Efficiency of T-cell receptor expression in dual-specific T cells is controlled by the intrinsic qualities of the TCR chains within the TCR-CD3 complex

Abstract

Genetic engineering of T lymphocytes is an attractive strategy to specifically redirect T-cell immunity toward viral infections and malignancies. We previously demonstrated redirected antileukemic reactivity of cytomegalovirus (CMV)-specific T cells by transfer of minor histocompatibility antigen HA-2-specific T-cell receptors (TCRs). HA-2-TCR-transferred CMV-specific T cells were potent effectors against HA-2-expressing leukemic cells, as well as CMV-expressing cells.Functional activity of these T cells correlated with TCR cell-surface expression. In the present study we analyzed which properties of transferred and endogenous TCRs are crucial for efficient cellsurface expression. We demonstrate that expression of the introduced TCR is not a random process but is determined by characteristics of both the introduced and the endogenously expressed TCR. The efficiency of TCR cell-surface expression is controlled by the intrinsic quality of the TCR complex. In addition, we demonstrate that chimeric TCRs can be formed and that efficiency of TCR expression is independent of whether TCRs are retrovirally introduced or naturally expressed. In conclusion, introduced, endogenous, and chimeric TCRs compete for cell-surface expression in favor of the TCR-CD3 complex with best-pairing properties. (Blood. 2007;109: [235][236][237][238][239][240][241][242][243]

PRAME and HLA Class I expression patterns make synovial sarcoma a suitable target for PRAME specific T-cell receptor gene therapy

“…9 The PRAME specific TCR of HSS1 is currently used for the treatment of refractory or relapsed acute myeloid leukemia in a Phase I TCR-gene therapy trial (ClinicalTrials.gov NCT02743611). Controls included T-cell clone HSS12 recognizing peptide FTWEGLYNV from the ubiquitously expressed gene USP11 in the context of HLA-A*02:01 to confirm HLA-A*02:01 expression, 9 and the negative control clone pp65-A2, 29 also HLA-A*02:01-restricted, recognizing an antigen from cytomegalovirus (CMV), that is not expressed in sarcoma cells. T-cells were co-incubated with sarcoma cell lines and primary SS cells at responder-to-stimulator ratios of 1:4 .…”

Progress and prospects: graft-versus-host disease

“…Mispairing between endogenous and exogeneous a-and b-TCR chains may result in autoreactive specificities. 61 Moreover, the limited availability of accessory molecules, required to express the TCR on the cell membrane, might reduce the avidity of transferred T cells. Current strategies, aimed at promoting preferential pairing and expression of exogenous TCR, and at reducing the rate of mispairing, exploit murine TCR constant regions-dominantly expressed in human lymphocytes but possibly immunogenic-and molecular modifications of the TCR constant regions (such as inclusion of a set of additional cysteins to promote disulfide bonds) finalized to increase their reciprocal affinity.…”

Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies

“…47,48 A different strategy to guarantee an improved and totally physiological activation of the T cells is to take advantage of the presence of an activated native TCR, transducing CTL which are already specific for a viral target (the so-called dual-specific T cells, as mentioned before). 27,49,50 In this condition the activation of the natural TCR should provide a powerful stimulus, maintaining the killing capacity, the proliferative activity and the durable persistence of the ChTCR-related functions, all present in the same cell. Brenner's group recently adopted EBV-specific CTL, transducing them with a ChTCR targeting the G(D2a) antigen expressed by neuroblastoma cells.…”