Immunodominant CD4
            <sup>+</sup>
            responses identified in a patient vaccinated with full-length NY-ESO-1 formulated with ISCOMATRIX adjuvant

Chen, Qiyuan; Jackson, Heather; Parente, Phillip; Luke, Tina; Rizkalla, Mark; Tai, Tsin Yee; Zhu, Hecheng; Mifsud, Nicole A.; Dimopoulos, Nektaria; Masterman, Kelly‐Anne; Hopkins, Wendie; Goldie, Heather; Maraskovsky, Eugene; Green, Simon; Miloradovic, Lena; McCluskey, James; Old, Lloyd J.; Davis, Ian D.; Cebon, Jonathan; Chen, Weisan

doi:10.1073/pnas.0403271101

Cited by 81 publications

(62 citation statements)

References 20 publications

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“…In this study, the new adjuvant ISCOMATRIX was used, which is able to stimulate CD4 + , CD8 + and antibody responses (17,30) and predominantly skews the immune response to a Th1 type (20), thus providing very favorable conditions to elicit a broad and efficient T cell response. A simple serologic analysis of the humoral immune response is enough for screening, whether the immune system reacted to the vaccine due to the interactions of the cellular and humoral immune system mentioned above.…”

Section: Discussionmentioning

confidence: 99%

Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad antibody responses in humans, a RAYS-based analysis

et al. 2011

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Abstract. Antibody responses to tumor antigens play an important role in initiating a cellular antitumor response with respect to antigen cross-presentation and T cell cross-priming. Successful vaccination strategies rely on an optimally timed activation of the humoral and cellular immune system by using appropriate adjuvant stimulation. The LUD99-008 trial used the cancer testis antigen NY-ESO-1 formulated with ISCOMATRIX adjuvant injected into patients intramuscularly. It was shown that this vaccination strategy is a safe and highly potent activator of the humoral and cellular immune system. Using the RAYS technology, we analyzed in detail the humoral immune response in these patients before and after vaccination: during the course of repeated vaccinations with the adjuvant, antibody titers against NY-ESO-1 and cross-reactivity to LAGE 1A and B increased as an indicator of an enhanced immune response, whereas no antibody response could be detected after vaccination without the adjuvant. Analysis of single fragments of the NY-ESO-1 protein revealed that the humoral response was almost exclusively directed against the N-terminal fragments and the number of fragments and their length being recognized by the NY-ESO-1-specific antibodies increased during the course of vaccination. The humoral immune response mainly consisted of antibodies of the IgG1 and IgG3 subclass. We rarely found IgG2 and IgG4 subclass antibodies. Our results support the implication that targetspecific antibodies raised after vaccination contribute to the stimulation of an effective T cell response against the target antigen. IntroductionBesides surgery, chemotherapy and radiation therapy, immunotherapy has emerged in the past decade as supplementary approach to fight cancer (1). Due to its specificity and efficacy, immunotherapy ideally targets the tumor selectively and spares normal tissue. A prerequisite in the field of cancer immunotherapy is the identification and characterization of appropriate target antigens for therapeutic approaches. In modern tumor serology, the powerful SEREX-technology (serological identification of antigens by recombinant expression cloning) allowed for the identification of a multitude of new cancer antigens in various tumor entities by screening of tumor-derived gene expression libraries with high-titered IgG antibodies obtained from the sera of cancer patients. The international SEREX database (www2.licr.org/Cancer ImmunomeDB/) by now holds >2000 different gene entries of potentially cancer related antigens. One group of antigens, the so-called cancer/testis antigens (CTAs) has gained special interest among the characterized tumor-specific antigens, as they are only expressed in the immunologically privileged germline cells and various types of human cancers but not in normal tissue (2-4). Of particular interest in this regard is the CTA NY-ESO-1. It is the most immunogenic CTA discovered so far and frequently elicits spontaneous humoral and cellular immune responses in patients with NY-ESO-1 expressing tumors...

