Publications (12)73.7 Total impact
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Article: Phase I trial of overlapping long peptides from a tumor self-antigen and Poly-ICLC shows rapid induction of integrated immune response in ovarian cancer patients.
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ABSTRACT: PURPOSE: Long peptides are efficiently presented to both CD4+ and CD8+ T-cells after intracellular processing by antigen presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations. Experimental design: Twenty-eight advanced ovarian cancer patients in second or third remission were enrolled sequentially in 3 cohorts and received at least one vaccination. Patients in Cohort 1 (n=4) received 1.0 mg OLP, Cohort 2 (n=13) received OLP in Montanide-ISA-51, and Cohort 3 (n=11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, tetramer staining). RESULTS: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1-specific antibody and CD8+ T-cells were undetectable after vaccination with OLP alone, but found in 6/13 (46%) and 8/13 (62%) patients respectively after vaccination with OLP+Montanide, and in 10/11 (91%) and 10/11 (91%) patients respectively after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4+ T-cells were detected in all patients, with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as adjuvant further accelerated induction of NY-ESO-1-specific immune responses. CONCLUSIONS: The current study demonstrates that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8+ and CD4+) in nearly all vaccinated patients when given with appropriate adjuvants.Clinical Cancer Research 10/2012; · 7.74 Impact Factor -
Article: Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma.
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ABSTRACT: Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup.Investigational New Drugs 08/2012; · 3.36 Impact Factor -
Article: Immunoediting and persistence of antigen-specific immunity in patients who have previously been vaccinated with NY-ESO-1 protein formulated in ISCOMATRIX™.
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ABSTRACT: NY-ESO-1 protein formulated in ISCOMATRIX™ results in CD4+, CD8+ T cell and antibody-mediated immunity. We evaluated persistence of immunity, relapse-free survival and tumour antigen expression upon relapse in patients vaccinated in an earlier trial. Immunity was measured in 28 patients with resected NY-ESO-1-expressing tumours (melanoma 25, breast 3) 252-1,155 days (median = 681) after vaccination. In the earlier vaccination, trial patients received NY-ESO-1 with ISCOMATRIX™ adjuvant at three protein doses 10 μg, 30 μg or 100 μg (n = 14); 100 μg NY-ESO-1 protein (n = 8) or placebo (n = 6), together with 1 μg of intradermal (ID) NY-ESO-1 protein twice for DTH skin testing. Immune responses assessed in the current study included antibody titres, circulating NY-ESO-1-specific T cells and DTH reactivity 2 days after DTH skin testing with NY-ESO-1 protein (1 μg) or peptides (10 μg). Relapse-free survival was determined for 42 melanoma patients. On relapse NY-ESO-1 and HLA, class I was assessed by immunohistochemistry in 17. Persisting anti-NY-ESO-1 immunity was detected in 10/14 recipients who had previously received vaccine with ISCOMATRIX™ adjuvant. In contrast, immunity only persisted in 3/14 who received 100 μg un-adjuvanted NY-ESO-1 protein (3/8) or 2 μg DTH protein (0/6) P = 0.02. Hence, persisting NY-ESO-1 immunity was associated with prior adjuvant. Tumour NY-ESO-1 or HLA class I was downregulated in participants who relapsed suggesting immunoediting had occurred. Immunoediting suggests that a signal of anti-tumour activity was observed in high-risk resected melanoma patients vaccinated with NY-ESO-1/ISCOMATRIX™. This was associated with measurable persisting immunity in the majority of vaccinated subjects tested. A prospective randomised trial has been undertaken to confirm these results.Cancer Immunology and Immunotherapy 06/2011; 60(11):1625-37. · 3.70 Impact Factor -
