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Review
. 2015 May;106(5):505-11.
doi: 10.1111/cas.12650. Epub 2015 Apr 1.

Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses

Yasuharu Nishimura  1 , Yusuke Tomita  1   2 , Akira Yuno  1   3 , Yoshihiro Yoshitake  3   4 , Masanori Shinohara  3   4
Affiliations
Review

Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses

Yasuharu Nishimura et al. Cancer Sci. 2015 May.

Abstract

Recent genome-wide cDNA microarray analysis of gene expression profiles in comprehensive tumor types coupled with isolation of cancer tissues by laser-microbeam microdissection have revealed ideal tumor-associated antigens (TAAs) that are frequently overexpressed in various cancers including head and neck squamous cell cancer (HNSCC) and lung cancer, but not in most normal tissues except for testis, placenta, and fetal organs. Preclinical studies using HLA-transgenic mice and human T cells in vitro showed that TAA-derived CTL-epitope short peptides (SPs) are highly immunogenic and induce HLA-A2 or -A24-restricted CTLs. Based on the accumulated evidence, we carried out a phase II clinical trial of the TAA-SP vaccine in advanced 37 HNSCC patients. This study showed a significant induction of TAA-specific CTLs in the majority of patients without serious adverse effects. Importantly, clinical responses including a complete response were observed in this study. Another phase II clinical trial of therapeutic TAA-SP vaccine, designed to evaluate the ability of prevention of recurrence, is ongoing in HNSCC patients who have received curative operations. Further studies in human preclinical studies and in vivo studies using HLA class I transgenic mice showed TAA-derived long peptides (TAA-LPs) have the capacity to induce not only promiscuous HLA class II-restricted CD4(+) T helper type 1 cells but also tumor-specific CTLs through a cross-presentation mechanism. Moreover, we observed an augmentation of TAA-LP-specific T helper type 1 cell responses and tumor antigen-spreading in HNSCC patients vaccinated with TAA-SPs. This accumulated evidence suggests that therapeutic TAA-SPs and LPs vaccines may provide a promising cancer immunotherapy.

Keywords: CTL epitope; Cancer immunotherapy; cDNA microarray analysis; helper T-cell epitope; tumor-associated antigen.

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Figures

Fig 1
Fig 1
Application of a genome-wide cDNA microarray analysis for identification of ideal tumor-associated antigens (TAAs). The genome-wide cDNA microarray analysis provides us with comprehensive data for gene expression profiles of both normal and cancerous tissues. These data allow us to identify new and ideal TAAs frequently overexpressed in various malignant tumors and applicable as targets of cancer immunotherapy.
Fig 2
Fig 2
Identification of tumor-associated antigen (TAA)-derived short peptides (SPs) recognized by CTLs and their application to cancer immunotherapy. We have identified many TAA-derived SPs recognized by HLA-A2 or A24-restricted CTLs using HLA transgenic mice in vivo and human T cells in in vitro studies. We have succeeded in induction of cancer–testis antigen-derived SP-specific CTLs in many head and neck squamous cell carcinoma (HNSCC) patients and a prolongation of survival period in a small fraction of patients by vaccination with three cancer–testis antigen-derived SPs. CR, complete response; ELISPOT, Enzyme-Linked ImmunoSpot assay; E/T, effector/target.
Fig 3
Fig 3
Positive results of a phase II clinical trial of three short peptide (SP)-based cancer immunotherapy for head and neck squamous cell carcinoma patients. (a) Prolongation of overall survival (OS) was observed in HLA-A24-positive HNSCC patients vaccinated with three tumor-associated antigen-derived SP vaccination compared to HLA-A24-negative patients treated with best supportive care without vaccination. (b) Longer prolongation of OS was observed in vaccinated patients showing positive CTL responses to multiple peptides. The OS was analyzed according to the Kaplan–Meier method, and statistical differences were assessed using the log–rank test. These figures are modified from figures 1A and 3A of our recent publication Yoshitake et al.
Fig 4
Fig 4
Development of effective cancer immunotherapy using tumor-associated antigens (TAA)-derived long peptides (LPs) carrying both T helper 1 (Th1) cells and CTL epitopes. We attempted to identify TAA-derived LPs (TAA-LPs) encompassing both LP-specific Th1 cells and CTL epitopes in order to further improve TAA-derived peptide-based cancer immunotherapy. We have succeeded in identification of highly immunogenic TAA-LPs activating both promiscuous HLA class II-restricted Th1 cells and CTLs specific to short peptides (SPs) cross-presented from TAA-LPs by dendritic cells. IFN-γ, γ-interferon; IL-2, interleukin-2.
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