Functional T Cells Targeting NY-ESO-1 or Melan-A Are Predictive for Survival of Patients With Distant Melanoma Metastasis

Weide, Benjamin; Zelba, Henning; Derhovanessian, Evelyna; Pflugfelder, Annette; Eigentler, Thomas; Giacomo, Anna Maria Di; Maio, Michele; Aarntzen, Erik H.J.G.; Vries, I. Jolanda M. de; Sucker, Antje; Schadendorf, Dirk; Büttner, Petra; Garbe, Claus; Pawelec, Graham

doi:10.1200/jco.2011.40.2271

Cited by 113 publications

(112 citation statements)

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“…These data show that ERAP1/2 negatively contributes to MART-1 [26][27][28][29][30][31][32][33][34][35] epitope generation and that in particular, ERAP1 is responsible for the impairment of epitope presentation by IFN-γ. To study the underlying molecular mechanism, we next performed in vitro trimming experiments using recombinant ERAPs in combination with the N-terminally extended 14-mer epitope precursor peptide MART-1 [22][23][24][25][26][27][28][29][30][31][32][33][34][35] . As shown by reversed-phase HPLC analyses, ERAP1 efficiently trimmed the MART-1 [22][23][24][25][26][27][28][29][30][31][32][33][34][35] precursor peptide.…”

Section: Erap1 Mediates Mart-1 26-35 Epitope Destructionmentioning

confidence: 99%

“…Understanding the role of different antigen-processing components and the underlying mechanisms in the generation of tumor antigen epitopes is of major importance in the light of recent advances in T-cell-based melanoma immunotherapy [20][21][22]. Here, we studied the processing of the 10-mer MART-1 [26][27][28][29][30][31][32][33][34][35] epitope as a model system.…”

Section: Introductionmentioning

confidence: 99%

“…In this context, increased epitope generation has been preferentially attributed to ERAP1, whereas the role of ERAP2 in epitope processing is still under debate [16]. Varying expression levels of ERAP1/2 have been described in different tumor entities with high/moderate expression in melanoma tissue, low levels in colon and lung cancer, and imbalanced expression in renal cell carcinoma [17][18][19].Understanding the role of different antigen-processing components and the underlying mechanisms in the generation of tumor antigen epitopes is of major importance in the light of recent advances in T-cell-based melanoma immunotherapy [20][21][22]. Here, we studied the processing of the 10-mer MART-1 26-35 epitope as a model system.…”

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confidence: 99%

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The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐1_26‐35‐specific T‐cell recognition

et al. 2015

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Eur. J. Immunol. 2015. 45: 3257-3268 IntroductionThe differentiation antigen melanoma antigen recognized by T cells/melanoma antigen A (thereafter named MART-1) has been a major target in antigen-specific immunotherapy of malignant melanoma and in particular its immunodominant HLA-A*0201-restricted CD8 + T-cell epitope MART-1 26(27)-35 [1,2]. But clinical efficacy of different MART-1-specific therapies has only been limited. In vitro studies employing high-affinity MART-1-specific CD8 + T-cell clones demonstrated that some melanoma cell lines, despite expression of MART-1 and the corresponding HLA allele, were only barely recognized by specific T cells [3]. While different variants of the MART-1 epitope (including the MART-1 [26][27][28][29][30][31][32][33][34][35] 10-mer and the MART-1 27-35 9-mer) have been identified, only the 9-mer epitope can be eluted in significant amounts from the cell surface of melanoma cells [4]. This suggests that mechanisms related to antigen processing interfere with efficient generation of the 10-mer MART-1 26-35 epitope in tumor cells. It has been demonstrated that MART-1 26-35 epitope processing is controlled by the proteasome, the major proteolytic machinery of the cytosol [5]. The standard proteasome (SP) contains the catalytic subunits β1, β2, and β5, whereas exposure of cells to IFN-γ enhances expression and incorporation of the immunosubunits β1i/LMP2 (LMP, low molecular weight protein), β2i/MECL-1 (multicatalytic endopeptidase complex-like 1), and β5i/LMP7 into nascent proteasome complexes. Immunosubunit-containing proteasomes represent catalytic properties that are different from that of SPs [6]. Interestingly, IFN-γ has been described to interfere with efficient MART-1 26-35 epitope generation due to the activity of the proteasome immunosubunits β1i/LMP2 and β5i/LMP7 [5,7,8].To degrade cellular proteins in an ubiquitin-dependent manner, 20S catalytic core particles are connected to 19S regulatory complexes. In the presence of IFN-γ, the expression of PA28α/β (PA, proteasome activator), an activator complex that in combination with the 19S regulatory complex and the 20S proteasome forms so-called PA28-20S-19S hybrid proteasome complexes, is induced [9,10]. The PA28 has been associated with positive effects on epitope processing due to facilitating the access of substrates to the active sites of the proteasome. Generation of the TRP2 360-368 epitope derived from the melanoma antigen tyrosinase-related protein 2 (TRP2) was shown to be completely dependent on PA28 activity by influencing the proteasomal structure and cleavage specificity [11]. Moreover, IFN-γ induces the expression of the ER-resident aminopeptidases ERAP1/2 that trim epitope precursor peptides released into the ER to bind MHC class I molecules [12][13][14][15]. In this context, increased epitope generation has been preferentially attributed to ERAP1, whereas the role of ERAP2 in epitope processing is still under debate [16]. Varying expression levels of ERAP1/2 have been described in different tumor enti...