Article: A phase I study of vaccination with NY‐ESO‐1f peptide mixed with Picibanil OK‐432 and Montanide ISA‐51 in patients with cancers expressing the NY‐ESO‐1 antigen
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ABSTRACT: We conducted a phase I clinical trial of a cancer vaccine using a 20-mer NY-ESO-1f peptide (NY-ESO-1 91–110) that includes multiple epitopes recognized by antibodies, and CD4 and CD8 T cells. Ten patients were immunized with 600 μg of NY-ESO-1f peptide mixed with 0.2 KE Picibanil OK-432 and 1.25 ml Montanide ISA-51. Primary end points of the study were safety and immune response. Subcutaneous injection of the NY-ESO-1f peptide vaccine was well tolerated. Vaccine-related adverse events observed were fever (Grade 1), injection-site reaction (Grade 1 or 2) and induration (Grade 2). Vaccination with the NY-ESO-1f peptide resulted in an increase or induction of NY-ESO-1 antibody responses in nine of ten patients. The sera reacted with recombinant NY-ESO-1 whole protein as well as the NY-ESO-1f peptide. An increase in CD4 and CD8 T cell responses was observed in nine of ten patients. Vaccine-induced CD4 and CD8 T cells responded to NY-ESO-1 91–108 in all patients with various HLA types with a less frequent response to neighboring peptides. The findings indicate that the 20-mer NY-ESO-1f peptide includes multiple epitopes recognized by CD4 and CD8 T cells with distinct specificity. Of ten patients, two with lung cancer and one with esophageal cancer showed stable disease. Our study shows that the NY-ESO-1f peptide vaccine was well tolerated and elicited humoral, CD4 and CD8 T cell responses in immunized patients.International Journal of Cancer 03/2011; 129(12):2836 - 2846. · 5.44 Impact Factor -
Article: Heteroclitic serological response in esophageal and prostate cancer patients after NY-ESO-1 protein vaccination.
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ABSTRACT: NY-ESO-1 is a prototypic cancer/testis antigen. In a recent phase I clinical trial, we vaccinated 13 patients bearing NY-ESO-1-expressing tumors with a complex of cholesterol-bearing hydrophobized pullulan (CHP) and NY-ESO-1 protein (CHP-NY-ESO-1) and showed efficient induction of NY-ESO-1 antibody, and CD4 and CD8 T cell responses using peripheral blood from the patients. In our study, we analyzed heteroclitic serological responses in those patients after vaccination. Serological response against 11 tumor antigens including MAGE-A1, MAGE-A3, MAGE-A4, CT7/MAGEC1, CT10/MAGEC2, CT45, CT46/HORMAD1, SOX2, SSX2, XAGE1B and p53 was examined by enzyme-linked immunosorbent assay (ELISA) using sera from ten vaccinated patients. Expression of tumor antigens was determined by reverse transcription-polymerase chain reaction or immunohistochemistry. Eight of nine patients who showed antibody responses against NY-ESO-1 also showed an antibody response against at least 1 of these 11 tumor antigens after vaccination. In one patient, seven tumor antigens were recognized. Specificity analysis of the antibody response by ELISA using control recombinant proteins and synthetic peptides and by Western blot showed that the response was not against His6-tag and/or bacterial products included in a preparation of CHP-NY-ESO-1 used for vaccination. Thus, heteroclitic serological responses appear to be indicative of the overall immune response against the tumor, and their analysis could be useful for immune monitoring in cancer vaccine.International Journal of Cancer 03/2011; 130(3):584-92. · 5.44 Impact Factor -
Article: A phase I study of vaccination with NY-ESO-1f peptide mixed with Picibanil OK-432 and Montanide ISA-51 in patients with cancers expressing the NY-ESO-1 antigen.
