CD3 limits the efficacy of TCR gene therapy in vivo

Ahmadi, M; King, J W; Xue, S A; Voisine, C; Holler, A; Wright, G P; Waxman, J; Morris, E; Stauss, H J

Abstract

The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR
/ 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 TCRCD3 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, TCRCD3 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.

• Journal Article Type: Article
• Acceptance Date: Jun 15, 2011
• Online Publication Date: Jul 12, 2011
• Publication Date: Sep 29, 2011
• Deposit Date: Aug 1, 2016
• Journal: Blood
• Print ISSN: 0006-4971
• Electronic ISSN: 1528-0020
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 118
• Issue: 13
• Pages: 3528-3537
• DOI: https://doi.org/10.1182/blood-2011-04-346338
• Keywords: Immunology; Cell Biology; Biochemistry; Hematology
• Public URL: http://researchrepository.napier.ac.uk/Output/320469