A Single TCRα-Chain with Dominant Peptide Recognition in the Allorestricted HER2/neu-Specific T Cell Repertoire

Abstract

T cells can recognize tumor cells specifically by their TCR and the transfer of TCR-engineered T cells is a promising novel tool in anticancer therapies. We isolated and characterized four allorestricted TCRs with specificity for the HER2/neu-derived peptide 369 (HER2369) demonstrating high peptide specificity. PBMCs transduced with especially one TCR, HER2-1, mediated specific tumor reactivity after TCR optimization suggesting that this TCR represents a potential candidate for targeting HER2 by TCR-transduced effector cells. Another TCR showed high-peptide specificity without tumor reactivity. However, the TCRα-chain of this TCR specifically recognized HER2369 not only in combination with the original β-chain but also with four other β-chains of the same variable family deriving from TCRs with diverse specificities. Pairing with one β-chain derived from another HER2369-specific TCR potentiated the chimeric TCRs in regard to functional avidity, CD8 independency, and tumor reactivity. Although the frequency of such TCR single chains with dominant peptide recognition is currently unknown, they may represent interesting tools for TCR optimization resulting in enhanced functionality when paired to novel partner chains. However, undirected mispairing with novel partner chains may also result in enhanced cross-reactivity and self-reactivity. These results may have an important impact on the further design of strategies for adoptive transfer using TCR-transduced T cells.

Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells

“…Remaining safety concerns could be relieved by inclusion of suicide gene constructs (31,32), or irradiation of the cells before in vivo application to block proliferation. This has previously been shown not to affect cell death activity of unmodified and retroviral NK-92 cells (10).…”

“…NK-92 cells possess the characteristics of activated NK cells but do not harbor Fc-γRIII (CD16) and lack the general killer inhibitory receptors (KIRs), except KIR2DL4 (8,9), which interacts with human leukocyte antigen (HLA) molecules on target cells and inhibits NK cell cytolytic activity (10). NK-92 cells are cytotoxic to tumor cells, but have no effect on nonmalig nant allogeneic cells.…”

Immuno-PET Imaging of Engineered Human T Cells in Tumors

“…This opens the possibility to use an anti-murine TCR monoclonal antibody (aTCRmu; ref. 22) for detection of TCR-transduced human T cells independent of the specificity of the transgenic TCR (23)(24)(25). We developed an F(ab') 2 -fragment-based imaging approach in a xenogenic human myeloid sarcoma model for sensitive tracking of TCR-transgenic T cells by PET/CT imaging in vivo.…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…The development of retrovirus/lentivirus vectors provided for more efficient transduction of T-lymphocytes and NK cells [272][273][274][275][276][277][278][279][280]. Various groups have sought to refine the CAR constructs, including tuning affinity of the HER2/neu antigen-recognition domain [275], utilizing the T-cell receptor peptide recognition domain instead of an antibody-based recognition domain [281] and incorporation of costimulatory elements [282] within the construct. With the identification of Heregulin as a ligand for heterodimers involving HER3 or HER4, including those with HER2/neu, a chimeric ligand molecule (heregulin and intracellular signaling component from the CD3 ζ-chain) was developed [283].…”