The T�bingen approach: identification, selection, and validation of tumor-associated HLA peptides for cancer therapy

Singh‐Jasuja, Harpreet; Emmerich, Niels; Rammensee, Hans‐Georg

doi:10.1007/s00262-003-0480-x

Cited by 115 publications

(79 citation statements)

References 61 publications

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“…Novel epitopes specific for tumorassociated antigens should be designed using high throughput "omics" technology with the aim to induce antitumor CD4 + and CD8 + Tcell responses. In this context, high resolution mass spectrometry has been used for directly sequencing peptides presented by HLA molecules from tumor cells so as to identify naturally processed class Ⅰ and Ⅱ tumorassociated peptides [89] . Combining key components of the tumor microenvironment, as compared to chemotherapy alone, would improve the clinical outcome.…”

Section: Gaps In Existing Knowledgementioning

confidence: 99%

Immunology of hepatocellular carcinoma

Sachdeva

Chawla

Arora

2015

WJH

100

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Hepatocellular carcinoma (HCC) is primarily a malignancy of the liver, advancing from a damaged, cirrhotic liver to HCC. Globally, HCC is the sixth most prevalent cancer and the third-most prevalent reason for neoplastic disease-related deaths. A diverse array of infiltrating immunocytes regulates the development and progression of HCC, as is the case in many other cancers. An understanding of the various immune components during HCC becomes necessary so that novel therapeutic strategies can be designed to combat the disease. A dysregulated immune system (including changes in the number and/or function of immune cells, cytokine levels, and the expression of inhibitory receptors or their ligands) plays a key role in the development of HCC. Alterations in either the innate or adaptive arm of the immune system and cross-talk between them make the immune system tolerant to tumors, leading to disease progression. In this review, we have discussed the status and roles of various immune effector cells (e.g. , dendritic cells, natural killer cells, macrophages, and T cells), their cytokine profile, and the chemokine-receptor axis in promoting or impeding HCC.

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Section: Gaps In Existing Knowledgementioning

confidence: 99%

Immunology of hepatocellular carcinoma

Sachdeva

Chawla

Arora

2015

WJH

100

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“…1,2 Efforts to vaccinate patients to such antigens have yielded some provocative results, but only a small subset of patients have demonstrated therapeutic responses, likely reflecting the many in vivo obstacles to generating potent responses to these proteins, particularly in patients with an established malignancy. 3 An alternative approach of isolating and expanding reactive T cells ex vivo followed by adoptive transfer into the patient circumvents many of these in vivo obstacles.…”

Section: Introductionmentioning

confidence: 99%

Facilitating matched pairing and expression of TCR chains introduced into human T cells

Kuball

Dossett

Wölfl

et al. 2006

Blood

321

293

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IntroductionThe application of molecular technologies to identify proteins differentially expressed by transformed cells is providing large numbers of candidate antigens that can be potentially targeted to selectively eliminate tumor cells by cancer immunotherapy. 1,2 Efforts to vaccinate patients to such antigens have yielded some provocative results, but only a small subset of patients have demonstrated therapeutic responses, likely reflecting the many in vivo obstacles to generating potent responses to these proteins, particularly in patients with an established malignancy. 3 An alternative approach of isolating and expanding reactive T cells ex vivo followed by adoptive transfer into the patient circumvents many of these in vivo obstacles. Although this adoptive therapy approach has demonstrated significant clinical promise, 4 generating the large numbers of T cells required for adoptive therapy of cancer patients, particularly within the time constraints posed by progressive tumors, is often not feasible. Molecular technologies have now provided a means to more broadly capture the therapeutic potential of this treatment strategy. Genes encoding the ␣ and ␤ chains of a T-cell receptor (TCR) can be isolated from a T cell reactive with the antigen of interest and restricted to a defined HLA allele, inserted into a shuttle expression vector, and then introduced into large numbers of T cells of individual patients sharing the restricting allele and the targeted protein. 5 This approach is already being pursued clinically, 6 and the goal is to establish a library of such defined TCR genes that could provide reagents for treating a diverse set of patients and diseases. Multiple virus-and tumor-reactive TCR genes have already been successfully isolated and re-expressed in T cells, including TCR genes with specificity for HLA*0201 (HLA-A2)-restricted epitopes from melanoma antigens 7-9 and HLA-A2-and HLA*2402-restricted WT1-derived epitopes. 10,11 The avidity of a T cell for its target reflects many factors, including the affinity of the TCR for its cognate antigen 12 and the level of TCR expression. [13][14][15] One difficulty with the TCR-transfer approach is that the TCR-transduced T cells are often of lower avidity than the parental T cell from which the TCR was derived due to failure to achieve wild-type levels of TCR expression, which likely contributed to the limited efficacy observed in the recently reported clinical trial pursuing this strategy. 6 Thus, the TCR chains introduced into T cells need to be initially selected for appropriate affinity 10,16 and inserted into vectors that can achieve and maintain high-level expression. 17 However, even if these criteria are met, the introduced exogenous ␣ and ␤ chains can potentially assemble as pairs not only with each other but also with the endogenous TCR ␣ and ␤ chains, thereby reducing the number of appropriately matched exogenous ␣␤TCR pairs at the cell surface and decreasing the achievable T-cell avidity. Such mismatched pairing poses a second substantive p...

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“…In surmounting this obstacle, strategies to identify tumor rejection antigens (TRAs) are highly valuable (Boon et al 1995;Singh-Jasuja et al 2004), as are the now manifold means for promoting and enhancing CD8(ϩ) T lymphocyte responses to tumor tissue (reviewed in Marincola et al 2003;Mapara and Sykes 2004). From this perspective, the likelihood of generating a clinically effective, antitumor immune response should be enhanced by targeting a diversity of tumor-specific antigens and by enhanced costimulatory and innate immune activation.…”

Section: Introductionmentioning

confidence: 99%

The messenger and the message: gp96 (GRP94)-peptide interactions in cellular immunity

Nicchitta¹,

Carrick²,

Baker-LePain³

2004

Cell Stress Chaper

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Vaccination of mice with tumor-derived stress proteins, such as Hsp70 and gp96 (GRP94), can elicit antitumor immune responses, yielding a marked suppression of tumor growth and metastasis. The molecular basis for this response is proposed to reflect a peptide-binding function for these proteins. In this view, stress proteins bind the antigenic peptide repertoire of their parent cell, and when provided to the immune system, tumor-derived stress proteinpeptide complexes are processed by antigen-presenting cells (APCs) to yield the subsequent activation of tumordirected cytotoxic T lymphocyte activity. This model predicts that stress proteins, whose primary intracellular function concerns the proper folding and assembly of nascent polypeptides, intersect with the cellular pathways responsible for the generation, processing, or assembly (or all) of peptide antigens onto nascent major histocompatability class I molecules. Recent insights into the pathways for peptide generation now allow this hypothesis to be critically examined, which is the subject of this review.

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The T�bingen approach: identification, selection, and validation of tumor-associated HLA peptides for cancer therapy

Cited by 115 publications

References 61 publications

Immunology of hepatocellular carcinoma

Immunology of hepatocellular carcinoma

Facilitating matched pairing and expression of TCR chains introduced into human T cells

The messenger and the message: gp96 (GRP94)-peptide interactions in cellular immunity

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