Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer

Abstract

NY-ESO-1 is a ''cancer-testis'' antigen expressed in epithelial ovarianHLA-DP4 ͉ peptide epitope ͉ tumor recognition ͉ vaccine T here is increasing evidence that the immune system has the ability to recognize tumor-associated antigens expressed in human malignancies and to induce antigen-specific humoral and cellular immune responses to these targets. In epithelial ovarian cancer (EOC), support for the role of immune surveillance of tumors comes from our recent observation indicating that the presence of intraepithelial CD8 ϩ -infiltrating T lymphocytes in tumors is associated with improved survival of patients with the disease (1). Although the majority of women with advanced-stage ovarian cancer respond to first-line chemotherapy, most of these responses are not durable, and Ͼ70% of patients die of recurrent disease within 5 years of diagnosis. Therefore, the development of strategies to enhance the potential of tumor antigen-specific CD8 ϩ T and CD4 ϩ T cells is urgently needed for extending remission rates in this disease. In this regard, cancer-testis antigens, a unique class of antigens that demonstrate high levels of expression in adult male germ cells but generally not in other normal adult tissues and aberrant expression in a variable proportion of a wide range of different cancer types, are promising candidates for immunotherapy. Among cancer-testis antigens, NY-ESO-1 (2) is one of the most spontaneously immunogenic tumor antigens described so far. Previously, we reported that NY-ESO-1 is a promising target for specific immunotherapy of EOC (3).Although the majority of cancer vaccine trials have focused on eliciting antigen-specific CD8 ϩ T cells, a growing body of evidence indicates that CD4 ϩ T cells play a pivotal role in orchestrating these responses. The multiple roles of antigen-specific CD4 ϩ T cells include the provision of help to CD8 ϩ T cells during the primary and secondary immune responses, direct cytolysis, and activation of B cells for production of tumor antigen-specific Abs. Therefore, we have focused on the NY-ESO-1 epitope, ESO 157-170 , a naturally processed helper epitope that is recognized by CD4 ϩ T cells in the context of HLA-DPB1*0401 and *0402 (4), prevalent MHC class II alleles present in Ϸ43-70% of Caucasians. Moreover, the NY-ESO-1 HLA-DP4 epitope has HLA-A2 (ESO 157-165 ) (5) and HLA-A24 (ESO 158-166 ) (6) motifs embedded in its natural sequence. In this study, we evaluated whether active immunization with ESO 157-170 would elicit NY-ESO-1-specific CD4 ϩ and CD8 ϩ T cell responses in ovarian cancer patients with minimal disease burden. In addition, we characterized NY-ESO-1-specific CD8 ϩ and CD4 ϩ T cell receptor (TCR) repertoires in conjunction with functional analysis of vaccine-elicited T cell clones.

An integrated humoral and cellular response is elicited in pancreatic cancer by α‐enolase, a novel pancreatic ductal adenocarcinoma‐associated antigen

“…The induction of an integrated humoral and cellular immune response to TAA has been proved to efficiently drive clinical responses by tumor patients. 42,43 Thus, the spontaneous humoral and cellular immune responses elicited by a-enolase in a subset of patients with a-enolase-expressing PDAC may be an highly favorable characteristic for a vaccine target.…”

Tumor-infiltrating NY-ESO-1–specific CD8 + T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer

“…In this study, we have focused on NY-ESO-1-specific CD8 + T cells detected directly ex vivo in human EOC specimens. We previously identified NY-ESO-1 as a prototypic tumor antigen target for specific immunotherapy of EOC (3,5) and are currently assessing the immunogenicity of NY-ESO-1-based candidate vaccines in early-phase clinical trials under the sponsorship of the Cancer Vaccine Collaborative (http://www. cancerresearch.org).…”

Immune targets and neoantigens for cancer immunotherapy and precision medicine

“…MAGE-A3 peptide/protein vaccines were also tested in phases II and III clinical trials [186][187][188], but a MAGE-A3 phase III clinical trial failed to meet the projected requirement in patients with resected nonsmall cell lung cancer. Consistent with these clinical development of cancer vaccines, phase I trials using NY-ESO-1 recombinant protein or synthetic peptides have been conducted in melanoma and ovarian cancer patients [189][190][191][192], showing that NY-ESO-1 vaccines can induce antigen-specific immune responses, but are insufficient to eradicate cancer cells. We recently completed a phase I clinical trial to evaluate the safety and feasibility of combined use of MHC class I and class II NY-ESO-1 peptides in metastatic prostate cancer patients.…”