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Section: Discussionmentioning

confidence: 99%

Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad antibody responses in humans, a RAYS-based analysis

et al. 2011

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“…The category of CT antigens is the common target for tumour immunotherapy in clinical trials, for example, NY-ESO-1 is a potent CT antigen and its eliciting integrated cellular and humoral responses have been observed in vaccinated patients in clinical trials, with little or no toxicity (Jager et al, 2000;Chen et al, 2004;Davis et al, 2004). The spontaneous CD8 þ T-cell response to HLA-A2-restricted NY-ESO-1b peptide in HCC has been reported by our group (Shang et al, 2004), and our application for clinical trial of NY-ESO-1b peptide vaccine for the immunotherapy in HCC patients is under way.…”

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confidence: 99%

Identification and analysis of tumour-associated antigens in hepatocellular carcinoma

Wang

et al. 2005

Br J Cancer

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To identify tumour and tumour-associated antigens in patients with hepatocellular carcinoma (HCC) one may find potential diagnostic markers and immunotherapeutic targets. In the current study, 30 distinct antigens reactive with serum IgG from HCC patients were identified by serological analysis of cDNA expression libraries (SEREX). The mRNA expression patterns of 14 of these 30 antigens were altered in cancer as further revealed by cDNA microarray, with upregulation for nine and downregulation for five antigens. One of the upregulated antigens was cancer-testis (CT) antigen (CAGE), which had been previously reported to be expressed exclusively in normal gametogenic tissues and aberrantly expressed in a variety of cancer cells. In our study, CAGE mRNA was expressed in 39.4% of HCC patients, 73.3% of patients with gastric cancer and 30.8% of patients with colorectal cancer. Antibodies against CAGE protein were detected in approximately 5.1% of the sera from HCC patients, 8.3% of that from gastric cancer patients and 7.3% of that from colorectal cancer patients. The relative high incidence of CAGE in cancer cells makes it a potential target for vaccine design. Another antigen of great interest is transgelin 2. The overexpression of transgelin 2 mRNA in a large per cent (69%) of HCC points to its potential as a diagnostic marker for HCC.

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“…Particularly, identification of this A*24:02 binding epitope and successful production of a tetramer with the epitope will be highly relevant when studying Japanese populations because of its high expression frequency (60%). Interestingly, within 25 HLA class I epitopes in the NY-ESO-1 molecule defined to date, [24][25][26] 15 epitopes including the epitopes shown in this study clustered in the peptide region NY-ESO-1 89-104. These findings suggested the usefulness of a long 20-mer NY-ESO-1f peptide harboring multiple CD8 T-cell epitopes for an NY-ESO-1 vaccine and this study indeed showed that vaccination with a long 20-mer NY-ESO-1f peptide elicited multiple HLA class I-restricted CD8 T-cell responses against the respective epitopes.…”

Section: Discussionmentioning

confidence: 99%

“…Essentially similar findings were obtained by studies using other preparations of NY-ESO-1 protein vaccine. 11,12,15 …”

mentioning

confidence: 99%

“…Essentially similar findings were obtained by studies using other preparations of NY-ESO-1 protein vaccine. 11,12,15 CD8 T-cells induced by immunization with NY-ESO-1 class I short epitope peptides have been shown to be of low affinity and do not recognize naturally processed NY-ESO-1 on tumor cells. 16 However, the advantage of synthetic long peptides over short peptides for use as vaccines has been reported.…”

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confidence: 99%

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Induction of CD8 T‐cell responses restricted to multiple HLA class I alleles in a cancer patient by immunization with a 20‐mer NY‐ESO‐1f (NY‐ESO‐1 91‐110) peptide

