HLA‐A2‐restricted glypican‐3 peptide‐specific CTL clones induced by peptide vaccine show high avidity and antigen‐specific killing activity against tumor cells

Yoshikawa, Toshiaki; Nakatsugawa, Munehide; Suzuki, Shiro; Soejima, Hirofumi; Nobuoka, Daisuke; Sakemura, Noriko; Motomura, Yutaka; Tanaka, Yukië; Hayashi, Shin Ichi; Nakatsura, Tetsuya

doi:10.1111/j.1349-7006.2011.01896.x

Cited by 70 publications

(104 citation statements)

References 25 publications

(87 reference statements)

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“…Melanoma-associated antigen-specific high-avidity tumor-reactive CTL clones have been generated by CD107a-guided sorting (44). In our laboratory, we recently generated GPC3(144-152)-specific high-avidity tumor-reactive CTL clones by CD107a-guided sorting from PBMCs of patients vaccinated with GPC3(144-152) peptide (45). In this study, we evaluated tumor reactivity using CTL clones, but not bulk CTL populations.…”

Section: Discussionmentioning

confidence: 99%

Identification of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from the lung carcinoma antigen, Lengsin

et al. 2011

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Abstract.Lengsin is an eye lens protein with a glutamine synthetase domain. We previously identified this protein as a lung carcinoma antigen through cDNA microarray analysis. Lengsin protein is overexpressed irrespective of the histological type of lung carcinoma, but not in normal tissues other than the lens. Therefore, to significantly extend the use of Lengsinbased T-cell immunotherapies for the treatment of patients with lung carcinoma, we searched for HLA-A * 0201-restricted epitopes from this protein by screening predicted Lengsin-derived candidate peptides for the induction of tumor-reactive CTLs. Four Lengsin-derived peptides were selected by computerized algorithm based on a permissive HLA-A * 0201 binding motif, and were used to immunize HLA-A * 0201 transgenic (HHD) mice. Two of the immunizing peptides, Lengsin(206-215)(FIYDFCIFGV) and Lengsin(270-279)(FLPEFGISSA), induced peptide-specific cytotoxic T lymphocytes (CTLs) in HHD mice, and thus were used to stimulate human peripheral blood lymphocytes in vitro. and Lengsin (270-279) also induced human peptide-specific CTLs, and we were able to generate

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Section: Discussionmentioning

confidence: 99%

Identification of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from the lung carcinoma antigen, Lengsin

et al. 2011

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“…An ex vivo IFN-g enzyme-linked immunospot (ELISPOT) assay was conducted to measure the antigen-specific CTL response, as described previously (21). Briefly, peripheral blood (30 mL) was obtained from each patient before the first vaccination and 2 weeks after each vaccination and centrifuged with a Ficoll-Paque gradient.…”

Section: Measurement Of Immunologic Responsementioning

confidence: 99%

“…Noncultured PBMCs (5 Â 10 5 per well) were added to plates in the presence of peptide antigens (10 mg/mL) and incubated for 20 hours at 37 C in 5% CO 2 . The GPC3 antigen was the HLA-A2-restricted GPC3 144 C. Flow cytometry was carried out using a FACSAria cell sorter (BD Biosciences), as described previously (21).…”

Section: Measurement Of Immunologic Responsementioning

confidence: 99%

“…On the basis of these results, we conducted a phase I clinical trial of this GPC3-derived peptide vaccine in patients with advanced HCC. We previously reported that several GPC3 144-152 peptide-specific CTL clones were established from peripheral blood mononuclear cells (PBMC) of patients vaccinated with HLA-A2-restricted GPC3 [144][145][146][147][148][149][150][151][152] peptide in this trial (21). We recently completed this phase I clinical trial of the GPC3-derived peptide vaccine.…”

Section: Introductionmentioning

confidence: 99%

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Phase I Trial of a Glypican-3–Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential for Improving Overall Survival

Sawada

Yoshikawa

Nobuoka

et al. 2012

Clinical Cancer Research

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Purpose: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC.Experimental Design: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-g ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS).Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers a-fetoprotein and/or des-g-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N ¼ 15) than in those with low frequencies (N ¼ 18; P ¼ 0.033).Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination.

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“…We have shown that GPC3 is an ideal target for anticancer immunotherapy because its expression is specifically detected in ~80% of HCCs even in the early stages and is correlated with a poor prognosis (18)(19)(20)(21). Moreover, GPC3-specific cytotoxic T lymphocytes (CTLs) have a high level of killing activity against HCC tumor cells (22). We have finished the phase I clinical trial of a GPC3-derived peptide vaccine for patients with advanced HCC (unpublished data), and just started the phase II clinical trial for adjuvant therapy after curative resection or RFA.…”

Section: Radiofrequency Ablation For Hepatocellular Carcinoma Inducesmentioning

confidence: 99%

Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

et al. 2011

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Abstract. Glypican-3 (GPC3), a carcinoembryonic antigen, is an ideal target for anticancer immunotherapy against hepatocellular carcinoma (HCC). In this study, we attempted to compare the induction of the GPC3-specific T-cell-mediated immune response after locoregional therapies in HCC patients and tumor-bearing mice. Twenty-seven HCC patients treated with locoregional therapies, including radiofrequency ablation (RFA), surgical resection and transcatheter arterial chemoembolization (TACE), were prospectively enrolled in this study. Additionally, we performed RFA experiments using a mouse model. GPC3-specific T-cell response was investigated pretreatment and post-treatment by an interferon-γ enzyme-linked immunospot assay using peripheral blood mononuclear cells from HCC patients and lymph node cells from tumor-bearing mice. Circulating GPC3-specific cytotoxic T lymphocytes (CTLs) were increased in 5 of 9 patients after RFA and in 4 of 9 patients after TACE, but in only 1 of 9 patients after surgical resection. All 7 patients with GPC3-expressing HCCs exhibited an increase in GPC3-specific CTLs after RFA or TACE, whereas none of the 7 patients did after surgical resection. The number of increased GPC3-specific CTLs after RFA was significantly larger than that after surgical resection (P= 0.023). Similarly, the frequency of GPC3-specific CTLs after RFA was significantly greater than that after surgical resection in the mouse model (P=0.049). We validated for the first time the stronger effect on the immune system brought by RFA compared with surgical resection for HCC patients and tumor-bearing mice. Combined treatment of RFA and immunotherapy is a reasonable strategy against HCC. IntroductionHepatocellular carcinoma (HCC) is one of the most common and most serious cancers worldwide (1). Locoregional therapies, including radiofrequency ablation (RFA), surgical resection, and transcatheter arterial chemoembolization (TACE), are recognized as the gold-standard therapies for HCC patients whose cancer lesions are limited to the liver (2). However, the recurrence rate remains quite high despite potentially curative treatment (3,4). The reasons for this are as follows: first, a multicentric new tumor frequently occurs from underlying active hepatitis or cirrhosis and, second, a small tumor undetectable by imaging modalities frequently exists before treatment and would be left untreated (5). Therefore, the establishment of effective adjuvant therapy to prevent recurrence is urgently required, and Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

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HLA‐A2‐restricted glypican‐3 peptide‐specific CTL clones induced by peptide vaccine show high avidity and antigen‐specific killing activity against tumor cells

Cited by 70 publications

References 25 publications

Identification of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from the lung carcinoma antigen, Lengsin

Identification of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from the lung carcinoma antigen, Lengsin

Phase I Trial of a Glypican-3–Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential for Improving Overall Survival

Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

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