PRAME-Specific Allo-HLA–Restricted T Cells with Potent Antitumor Reactivity Useful for Therapeutic T-Cell Receptor Gene Transfer

Amir, Avital L.; Steen, Dirk M. van der; Loenen, Marleen M. van; Hagedoorn, Renate S.; Boer, Renate de; Kester, Michel D.G.; Ru, Arnoud H. de; Lugthart, Gertjan; Kooten, Cees van; Hiemstra, Pieter S.; Jedema, Inge; Griffioen, Marieke; Veelen, Peter A. van; Falkenburg, J.H. Frederik; Heemskerk, Mirjam H.M.

doi:10.1158/1078-0432.ccr-11-1066

Cited by 103 publications

(130 citation statements)

References 36 publications

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“…This is reflected by the emergence of antigen-specific CD8 þ T cells in the peripheral blood of AML patients following transplantation. Such CTL responses have been reported against a broad range of AML-related tumor antigens, including HOXA9 (HOXA9 146-154 ), 62 hTERT (hTERT 540-548 ), 62 27,62 and RAGE-1 (RAGE-1 [11][12][13][14][15][16][17][18][19][20] (Table 1). 79 NuSAP1 has been identified as a target of humoral immunity following allogeneic HSCT.…”

Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 82%

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Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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The graft-versus-leukemia effect of allogeneic hematopoietic stem cell transplantation (HSCT) has shown that the immune system is capable of eradicating acute myeloid leukemia (AML). This knowledge, along with the identification of the target antigens against which antileukemia immune responses are directed, has provided a strong impetus for the development of antigen-targeted immunotherapy of AML. The success of any antigen-specific immunotherapeutic strategy depends critically on the choice of target antigen. Ideal molecules for immune targeting in AML are those that are: (1) leukemia-specific; (2) expressed in most leukemic blasts including leukemic stem cells; (3) important for the leukemic phenotype; (4) immunogenic; and (5) clinically effective. In this review, we provide a comprehensive overview on AML-related tumor antigens and assess their applicability for immunotherapy against the five criteria outlined above. In this way, we aim to facilitate the selection of appropriate target antigens, a task that has become increasingly challenging given the large number of antigens identified and the rapid pace at which new targets are being discovered. The information provided in this review is intended to guide the rational design of future antigen-specific immunotherapy trials, which will hopefully lead to new antileukemia therapies with more selectivity and higher efficacy.

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Section: Criterion 4: Immunogenicity Humoral and Cellular Immune Respmentioning

confidence: 82%

“…26 Moreover, it was recently shown that PRAME-specific T cells may recognize normal kidney epithelial cells and dendritic cells. 27 On the opposite end of the spectrum are ubiquitous antigens, which are not only expressed in leukemic cells, but also in a wide variety of normal human tissues. Examples of such antigens are listed in Table 1.…”

Section: Introductionmentioning

confidence: 99%

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

2012

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“…In the past, this relation was demonstrated in more than 50 other cancer cell lines as well. 9,16 We hereby proofed that mRNA expression leads to the expression of the relevant PRAME peptide because PRAME-T-cells could only have recognized the sarcoma cells if the PRAME peptide was processed by the proteasome and presented in the context of HLA-I. Whether a full length and functional protein is transcribed as well is not certain, but not relevant either, because expression and processing of the 9-amino acid long peptide is enough for T-cell recognition.…”

Section: Discussionmentioning

confidence: 99%

“…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 .…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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Synovial sarcoma expresses multiple cancer testis antigens that could potentially be targeted by T-cell receptor (TCR) gene therapy. In this study we investigated whether PRAME-TCR-gene therapy could be an effective treatment for synovial sarcoma by investigating the potential of PRAME-specific T-cells to recognize sarcoma cells and by evaluating the expression patterns of PRAME and HLA class I (HLA-I) in synovial sarcoma tumor samples. All PRAME expressing sarcoma cell lines, including 2 primary synovial sarcoma cell cultures (passage < 3), were efficiently recognized by PRAME-specific T-cells. mRNA FISH demonstrated that PRAME was expressed in all synovial sarcoma samples, mostly in an homogeneous pattern. Immunohistochemistry demonstrated low HLA-I baseline expression in synovial sarcoma, but its expression was elevated in specific areas of the tumors, especially in biphasic components of biphasic synovial sarcoma. In 5/11 biphasic synovial sarcoma patients and in 1/17 monophasic synovial sarcoma patients, elevated HLA-I on tumor cells was correlated with infiltration of T-cells in these specific areas. In conclusion, low-baseline expression of HLA-I in synovial sarcoma is elevated in biphasic areas and in areas with densely infiltrating T-cells, which, in combination with homogeneous and high PRAME expression, makes synovial sarcoma potentially a suitable candidate for PRAME-specific TCR-gene therapy.

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PRAME as a Potential Target for Immunotherapy in Metastatic Uveal Melanoma

et al. 2017

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IMPORTANCE Uveal melanoma (UM) is an intraocular primary malignant neoplasm that often gives rise to metastatic disease for which there are no effective therapies. A substantial proportion of UMs express the cancer-testis antigen PRAME (preferentially expressed antigen in melanoma), which can potentially be targeted by adoptive T-cell therapy.OBJECTIVE To determine whether there may be a rationale for PRAME-directed T-cell therapy for metastatic UM.DESIGN, SETTING, AND PARTICIPANTS An experimental study using a retrospective cohort of 64 patients with UM (median follow-up, 62 months) was conducted from January 8, 2015, to November 20, 2016, at the Leiden University Medical Center. Clinical, histopathologic, and genetic parameters were compared between 64 PRAME-positive and PRAME-negative UMs. HLA class I restricted, PRAME-specific T cells were stimulated with UM cell lines to measure their antigen-specific reactivity against these cell lines, which were analyzed for PRAME expression by real-time quantitative polymerase chain reaction. Uveal melanoma metastases from 16 unrelated patients were assessed for PRAME expression by messenger RNA fluorescence in situ hybridization and for HLA class I expression by immunofluorescence staining.MAIN OUTCOMES AND MEASURES Interferon γ production for antigen-specific reactivity and detection of PRAME and HLA class I expression in primary and metastatic UM. RESULTSOf the 64 patients in the study (31 women and 33 men; mean [SD] age at the time of enucleation, 60.6 [15.6] years), PRAME expression was negative in 35 primary UMs and positive in 29 primary UMs. Positive PRAME expression was associated with a high largest basal diameter (15.0 vs 12.0 mm; P = .005), ciliary body involvement (59% vs 26%; P = .008), and amplification of chromosome 8q (66% vs 23%; P = .002). PRAME-specific T cells reacted against 4 of 7 UM cell lines, demonstrating that T-cell reactivity correlated with PRAME expression. Metastatic UM samples were positive for PRAME messenger RNA in 11 of 16 patients and for HLA class I in 10 of 16 patients, with 8 of 16 patients demonstrating coexpression of both PRAME and HLA class I.CONCLUSIONS AND RELEVANCE PRAME is expressed in many primary and metastatic UMs, and about half of the metastatic UMs coexpress PRAME and HLA class I. The finding that PRAME-specific T cells in this study reacted against PRAME-positive UM cell lines suggests a potential role for PRAME-directed immunotherapy for selected patients with metastatic UM.

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PRAME-Specific Allo-HLA–Restricted T Cells with Potent Antitumor Reactivity Useful for Therapeutic T-Cell Receptor Gene Transfer

Cited by 103 publications

References 36 publications

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

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

PRAME as a Potential Target for Immunotherapy in Metastatic Uveal Melanoma

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