Eikawa

Kakimi

Isobe

et al. 2012

Intl Journal of Cancer

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Immunogenicity of a long 20-mer NY-ESO-1f peptide vaccine was evaluated in a lung cancer patient TK-f01, immunized with the peptide with Picibanil OK-432 and Montanide ISA-51. We showed that internalization of the peptide was necessary to present CD8 T-cell epitopes on APC, contrasting with the direct presentation of the short epitope. CD8 T-cell responses restricted to all five HLA class I alleles were induced in the patient after the peptide vaccination. Clonal analysis showed that B*35:01 and B*52:01-restricted CD8 T-cell responses were the two dominant responses. The minimal epitopes recognized by A*24:02, B*35:01, B*52:01 and C*12:02-restricted CD8 T-cell clones were defined and peptide/HLA tetramers were produced. NY-ESO-1 91-101 on A*24:02, NY-ESO-1 92-102 on B*35:01, NY-ESO-1 96-104 on B*52:01 and NY-ESO-1 96-104 on C*12:02 were new epitopes first defined in this study. Identification of the A*24:02 epitope is highly relevant for studying the Japanese population because of its high expression frequency (60%). High affinity CD8 T-cells recognizing tumor cells naturally expressing the epitopes and matched HLA were induced at a significant level. The findings suggest the usefulness of a long 20-mer NY-ESO-1f peptide harboring multiple CD8 T-cell epitopes as an NY-ESO-1 vaccine. Characterization of CD8 T-cell responses in immunomonitoring using peptide/HLA tetramers revealed that multiple CD8 T-cell responses comprised the dominant response.The NY-ESO-1 antigen was originally identified in esophageal cancer by serological expression cloning (SEREX) using autologous patient serum. 1,2 NY-ESO-1 expression is observed in a wide range of human malignancies, but the expression is restricted to germ cells in the testes in normal adult tissues. [1][2][3][4] Therefore, NY-ESO-1 has emerged as a prototype of a class of cancer/testis (CT) antigens. 5 The efficacy of the NY-ESO-1 antigen as a cancer vaccine has been studied extensively using various preparations, e.g., peptide, protein or DNA, etc. of the antigen with various adjuvants. [6][7][8][9][10][11][12][13][14] These studies established the safety of the NY-ESO-1 vaccine and demonstrated its immunogenicity.In a phase I clinical trial, we immunized cancer patients with a complex of cholesterol-bearing hydrophobized pullulan and NY-ESO-1 whole protein (CHP-NY-ESO-1) and showed that the vaccine had potent capacity to induce the NY-ESO-1 antibody in vaccinated patients. 13,14 The most dominant serological antigenic epitope was NY-ESO-1 91-108. The CHP-NY-ESO-1 vaccine also elicited CD4 and CD8 T-cell responses in immunized patients. 14 Analysis of T cell responses against overlapping peptides (OLPs) spanning the NY-ESO-1 molecule revealed that two dominant NY-ESO-1 regions, regions II (73-114) and III (121-144), were recognized by either CD4 or CD8 T-cells in most patients irrespective of their HLA type. Essentially similar findings were obtained by studies using other preparations of NY-ESO-1 protein vaccine. 11,12,15

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Immunodominant CD4 ⁺ responses identified in a patient vaccinated with full-length NY-ESO-1 formulated with ISCOMATRIX adjuvant

Cited by 81 publications

References 20 publications

Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad antibody responses in humans, a RAYS-based analysis

Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad antibody responses in humans, a RAYS-based analysis

Identification and analysis of tumour-associated antigens in hepatocellular carcinoma

Induction of CD8 T‐cell responses restricted to multiple HLA class I alleles in a cancer patient by immunization with a 20‐mer NY‐ESO‐1f (NY‐ESO‐1 91‐110) peptide

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Immunodominant CD4 + responses identified in a patient vaccinated with full-length NY-ESO-1 formulated with ISCOMATRIX adjuvant

Cited by 81 publications

References 20 publications

Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad antibody responses in humans, a RAYS-based analysis

Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad antibody responses in humans, a RAYS-based analysis

Identification and analysis of tumour-associated antigens in hepatocellular carcinoma

Induction of CD8 T‐cell responses restricted to multiple HLA class I alleles in a cancer patient by immunization with a 20‐mer NY‐ESO‐1f (NY‐ESO‐1 91‐110) peptide

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Product

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Immunodominant CD4 ⁺ responses identified in a patient vaccinated with full-length NY-ESO-1 formulated with ISCOMATRIX adjuvant