Melanoma patients respond to a new HLA‐A*01‐presented antigenic ligand derived from a multi‐epitope region of melanoma antigen TRP‐2

Paschen, Annette; Jing, Weiqing; Drexler, Ingo; Klemm, Moritz; Song, Mingxia; Müller-Berghaus, Jan; Nguyen, Xuan Duc; Osen, Wolfram; Stevanović, Stefan; Sutter, Gerd; Schadendorf, Dirk

doi:10.1002/ijc.21132

Cited by 8 publications

(7 citation statements)

References 20 publications

(21 reference statements)

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“…TRP2 constitutes an attractive and poorly explored melanoma antigen for clinical development of human SMART-DCs. CTL precursors against TRP2 have been detected in a subset of melanoma patients, 43, 44 indicating that central tolerance to TRP2 is not complete, even during the slow (hence possibly tolerogenic) disease development of human melanoma, which is a different scenario when contrasted to the ‘explosive' tumor burden resulting of s.c. implanted B16 cells.…”

Section: Discussionmentioning

confidence: 99%

Lentiviral vectors for induction of self-differentiation and conditional ablation of dendritic cells

et al. 2011

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Development of lentiviral vectors (LVs) in the field of immunotherapy and immune regeneration will strongly rely on biosafety of the gene transfer. We demonstrated previously the feasibility of ex vivo genetic programming of mouse bone marrow precursors with LVs encoding granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), which induced autonomous differentiation of long-lived dendritic cells (DCs), referred to as self-differentiated myeloid-derived antigen-presenting-cells reactive against tumors (SMART-DCs). Here, LV biosafety was enhanced by using a DC-restricted and physiological promoter, the major histocompatibility complex (MHC) II promoter, and including co-expression of the herpes simplex virus-thymidine kinase (sr39HSV-TK) conditional suicide gene. Tricistronic vectors co-expressing sr39HSV-TK, GM-CSF and IL-4 transcriptionally regulated by the MHCII promoter or the ubiquitous cytomegalovirus (CMV) promoter were compared. Despite the different gene transfer effects, such as the kinetics, levels of transgene expression and persistency of integrated vector copies, both vectors induced highly viable SMART-DCs, which persisted for at least 70 days in vivo and could be ablated with the pro-drug Ganciclovir (GCV). SMART-DCs co-expressing the tyrosine-related protein 2 melanoma antigen administered subcutaneously generated antigen-specific, anti-melanoma protective and therapeutic responses in the mouse B16 melanoma model. GCV administration after immunotherapy did not abrogate DC vaccination efficacy. This demonstrates proof-of-principle of genetically programmed DCs that can be ablated pharmacologically.

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Section: Discussionmentioning

confidence: 99%

Lentiviral vectors for induction of self-differentiation and conditional ablation of dendritic cells

et al. 2011

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“…IFNγ enzyme-linked immunospot (ELISpot) assay was performed as previously described61. Briefly, multiscreen-HA plates (Millipore, Bedford, MA) were coated with 5 μg ml −1 anti-hIFNγ-mAb 1-D1K (Mabtech).…”

Section: Methodsmentioning

confidence: 99%

Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions

et al. 2017

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Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8+ T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making.

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“…Selection was carried out with antihuman CD4 specific mAb conjugated microbeads according to the instructions of the manufacturer (Miltenyi Biotec). T cells were analyzed for their specificity by IFN-g ELISpot assays as described (20), by incubation of 10 5 responder T cells with 5 Â 10 4 stimulator cells. All determinations were done at least in duplicates.…”

Section: Methodsmentioning

confidence: 99%

“…Controls were incubated with DMSO only. The assay was done as described (20). Data are presented as mean IFN-g spots per 10…”

Section: Methodsmentioning

confidence: 99%

Detection of Spontaneous CD4+ T-Cell Responses in Melanoma Patients against a Tyrosinase-Related Protein-2–Derived Epitope Identified in HLA-DRB1*0301 Transgenic Mice

Paschen

Song

Osen

et al. 2005

Clinical Cancer Research

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Purpose: The frequently expressed differentiation antigen tyrosinase-related protein-2 (TRP-2) has repeatedly been described as a target of spontaneous cytotoxic T-cell responses in melanoma patients, suggesting that it might be an ideal candidate antigen for T cell^based immunotherapy. As a prerequisite for immunization, T-cell epitopes have to be identified.Whereas a number of HLA class I^presented TRP-2^derived epitopes are known, information about HLA class IIp resented antigenic ligands recognized by CD4 + T helper (Th) cells is limited. Experimental Design: The search forTRP-2^derived Th epitopes was carried out by competitive in vitro peptide binding studies with predicted HLA-DRB1*0301ligands in combination with peptide and protein immunizations of HLA-DRB1*0301 transgenic mice. In vivo selected candidate epitopes were subsequently verified for their immunogenicity in humanT-cell cultures.Results: This strategy led to the characterization of TRP-2 60-74 as an HLA-DRB1*0301^restricted Th epitope. Importantly, TRP-2 60-74^r eactive human CD4 + Th cell lines, specifically recognizing target cells loaded with recombinant TRP-2 protein, could be established by repeated peptide stimulation of peripheral blood lymphocytes from several HLA-DRB1*03 + melanoma patients. Even short-term peptide stimulation of patients' peripheral blood lymphocytes showed the presence of TRP-2 60-74^r eactive T cells, suggesting that these T cells were already activated in vivo. Conclusion: Peptide TRP-2 60-74 might be a useful tool for the improvement of immunotherapy and immune monitoring of melanoma patients.

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Melanoma patients respond to a new HLA‐A*01‐presented antigenic ligand derived from a multi‐epitope region of melanoma antigen TRP‐2

Cited by 8 publications

References 20 publications

Lentiviral vectors for induction of self-differentiation and conditional ablation of dendritic cells

Lentiviral vectors for induction of self-differentiation and conditional ablation of dendritic cells

Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions

Detection of Spontaneous CD4+ T-Cell Responses in Melanoma Patients against a Tyrosinase-Related Protein-2–Derived Epitope Identified in HLA-DRB1*0301 Transgenic Mice

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