4.7 Article

CD3 limits the efficacy of TCR gene therapy in vivo

Journal

BLOOD
Volume 118, Issue 13, Pages 3528-3537

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-04-346338

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Funding

  1. Leukemia and Lymphoma Research
  2. Experimental Cancer Medicine Center
  3. ATTACK EU Consortium
  4. MRC
  5. Dinwoodie Settlement Charitable Trust
  6. Medical Research Council [G0902209] Funding Source: researchfish
  7. Versus Arthritis [19225] Funding Source: researchfish
  8. MRC [G0902209] Funding Source: UKRI

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The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR alpha/beta 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. (Blood. 2011;118(13):3528-3537)

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