CD3 limits the efficacy of TCR gene therapy in vivo

M Ahmadi, JW King, SA Xue, C Voisine… - Blood, The Journal …, 2011 - ashpublications.org
M Ahmadi, JW King, SA Xue, C Voisine, A Holler, GP Wright, J Waxman, E Morris, HJ Stauss
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface
expression of the introduced TCR α/β heterodimer. We tested whether endogenous CD3
chains are rate-limiting for TCR expression and antigen-specific T-cell function. We show
that co-transfer of CD3 and TCR genes into primary murine T cells enhanced TCR
expression and antigen-specific T-cell function in vitro. Peptide titration experiments showed
that T cells expressing introduced CD3 and TCR genes recognized lower concentration of …
Abstract
The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR α/β heterodimer. We tested whether endogenous CD3 chains are rate-limiting for TCR expression and antigen-specific T-cell function. We show that co-transfer of CD3 and TCR genes into primary murine T cells enhanced TCR expression and antigen-specific T-cell function in vitro. Peptide titration experiments showed that T cells expressing introduced CD3 and TCR genes recognized lower concentration of antigen than T cells expressing TCR only. In vivo imaging revealed that TCR+CD3 gene modified T cells infiltrated tumors faster and in larger numbers, which resulted in more rapid tumor elimination compared with T cells modified by TCR only. After tumor clearance, TCR+CD3 engineered T cells persisted in larger numbers than TCR-only T cells and mounted a more effective memory response when rechallenged with antigen. The data demonstrate that provision of additional CD3 molecules is an effective strategy to enhance the avidity, anti-tumor activity and functional memory formation of TCR gene modified T cells in vivo.
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