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ABSTRACT: We conducted a phase I clinical trial of a cancer vaccine using a 20-mer NY-ESO-1f peptide (NY-ESO-1 91-110) that includes multiple epitopes recognized by antibodies, and CD4 and CD8 T cells. Ten patients were immunized with 600 μg of NY-ESO-1f peptide mixed with 0.2 KE Picibanil OK-432 and 1.25 ml Montanide ISA-51. Primary end points of the study were safety and immune response. Subcutaneous injection of the NY-ESO-1f peptide vaccine was well tolerated. Vaccine-related adverse events observed were fever (Grade 1), injection-site reaction (Grade 1 or 2) and induration (Grade 2). Vaccination with the NY-ESO-1f peptide resulted in an increase or induction of NY-ESO-1 antibody responses in nine of ten patients. The sera reacted with recombinant NY-ESO-1 whole protein as well as the NY-ESO-1f peptide. An increase in CD4 and CD8 T cell responses was observed in nine of ten patients. Vaccine-induced CD4 and CD8 T cells responded to NY-ESO-1 91-108 in all patients with various HLA types with a less frequent response to neighboring peptides. The findings indicate that the 20-mer NY-ESO-1f peptide includes multiple epitopes recognized by CD4 and CD8 T cells with distinct specificity. Of ten patients, two with lung cancer and one with esophageal cancer showed stable disease. Our study shows that the NY-ESO-1f peptide vaccine was well tolerated and elicited humoral, CD4 and CD8 T cell responses in immunized patients.International Journal of Cancer 02/2011; 129(12):2836-46. · 5.44 Impact Factor -
Article: Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma.
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ABSTRACT: NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. We recently developed a vaccine consisting of full-length recombinant NY-ESO-1 protein formulated with ISCOMATRIX adjuvant, which generated strong humoral and T-cell-mediated immune responses and seemed to reduce the risk of disease relapse in patients with fully resected melanoma. This study examines the clinical and immunologic efficacy of the same vaccine in patients with advanced metastatic melanoma. Delayed-type hypersensitivity responses, circulating NY-ESO-1-specific CD4(+) and CD8(+) T cells, and proportions of regulatory T cells (Treg) were assessed in patients. In contrast to patients with minimal residual disease, advanced melanoma patients showed no clinical responses to vaccination. Although strong antibody responses were mounted, the generation of delayed-type hypersensitivity responses was significantly impaired. The proportion of patients with circulating NY-ESO-1-specific CD4(+) T cells was also reduced, and although many patients had CD8(+) T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting. Tregs were enumerated in the blood by flow cytometric detection of cells with a CD4(+)CD25(+)FoxP3(+) and CD4(+)CD25(+)CD127(-) phenotype. Patients with advanced melanoma had a significantly higher proportion of circulating Treg compared with those with minimal residual disease. Our results point to a tumor-induced systemic immune suppression, showing a clear association between the stage of melanoma progression, the number of Treg in the blood, and the clinical and immunologic efficacy of the NY-ESO-1 ISCOMATRIX cancer vaccine.Clinical Cancer Research 04/2009; 15(6):2166-73. · 7.74 Impact Factor -
Article: Immunization of malignant melanoma patients with full-length NY-ESO-1 protein using TLR7 agonist imiquimod as vaccine adjuvant.
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ABSTRACT: T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via TLRs. In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations against the cancer/testis Ag NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod preconditioned sites followed by additional topical applications of imiquimod. The regimen was very well tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod's in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs, NK cells, and, to a lesser extent, plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist used as a vaccine adjuvant in cancer patients. Imiquimod's adjuvant effects require further evaluation and likely need optimization of parameters such as formulation, dose, and timing relative to Ag exposure for maximal immunogenicity.The Journal of Immunology 08/2008; 181(1):776-84. · 5.79 Impact Factor -
Article: Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer.
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ABSTRACT: NY-ESO-1 is a "cancer-testis" antigen expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. The NY-ESO-1 peptide epitope, ESO(157-170), is recognized by HLA-DP4-restricted CD4+ T cells and HLA-A2- and A24-restricted CD8+ T cells. To test whether providing cognate helper CD4+ T cells would enhance the antitumor immune response, we conducted a phase I clinical trial of immunization with ESO(157-170) mixed with incomplete Freund's adjuvant (Montanide ISA51) in 18 HLA-DP4+ EOC patients with minimal disease burden. NY-ESO-1-specific Ab responses and/or specific HLA-A2-restricted CD8+ and HLA-DP4-restricted CD4+ T cell responses were induced by a course of at least five vaccinations at three weekly intervals in a high proportion of patients. There were no serious vaccine-related adverse events. Vaccine-induced CD8+ and CD4+ T cell clones were shown to recognize NY-ESO-1-expressing tumor targets. T cell receptor analysis indicated that tumor-recognizing CD4+ T cell clones were structurally distinct from non-tumor-recognizing clones. Long-lived and functional vaccine-elicited CD8+ and CD4+ T cells were detectable in some patients up to 12 months after immunization. These results confirm the paradigm that the provision of cognate CD4+ T cell help is important for cancer vaccine design and provides the rationale for a phase II study design using ESO(157-170) epitope or the full-length NY-ESO-1 protein for immunotherapy in patients with EOC.Proceedings of the National Academy of Sciences 08/2007; 104(31):12837-42. · 9.68 Impact Factor -
Article: Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming.
