Reprogramming of Virus-specific T Cells into Leukemia-reactive T Cells Using T Cell Receptor Gene Transfer

Heemskerk, Mirjam H.M.; Hoogeboom, Manja; Hagedoorn, Renate S.; Kester, Michel G.D.; Willemze, R.; Falkenburg, J.H. Frederik

doi:10.1084/jem.20031110

Cited by 174 publications

(145 citation statements)

References 34 publications

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“…Immunogens used to date are alloantigen 8 in mouse cells, and Epstein-Barr (virus) EBV 27 and cytomegalovirus (CMV) 28 and influenza virus 29 in human cells. Importantly, the potential utility of dual-specific T cells was highlighted by the demonstration of tumor inhibition in mice using mouse dual-specific T cells recognizing alloantigen and the ovarian cancerassociated antigen FBP.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of dual-specific T cells and influenza virus

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Antitumor activity of dual-specific T cells and influenza virus

et al. 2007

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“…We previously demonstrated that TCRtransferred T-cell clones can have different expression levels of the introduced TCR, explaining the observed variation in cytolytic activity. 19 Different TCR expression levels might arise due to differences in the expression levels of the retrovirally encoded TCRab chains or competition for cell surface expression with the endogenous TCR and mixed TCR dimers. Based on the potent cytolytic effector function of CD8 + T cells, we hypothesized that T cells with higher antigenspecific cytolytic activity could be obtained by transferring the DBY-TCR to CD8 + CTL.…”

Section: Discussionmentioning

confidence: 99%

“…Since the specificity of the mixed TCR dimers is unknown, autoreactivity cannot be excluded. 19,32 The number of T cells with different TCR chains and thus the chance to generate autoreactive T cells can be limited by TCR gene transfer to T cells with defined antigen specificity. We previously demonstrated the reprogramming of cytomegalovirus (CMV)-specific T cells into leukemia-reactive T cells by transferring a TCR specific for the mHag HA-2.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated the reprogramming of cytomegalovirus (CMV)-specific T cells into leukemia-reactive T cells by transferring a TCR specific for the mHag HA-2. 19 The amounts and type of cytokines produced by different T-cell subsets may have major impact on the eventual outcome of immune responses. T cells producing Th1 cytokines (IFNg and IL-2) have been shown to be responsible for antitumor reactivity.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Reconstitution of anti‐HIV effector functions of primary human CD8 T lymphocytes by transfer of HIV‐specific αβ TCR genes

et al. 2004

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We redirected the antigen specificity of primary human CD8 T cells by retrovirus-mediated transduction of genes encoding ab TCR specific to HIV-1 Pol protein. A large polyclonal population of TCR-transduced CD8 T cells showed substantial cytotoxic and cytokine production activities toward target cells either pulsed with the peptide or infected with HIV-1, and their functional activities were comparable to those of the parental CTL clone. Peptide fine-specificity and promiscuous recognition of HLA class I supertypes of the parental CTL clone were also preserved in the TCR-transduced cells. There were no signs of allogeneic responses in these cells, although hybrid TCR dimers consisting of transduced TCR and endogenous TCR were suspected to have been formed in these cells, as the effect of transgene expression on the surface expression of the desired TCR was limited. Moreover, the TCR-transduced cells showed potent inhibitory activity against HIV-1 replication in vitro, although the differential surface expression of the desired TCR resulted in differential functional avidity of individual TCR-transduced cells toward the peptide-pulsed target cells. These data suggest that the reconstitution of HIV-specific immunoreactive T cells engineered by genetic transfer of HIV-specific TCR is a potential alternative to immunotherapeutic applications against HIV infections.

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Reprogramming of Virus-specific T Cells into Leukemia-reactive T Cells Using T Cell Receptor Gene Transfer

Cited by 174 publications

References 34 publications

Antitumor activity of dual-specific T cells and influenza virus

Antitumor activity of dual-specific T cells and influenza virus

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

Reconstitution of anti‐HIV effector functions of primary human CD8 T lymphocytes by transfer of HIV‐specific αβ TCR genes

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