Directions in the immune targeting of cancer: Lessons learned from the cancer‐testis Ag NY‐ESO‐1

Abstract

Summary Since the early 1990s, numerous cancer Ag have been defined and for a handful of these there is now some clinical experience, which has made it possible to assess their value as targets for cancer immunotherapy. The cancer-testis Ag have been particularly attractive because their expression is limited to cancer and virtually no nonmalignant cells apart from germ cells and trophoblast. Among these, NY-ESO-1 has been the focus of our attention. The exceptional immunogenicity of this Ag coupled with its widespread distribution among many cancer types make it a very good vaccine candidate, with the potential to be used in vaccines against many types of malignancies. This article reviews emerging knowledge about the biology of NY-ESO-1 and experience with the early clinical development of vaccines directed against NY-ESO-1. These early studies have yielded a wealth of information about the immunology of NY-ESO-1 and set the scene for future clinical strategies for immune targeting of cancer.Key words: cancer immunology, cancer-testis Ag, cancer vaccine, dendritic cell, ISCOMATRIX, NY-ESO-1. Biology of NY-ESO-1NY-ESO-1 was first discovered using 'SERological identification of antigens by recombinant EXpression cloning' (SEREX). This is a method used for identifying the antibody repertoire of cancer-bearing patients by screening their serum against an expression library that typically displays protein Ag derived from a cancer source such as an autologous tumour or a cell line. In this case, NY-ESO-1 was found by using serum from a patient with squamous cell carcinoma (SCC) of the oesophagus. 1,2 Expression of NY-ESO-1 protein has been shown in multiple cancer types (Table 1), as well as in spermatogonia, oogonia and placenta. 3,4 Although NY-ESO-1 mRNA expression has been detected at low levels in some other normal tissues, it is unclear whether this is significant in the absence of detectable protein. 4,5 Other genes with similar names (NY-ESO-2, -3, -4, -5, -6, -7, -8) have no homology with NY-ESO-1. 2 The NY-ESO-1 gene is located on chromosome Xq28, 1 which carries a disproportionately high number of cancertestis (CT) Ag genes. 6 Up to 10% of the genes on chromosome X are CT Ag genes. The expression of these genes seems to be related to the demethylation of the promoter regions because experimental demethylation leads to the upregulation of CT Ag expression. [7][8][9][10][11][12][13][14][15][16][17][18] The NY-ESO-1 gene encodes a protein of 180 amino acids with M r 18 kDa, 2 which is expressed primarily in the cytoplasm although nuclear expression can be seen in some spermatogonia. 4 A homologue of NY-ESO-1, termed LAGE-1, was identified using representational difference analysis. 14 LAGE-1 and NY-ESO-1 are 84-89% homologous at the protein level. 14 Alternative splicing of LAGE-1 mRNA leads to the expression of two major transcripts encoding proteins of 210 and 180 amino acids, respectively. LAGE-1 is expressed in a wide variety of cancers (Table 1), usually, but not always, in conjunction with NY-ESO-1 or ...

MAGE-C1/CT7 is the dominant cancer-testis antigen targeted by humoral immune responses in patients with multiple myeloma

“…Similar observations were made previously for other tumor antigens such as NY-ESO-1. 8 The present study demonstrates the immunogenicity of CT7 in vivo, which leads to high frequency of specific IgG Abs in patients with MM. This observation is intriguing, since recent work suggests an underlying alteration in anti-myeloma immunity.…”

“…6 Hence, the observed specific immune responses against CT7 underline that anti-myeloma immunity may be generated in patients and may overcome at least in part those immunomodulatory mechanisms. On the basis of the observed close association between T-cell reactivity and NY-ESO-1 Ab status, 8 the presence of spontaneous Ab responses toward CT7 suggests that there may already exist a reservoir of CT7-specific T cells. Importantly, those T cells may be targeted in active immunotherapy approaches.…”

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

“…2,3 NY-ESO-1 is of particular interest to researchers and clinicians because it is highly immunogenic and is expressed in a variety of carcinomas, melanomas, and sarcomas. 4 A recent clinical trial of adoptive immunotherapy, using genetically modified T cells directed against NY-ESO-1, demonstrated objective clinical responses in a number of metastatic synovial sarcoma and melanoma patients with NY-ESO-1-positive tumors. 5 The results of that clinical trial highlight the potential effectiveness of immunotherapy against tumors expressing NY-ESO-1, and several clinical trials (using antigen sensitization, adoptive T-cell transfer, and dendritic cell vaccine strategies) are currently underway.…”

NY-ESO-1 is a sensitive and specific immunohistochemical marker for myxoid and round cell liposarcomas among related mesenchymal myxoid neoplasms

“…5 NY-ESO-1 is a highly immunogenic cancer testis antigen that is present in a variety of malignancies, including melanoma, sarcomas, and carcinomas. [7][8][9][10] Prompted by recent studies showing frequent expression of the cancer testis antigen NY-ESO-1 in myxoid and round cell liposarcoma, we sought to evaluate the utility of NY-ESO-1 as an immunohistochemical marker for this tumor type among mesenchymal myxoid neoplasms within the differential diagnosis, including extra-cardiac soft tissue myxomas, myxofibrosarcomas, low-grade fibromyxoid sarcomas, well-differentiated liposarcomas, lipomas, and extraskeletal myxoid chondrosarcoma. 11,12 …”