Antibody-dependent cellular cytotoxicity (ADCC) is mediated by genetically modified antigen-specific human T lymphocytes

BéAtrice CléMenceau,Nicolas Congy-Jolivet,Henri Vié,GéRaldine Gallot,RéGine Vivien,JoëLle Gaschet,Gilles Thibault

doi:10.1182/blood-2005-09-3775

Abstract

AbstractIn the context of transplantation, donor and virus-specific T-lymphocyte infusions have demonstrated the dramatic potential of T cells as immune effectors. Unfortunately, most attempts to exploit the T-cell immune system against nonviral malignancies in the syngeneic setting have been disappointing. In contrast, treatments based on monoclonal antibodies (Abs) have been clinically successful and have demonstrated the clinical relevance of several antigens as therapeutic targets and the importance of the antibody-dependent cellular cytotoxicity (ADCC) pathway. In the present study, we considered the possibility of arming specific T cells with a receptor that would enable them to mediate ADCC. After transduction with a CD16/γ receptor gene, CD4+ and CD8+ cytotoxic T lymphocytes displayed stable expression of the CD16 receptor at their surface. In the absence of Ab, CD16/γ expression did not affect the capacity of specific T lymphocytes to kill their target following “natural” T-cell receptor recognition. When tested against the autologous B-lymphoblastoid cell line (BLCL) coated with anti-CD20 mAb, the newly expressed Fc receptor enabled the T cells to kill the BLCL through ADCC. Adoptive transfer of such newly designed immune effector may be considered to increase antibody efficiency by harnessing the immune potential of T cells.

Highlights

The binding specificity of the human IgG isotypes for the T-cell clones was similar in our hands to that observed for purified natural killer (NK) cells (IgG3 Ͼ IgG1 Ͼ IgG2 Ͼ IgG4), and the binding was almost totally inhibited in the presence of saturating amounts of the anti-CD16 monoclonal antibodies (mAbs) 3G8
When tested against target B-lymphoblastoid cell line (BLCL) coated with the humanized anti-CD20 mAb rituximab, the newly expressed Fc receptor enabled the T cells to kill the BLCLs through antibody-dependent cellular cytotoxicity (ADCC)
Aside from the case where the target BLCL was loaded in vitro with high concentrations of CMV peptide, which does not correspond to a physiologic situation, when both the T-cell receptor (TCR) and CD16/␥ chain molecule recognize the same target, the increase in cytotoxicity appeared different for the allospecific (Figure 3) and the EBVspecific (Figure 7) T-cell clones

Summary

Introduction

When tested against the autologous B-lymphoblastoid cell line (BLCL) coated with anti-CD20 mAb, the newly expressed Fc receptor enabled the T cells to kill the BLCL through ADCC Adoptive transfer of such newly designed immune effector may be considered to increase antibody efficiency by harnessing the immune potential of T cells. Adoptive immunotherapy with mAbs targeting molecules such as CD20 or Her2/Neu recently has shown its capability to produce a clear clinical benefit,[13] and it is thanks to these studies that the clinical pertinence of several antigens as immune therapeutic targets has been established Such passively acquired antibodies can trigger apoptosis of tumor cells and activate complement-mediated (CDC) or antibody-dependent cellular cytotoxicity (ADCC) in treated patients. Solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734

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Conclusion