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Section: Erap1 Mediates Mart-1 26-35 Epitope Destructionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐1_26‐35‐specific T‐cell recognition

et al. 2015

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“…NY-ESO-1-and Melan-A-specific T-cell responses were detected as described previously (31). Influenza-specific T-cell responses were also analyzed as a control.…”

Section: Analysis Of Immune Cell Subsetsmentioning

confidence: 99%

“…S2. Data interpretation for the analysis of antigen-specific T cells was performed as described in detail elsewhere (31).…”

Section: Analysis Of Immune Cell Subsetsmentioning

confidence: 99%

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

Weide¹,

Eigentler²,

Pflugfelder³

et al. 2014

Cancer Immunology Research

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L19-IL2 is a recombinant protein comprising the cytokine IL2 fused to the single-chain monoclonal antibody L19. In previous studies, intralesional injection with IL2 has shown efficacy for the locoregional treatment of cutaneous/subcutaneous metastases in patients with advanced melanoma. The objectives of this study were to investigate whether (i) intralesional delivery of a targeted form of IL2 would yield similar results, with reduction of injection frequency and treatment duration; and (ii) systemic immune responses were induced by the local treatment. Patients with stage IIIB/IIIC melanoma and cutaneous/subcutaneous injectable metastases received weekly intratumoral injections of L19-IL2 at a maximum dose of 10 MIU/week for 4 consecutive weeks. Tumor response was evaluated 12 weeks after the first treatment. Twenty-four of 25 patients were evaluable for therapyinduced responses. A complete response (CR) by modified immune-related response criteria (irRC) of all treated metastases was achieved in 6 patients (25%), with long-lasting responses in most cases (5 patients for !24 months). Objective responses were documented in 53.9% of all index lesions [44.4% CR and 9.5% partial responses (by irRC)], and 36.5% of these remained stable, while 9.5% progressed. Toxicity was comparable with that of free IL2, and no serious adverse events were recorded. A significant temporary increase of peripheral regulatory T cells and natural killer cells, sustained increase of absolute CD4 þ lymphocytes, and decrease of myeloid-derived suppressor cells were observed upon treatment. Finally, we recorded encouraging data about the progression time to distant metastases and overall survival. Cancer Immunol Res; 2(7); 668-78. Ó2014 AACR.

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PD-1 Blockade in Melanoma

Bhatia

Thompson

2016

JAMA

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Immune checkpoint blockade with anti-PD-1 antibodies is showing great promise for patients with metastatic melanoma and other malignancies, but despite good responses by some patients who achieve partial or complete regression, many others still do not respond. Here, we sought peripheral blood T-cell biomarker candidates predicting treatment outcome in 75 stage IV melanoma patients treated with anti-PD-1 antibodies. We investigated associations with clinical response, progression-free survival (PFS) and overall survival (OS). Univariate analysis of potential biological confounders and known biomarkers, and a multivariate model, was used to determine statistical independence of associations between candidate biomarkers and clinical outcomes. We found that a lower than median frequency of peripheral PD-1+CD56+ T-cells was associated with longer OS (p = 0.004), PFS (p = 0.041) and superior clinical benefit (p = 0.009). However, neither frequencies of CD56-CD4+ nor CD56-CD8+ T-cells, nor of the PD-1+ fraction within the CD4 or CD8 subsets was associated with clinical outcome. In a multivariate model with known confounders and biomarkers only the M-category (HR, 3.11; p = 0.007) and the frequency of PD-1+CD56+ T-cells (HR, 2.39; p = 0.028) were identified as independent predictive factors for clinical outcome under PD-1 blockade. Thus, a lower than median frequency of peripheral blood PD-1+CD56+ T-cells prior to starting anti-PD-1 checkpoint blockade is associated with superior clinical response, longer PFS and OS of stage IV melanoma patients.

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Functional T Cells Targeting NY-ESO-1 or Melan-A Are Predictive for Survival of Patients With Distant Melanoma Metastasis

Abstract: The presence of circulating T cells responding to Melan-A or NY-ESO-1 had strong independent prognostic impact on survival in advanced melanoma. Our findings support the therapeutic relevance of Melan-A and NY-ESO-1 as targets for immunotherapy.

Cited by 113 publications

References 34 publications

The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐1_26‐35‐specific T‐cell recognition

The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐1_26‐35‐specific T‐cell recognition

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

PD-1 Blockade in Melanoma

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Functional T Cells Targeting NY-ESO-1 or Melan-A Are Predictive for Survival of Patients With Distant Melanoma Metastasis

Abstract: The presence of circulating T cells responding to Melan-A or NY-ESO-1 had strong independent prognostic impact on survival in advanced melanoma. Our findings support the therapeutic relevance of Melan-A and NY-ESO-1 as targets for immunotherapy.

Cited by 113 publications

References 34 publications

The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐126‐35‐specific T‐cell recognition

The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐126‐35‐specific T‐cell recognition

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

PD-1 Blockade in Melanoma

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Product

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The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐1_26‐35‐specific T‐cell recognition

The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐1_26‐35‐specific T‐cell recognition