specific T cells. The use of viral vectors to introduce exogenous HBV-specific T-cell receptors (TCR) on T cells to redirect their specificity is complex and expensive to implement in clinical trials. Moreover, it raises safety concerns related to insertional mutagenesis and potential toxicity of long-lived HBV-specific T cells in patients with persistent infection. To develop a more practical and safer approach to cell therapy of HCC, we used electroporation of mRNA encoding anti-HBV TCR. Approximately 80% of CD8+ T cells expressed functional HBV TCR 24 hours postelectroporation, an expression efficiency much higher than that obtained by retroviral transduction (~18%). Antigen-specific cytokine production of electroporated T cells was efficient within 72-hour period, after which the redirected T cells lost their HBV-specific function. Despite this transient functionality, the TCR-electroporated T cells efficiently prevented tumor seeding and suppressed the growth of established tumors in a xenograft model of HCC. Finally, we established a method for large-scale TCR mRNA electroporation that yielded large numbers of highly functional clinical-grade anti-HBV T cells. This method represents a practical approach to cell therapy of HCC and its inherently self-limiting toxicity suggests potential for application in other HBV-related pathologies.
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