αβ T-Cell Receptor Engineered γδ T Cells Mediate Effective Antileukemic Reactivity

Veken, Lars T. van der; Hagedoorn, Renate S.; Loenen, Marleen M. van; Willemze, R.; Falkenburg, J.H. Frederik; Heemskerk, Mirjam H.M.

doi:10.1158/0008-5472.can-05-4190

Cited by 92 publications

(100 citation statements)

References 44 publications

(41 reference statements)

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“…To completely rule out formation of harmful mixed TCR dimers, another option would be to transduce γδ-T cells, as the γδ-TCR chains are not able to pair with αβ-TCR chains (19). Human γδ-T cells redirected with αβ-TCRs were fully functional in vitro (19) and in vivo (24).…”

Section: Discussionmentioning

confidence: 99%

“…Human γδ-T cells redirected with αβ-TCRs were fully functional in vitro (19) and in vivo (24). However, further analyses will be required to determine to what extent redirected γδ-T cells and αβ-T cells are different with respect to homing properties and specificity of the endogenous TCR.…”

Section: Discussionmentioning

confidence: 99%

“…Not only the decrease in TCR expression of the introduced Agspecific TCR, but also the formation of mixed TCR dimers with unknown specificity is an additional potential drawback of clinical application of TCR gene transfer (13,18,19). Because the specificity of mixed TCR dimers is unpredictable, hazardous specificities may be formed.…”

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confidence: 99%

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Mixed T cell receptor dimers harbor potentially harmful neoreactivity

Loenen¹,

Boer²,

Amir³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Adoptive transfer of T cell receptor (TCR)-transduced T cells may be an attractive strategy to target both hematological malignancies and solid tumors. By introducing a TCR, large numbers of T cells with defined antigen (Ag) specificity can be obtained. However, by introduction of a TCR, mixed TCR dimers can be formed. Besides the decrease in TCR expression of the introduced and endogenous TCR, these mixed TCR dimers could harbor potentially harmful specificities. In this study, we demonstrate that introduction of TCRs resulted in formation of neoreactive mixed TCR dimers, composed of the introduced TCR chains pairing with either the endogenous TCR α or β chain. Neoreactivities observed were HLA class I or class II restricted. Most neoreactive mixed TCR dimers were allo-HLA reactive; however, neoreactive mixed TCR dimers with autoreactive activity were also observed. We demonstrate that inclusion of an extra disulfide bond between the constant domains of the introduced TCR markedly reduced neoreactivity, whereas enhanced effectiveness of the introduced TCR was observed. In conclusion, TCR transfer results in the formation of neoreactive mixed TCR dimers with the potential to generate off-target effects, underlining the importance of searching for techniques to facilitate preferential pairing.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mixed T cell receptor dimers harbor potentially harmful neoreactivity

Loenen¹,

Boer²,

Amir³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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200

197

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“…Moreover, in the patients with median-stage or late-stage malignant tumors or who are being treated with chemotherapy, neither the quantity nor immunological activity of their seed c9d2T cells can meet the treatment demands. As the antitumor effect of c9d2T cells mainly depends on the cdTCR, which cannot exchange chains with the abTCR, 21,22 we hypothesized that large numbers of cytolytic cdT cells could be generated through forced expression of cdTCRs on lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

CDR3δ -grafted γ9δ2T cells mediate effective antitumor reactivity

Zhao

Cui

et al. 2011

Cell Mol Immunol

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Adoptive cell-transfer therapy (ACT) has been reported to suppress growing tumors and to overcome tumor escape in animal models. As a candidate ACT effector, c9d2T cells can be activated and expanded in vitro and in vivo and display strong antitumor activity against colorectal, lung, prostate, ovarian and renal cell carcinomas. However, it is difficult to obtain a large enough number of cdT cells to meet the need for immunotherapy that can overcome the cancer patients' immune suppressive tumor microenvironment. In previous studies, our lab confirmed that c9d2T cells recognized tumor cells via the CDR3d region of the cd-T-cell receptor (TCR). We constructed full-length human peripheral blood mononuclear cell (PBMC)-derived c9 and d2 chains in which the CDR3 region was replaced by an ovarian epithelial carcinoma (OEC)-derived CDR3. We transferred the CDR3d-grafted c9d2TCR into peripheral blood lymphocytes (PBLs) to develop genetically modified c9d2T cells. In vitro studies have shown that these CDR3d-grafted c9d2T cells can produce cytokines after stimulation with tumor cell extracts and exhibit cytotoxicity towards tumor cells, including human OEC and cervical adenocarcinoma. CDR3d-grafted c9d2T cells adoptively transferred into nude mice bearing a human OEC cell line demonstrated significant antitumor effects. These results indicate that CDR3d-grafted c9d2T cells might be candidates for clinical tumor immunotherapy.

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“…2,3 However, one of the inherent disadvantages of ab TCR transfer to other ab T cells is the possible formation of mixed TCR heterodimers, namely the introduced a or b TCR could pair with the endogenous a or b TCR chains to generate unfavorable T cells with self-antigen specificity. 2,4 gd T cells have several important features, some of which are distinct from conventional ab T cells. 5,6 The gd T cells rapidly expand upon antigen challenge.…”

Section: Introductionmentioning

confidence: 99%

Rapid αβ TCR-mediated responses in γδ T cells transduced with cancer-specific TCR genes

et al. 2009

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Adoptive T-cell transfer of in vitro cultured T cells derived from cancer patients with naturally developed immune responses has met with some success as an immunotherapeutic approach, although only a limited number of patients showed spontaneous immune responses. To find alternative ways, such as cancer-specific T-cell receptor (TCR) gene transfer, in preparation for sufficient numbers of antigenspecific T cells is an important issue in the field of adoptive T-cell therapy. Given the inherent disadvantage of ab TCR transfer to other ab T cells, namely the possible formation of mixed TCR heterodimers with endogenous a or b TCR, we employed gd T cells as a target for retroviral transfer of cancer-specific TCR and examined whether gd T cells were useful as an alternative population for TCR transfer. Although retroviral transduction to gd T cells with TCR ab genes alone, isolated from a MAGE-A4 143-151 -specific ab CD8 + cytotoxic T lymphocyte (CTL) clone, did not provide sufficient affinity to recognize major histocompatibility (MHC)-peptide complexes due to the lack of CD8 co-receptor, gd T cells co-transduced with TCR ab and CD8 ab genes acquired cytotoxicity against tumor cells and produced cytokines in both ab-and gd-TCR-dependent manners. Furthermore, ab TCR and CD8-transduced gd T cells, stimulated either through ab TCR or gd TCR, rapidly responded to target cells compared with conventional ab T cells, reminiscent of gd T cells. We propose ab TCRtransduced gd T cells as an alternative strategy for adoptive T-cell transfer.

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αβ T-Cell Receptor Engineered γδ T Cells Mediate Effective Antileukemic Reactivity

Cited by 92 publications

References 44 publications

Mixed T cell receptor dimers harbor potentially harmful neoreactivity

Mixed T cell receptor dimers harbor potentially harmful neoreactivity

CDR3δ -grafted γ9δ2T cells mediate effective antitumor reactivity

Rapid αβ TCR-mediated responses in γδ T cells transduced with cancer-specific TCR genes

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