Priming of PRAME- and WT1-specific CD8<sup>+</sup>T cells in healthy donors but not in AML patients in complete remission

Ancker, Willemijn van den; Ruben, Jurjen M.; Westers, Theresia M.; Wulandari, Dewi; Bontkes, Hetty J.; Hooijberg, Erik; Stam, Anita G.M.; Santegoets, Saskia J.; Ossenkoppele, Gert J.; Gruijl, Tanja D. de; Loosdrecht, Arjan van de

doi:10.4161/onci.23971

Cited by 16 publications

(7 citation statements)

References 32 publications

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“…Our studies focused on patients after HSCT and might, therefore, be in accordance with the finding of PRAME reactive cytotoxic T precursor cells in healthy donors and not in AML patients ( 108 ). Encouraging results for PRAME as a target for immunotherapy in leukemia were, however, reported by Rezvani and colleagues ( 109 ).…”

Section: Improvement Of the Responsesupporting

confidence: 87%

Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

et al. 2017

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The success of hematopoietic stem cell transplantation (HSCT) lies with the ability of the engrafting immune system to remove residual leukemia cells via a graft-versus-leukemia effect (GvL), caused either spontaneously post-HSCT or via donor lymphocyte infusion. GvL effects can also be initiated by allogenic mismatched natural killer cells, antigen-specific T cells, and activated dendritic cells of leukemic origin. The history and further application of this GvL effect and the main mechanisms will be discussed and reviewed in this chapter.

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Section: Improvement Of the Responsesupporting

confidence: 87%

Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

et al. 2017

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“…TAA specific T cells recognizing non polymorphic antigens can also be found in the T cell repertoire of healthy donors. A variety of WT1, NY‐eso, PRAME, Proteinase‐3 and other TAA‐specific T cells restricted by the autologous HLA‐molecules have been found with various frequencies in the T cell repertoire of healthy donors (Rezvani et al., 2005; van den Ancker et al., 2013; Weber et al., 2013). A large variety of avidities have been observed but at present it is unclear whether these T cells are of sufficient avidity to execute a profound anti‐tumor effect after transplantation.…”

Section: Targeting Of Hematopoietic Malignancies By Antigen Specific mentioning

confidence: 99%

Allo‐reactive T cells for the treatment of hematological malignancies

Falkenburg

Jedema

2015

Molecular Oncology

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Several mechanisms can be responsible for control of hematological tumors by allo-reactive T cells. Following allogeneic stem cell transplantation (alloSCT) donor T cells recognizing genetic disparities presented on recipient cells and not on donor cells are main effectors of tumor control, but also of the detrimental graft versus host disease (GVHD). Since after transplantation normal hematopoiesis is of donor origin, any T cell response directed against polymorphic antigens expressed on hematopoietic recipient cells but not on donor cells will result in an anti-tumor response not affecting normal hematopoiesis. After fully HLA-matched alloSCT, T cells recognizing polymorphic peptides derived from proteins encoded by genes selectively expressed in hematopoietic lineages may result in anti-tumor responses without GVHD. Due to the high susceptibility of hematopoietic cells for T cell recognition, a low amplitude of the overall T cell response may also be in favor of the anti-tumor reactivity in hematological malignancies. A mismatch between donor and patient for specific HLA-alleles can also be exploited to induce a selective T cell response against patient (malignant) hematopoietic cells. If restricting HLA class II molecules are selectively expressed on hematopoietic cells under non-inflammatory circumstances, allo HLA class-II responses may control the tumor with limited risk of GVHD. Alternatively, T cells recognizing hematopoiesis-restricted antigens presented in the context of mismatched HLA alleles may be used to treat patients with hematological cancers. This review discusses various ways to manipulate the allo-immune response aiming to exploit the powerful ability of allo-reactive T-cells to control the malignancies without causing severe damage to non-hematopoietic tissues.

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“…Noteworthy, we were not able to generate detectable PRAME peptide‐specific CTLs from PBMCs failing at producing IFN‐γ following stimulation with PRAME peptide mix. Along with other studies reporting on the failure to generate PRAME‐specific CTL lines from a certain fraction of donors, our approach of detecting LAA peptide‐specific T cells might disclose PBMCs favorable for PRAME‐specific T‐cell expansion and therefore improve the efficiency of generation of LAA‐specific T cells using expansion protocols.…”

Section: Discussionmentioning

confidence: 65%

PRAME peptide‐specific CD8⁺ T cells represent the predominant response against leukemia‐associated antigens in healthy individuals

et al. 2018

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Antigen-specific T cells isolated from healthy individuals (HIs) have shown great therapeutic potential upon adoptive transfer for the treatment of viremia in immunosuppressed patients. The lack of comprehensive data on the prevalence and characteristics of leukemia-associated antigen (LAA)-specific T cells in HIs still limits such an approach for tumor therapy. Therefore, we have investigated T-cell responses against prominent candidates comprising Wilms' tumor protein 1 (WT1), preferentially expressed antigen in melanoma (PRAME), Survivin, NY-ESO, and p53 by screening PBMCs from HIs using intracellular IFN-γ staining following provocation with LAA peptide mixes. Here, we found predominantly poly-functional effector/effector memory CCR7 /CD45RA /CD8 LAA peptide-specific T cells with varying CD95 expression in 34 of 100 tested HIs, whereas CD4 T cells responses were restricted to 5. Most frequent LAA peptide-specific T cell responses were directed against WT1 and PRAME peptides with a prevalence of 20 and 17%, respectively, showing the highest magnitude (0.16% ± 0.22% (mean ± SD)) for PRAME peptides. Cytotoxicity of PRAME peptide-specific T cells was demonstrated by specific killing of PRAME peptide-pulsed T2 cells. Furthermore, the proliferative capacity of PRAME peptide-specific T cells was confined to HIs responsive toward PRAME peptide challenge corroborating the accuracy of the screening results. In conclusion, we identified PRAME as a promising target antigen for adoptive leukemia therapy.

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Priming of PRAME- and WT1-specific CD8⁺T cells in healthy donors but not in AML patients in complete remission

Cited by 16 publications

References 32 publications

Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

Allo‐reactive T cells for the treatment of hematological malignancies

PRAME peptide‐specific CD8⁺ T cells represent the predominant response against leukemia‐associated antigens in healthy individuals

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Priming of PRAME- and WT1-specific CD8+T cells in healthy donors but not in AML patients in complete remission

Cited by 16 publications

References 32 publications

Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

Allo‐reactive T cells for the treatment of hematological malignancies

PRAME peptide‐specific CD8+ T cells represent the predominant response against leukemia‐associated antigens in healthy individuals

Contact Info

Product

Resources

About

Priming of PRAME- and WT1-specific CD8⁺T cells in healthy donors but not in AML patients in complete remission

PRAME peptide‐specific CD8⁺ T cells represent the predominant response against leukemia‐associated antigens in healthy individuals