Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer

Stanislawski, Thomas; Voss, Ralf-Holger; Lotz, Carina; Sadovnikova, Elena; Willemsen, Ralph A.; Kuball, Jürgen; Ruppert, Thomas; Bolhuis, R. L. H.; Melief, C.J.M.; Huber, Christoph; Stauss, Hans J.; Theobald, Matthias

doi:10.1038/ni1001-962

Cited by 347 publications

(290 citation statements)

References 42 publications

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“…Until now, the application of retroviral transfer of TCRs has mainly been limited to the transfer of HLA class I restricted TCRs. [15][16][17][18][19][20] However, the specificity of HLA class II restricted T lymphocytes can also be transferred to other T cells. [21][22][23] Previously, we demonstrated the retroviral transfer of a dual-specific TCR recognizing both an antigenic peptide in the context of HLA class I and an antigenic peptide in the context of HLA class II.…”

Section: Introductionmentioning

confidence: 99%

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

et al. 2005

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Both cytotoxic T cells and helper T cells are important in immune responses against pathogens and malignant cells.In hematological malignancies which express HLA class II molecules, immunotherapy may be directed to HLA class II restricted antigens. We investigated whether it is possible to engineer HLA class II restricted T cells with both antigenspecific cytolytic activity and the capacity to produce high amounts of cytokines. CD4 + and CD8 + peripheral-bloodderived T cells were retrovirally transduced with the HLA class II restricted minor histocompatibility antigen dead box RNA helicase Y (DBY)-specific TCR. The TCR-transduced CD4 + T cells exerted DBY-specific cytolytic activity, produced Th0, Th1, or Th2 cytokines, and proliferated upon DBY-specific stimulation. TCR-transduced CD8 + T cells exerted cytolytic activity which equaled the level of cytolytic activity of the TCR-transferred CD4 + T cells. Cotransfer of CD4 enhanced the cytolytic activity of the TCR-transduced CD8 + T cells, but introduction of CD4 was not sufficient to generate DBY-specific CD8 + T cells with the capacity to produce high amounts of cytokines. In this study, we demonstrated the feasibility to engineer T cells with antigen-specific cytolytic activity, as well as the ability to produce significant amounts of cytokines, by TCR transfer to CD4 + T cells. Gene Therapy (2005) IntroductionPatients relapsing from leukemia after allogeneic stem cell transplantation can successfully be treated by donor lymphocyte infusions (DLI), due to the graft-versusleukemia (GVL) response of the donor-derived T cells. [1][2][3][4] However, DLI is also associated with graft-versus-hostdisease (GVHD). Several studies have illustrated that depletion of CD8 + T cells from the DLI may preserve the beneficial GVL reactivity without the induction of GVHD, indicating that the CD4 + T lymphocytes may play an essential role in the antileukemic reactivity. [5][6][7][8][9][10] The mechanism by which the CD4 + T cells contribute to the GVL response is, however, not known. CD4 + T cells have been suggested to elicit the antileukemic response via the induction of minor histocompatibility antigen (mHag)-specific CD8 + T cells. 5 In addition, mHag-specific CD4 + T-helper cells have been reported to mature dendritic cells and enhance the expansion of mHag-specific cytotoxic T lymphocytes in vitro. 11 Alternatively, we have demonstrated that CD4 + T cells are capable of exerting direct cytolytic activity against leukemic cells. [12][13][14] Cellular immunotherapeutic approaches based on the adoptive transfer of T lymphocytes may require large cell numbers. Large numbers of T cells with a defined antigen specificity can be acquired by retroviral transfer of the T-cell receptor to peripheral-blood-derived T lymphocytes. Until now, the application of retroviral transfer of TCRs has mainly been limited to the transfer of HLA class I restricted TCRs. [15][16][17][18][19][20] However, the specificity of HLA class II restricted T lymphocytes can also be transferred to other T c...

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Section: Introductionmentioning

confidence: 99%

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

et al. 2005

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“…The cysteine-modified TCRs, which form dimmers easily by additional interchain disulfide bond, were more highly expressed on the surface of human lymphocytes compared with their wild-type counterparts and were able to mediate higher levels of cytokine secretion and specific lysis when co-cultured with specific tumor cell lines (100). To decrease the proportion of mispairing between α and β chain, Thomas and colleagues developed a chimeric, partially humanized double-chain TCR construct by exchanging mouse αβ constant (C) with human αβ regions (101). In contrast, Biswas et al used directed evolution method to generate a panel of high affinity TCRs for TSST-1, allowing the mutation serve as potential leads toward the development of therapeutic agents for superantigen-mediated disease (102).…”

Section: Engineering Tcrmentioning

confidence: 99%

Manipulation of MHC-I/TCR Interaction for Immune Therapy

Liu

Gao

2008

Cell Mol Immunol

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“…T-cell receptor chains to date have been generated against known antigens with the principal targeted disease being melanoma due to the fact that MHC restricted antigens are numerous and well defined (Rivoltini et al, 2002). Aside from melanoma, there is an increasing diversity of targets being exploited for TCR therapy including MDM-2, a potential target in a wide range of malignancies (Stanislawski et al, 2001) and WT-1 targeting in leukaemia . However, the rate-limiting step is the identification and isolation of the critical responding T cell to serve as a source to generate the TCR genes with (generally speaking) a great deal of effort generally required to generate antigen-specific T cells.…”

Section: Isolation and Expression Of Suitable Tcra And Tcrb Chainsmentioning

confidence: 99%

Engineering T cells for cancer therapy

et al. 2005

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It is generally accepted that the immune system plays an important role in controlling tumour development. However, the interplay between tumour and immune system is complex, as demonstrated by the fact that tumours can successfully establish and develop despite the presence of T cells in tumour. An improved understanding of how tumours evade T-cell surveillance, coupled with technical developments allowing the culture and manipulation of T cells, has driven the exploration of therapeutic strategies based on the adoptive transfer of tumour-specific T cells. The isolation, expansion and re-infusion of large numbers of tumour-specific T cells generated from tumour biopsies has been shown to be feasible. Indeed, impressive clinical responses have been documented in melanoma patients treated with these T cells. These studies and others demonstrate the potential of T cells for the adoptive therapy of cancer. However, the significant technical issues relating to the production of natural tumour-specific T cells suggest that the application of this approach is likely to be limited at the moment. With the advent of retroviral gene transfer technology, it has become possible to efficiently endow T cells with antigen-specific receptors. Using this strategy, it is potentially possible to generate large numbers of tumour reactive T cells rapidly. This review summarises the current gene therapy approaches in relation to the development of adoptive T-cell-based cancer treatments, as these methods now head towards testing in the clinical trial setting.

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Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer

Cited by 347 publications

References 42 publications

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

Manipulation of MHC-I/TCR Interaction for Immune Therapy

Engineering T cells for cancer therapy

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