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ABSTRACT: The use of recombinant tumor antigen proteins is a realistic approach for the development of generic cancer vaccines, but the potential of this type of vaccines to induce specific CD8(+) T cell responses, through in vivo cross-priming, has remained unclear. In this article, we report that repeated vaccination of cancer patients with recombinant NY-ESO-1 protein, Montanide ISA-51, and CpG ODN 7909, a potent stimulator of B cells and T helper type 1 (Th1)-type immunity, resulted in the early induction of specific integrated CD4(+) Th cells and antibody responses in most vaccinated patients, followed by the development of later CD8(+) T cell responses in a fraction of them. The correlation between antibody and T cell responses, together with the ability of vaccine-induced antibodies to promote in vitro cross-presentation of NY-ESO-1 by dendritic cells to vaccine-induced CD8(+) T cells, indicated that elicitation of NY-ESO-1-specific CD8(+) T cell responses by cross-priming in vivo was associated with the induction of adequate levels of specific antibodies. Together, our data provide clear evidence of in vivo cross-priming of specific cytotoxic T lymphocytes by a recombinant tumor antigen vaccine, underline the importance of specific antibody induction for the cross-priming to occur, and support the use of this type of formulation for the further development of efficient cancer vaccines.Proceedings of the National Academy of Sciences 06/2007; 104(21):8947-52. · 9.68 Impact Factor -
Article: LUD 00-009: phase 1 study of intensive course immunization with NY-ESO-1 peptides in HLA-A2 positive patients with NY-ESO-1-expressing cancer.
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ABSTRACT: NY-ESO-1 is a cancer-testis antigen and an attractive target for immunotherapy in patients with different malignancies. Here we report the results of a phase I clinical study of intensive course NY-ESO-1 peptide vaccination, evaluating the safety, immunogenicity and clinical response in HLA-A2 positive patients with NY-ESO-1 expressing cancers. Of 20 patients enrolled in the trial, 14 completed at least 2 cycles of immunization and were evaluable for clinical and immunological response. Five of these evaluable patients were treated in cohort 1 (baseline seropositive) and 9 patients were treated in cohort 2 (baseline seronegative). During vaccination, NY-ESO-1-specific CD8+ T-cells were induced in 3 of 9 baseline seronegative patients. In patients with pre-existing antigen-specific CD8+ T-cells, their number increased or remained stable. In contrast to previous immunization protocols with less intensive immunization schedules, we observed a rapid induction of high magnitude NY-ESO-1 peptide-specific T-cell responses detectable already on day 15-22 of immunization. A specific immune response of high magnitude and early onset may be more effective in eliminating minimal residual disease in adjuvant treatment situations and in preventing tumor progression due to immune escape mechanisms.Cancer immunity: a journal of the Academy of Cancer Immunology 02/2007; 7:16. -
Article: Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients.
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ABSTRACT: NY-ESO-1 is a cancer/testis antigen expressed in a range of human malignancies, and a number of vaccine strategies targeting NY-ESO-1 are being developed. In the present study, the safety and immunogenicity of recombinant vaccinia-NY-ESO-1 and recombinant fowlpox-NY-ESO-1 were analyzed in a series of 36 patients with a range of different tumor types. Each construct was first tested individually at two different dose levels and then in a prime-boost setting with recombinant vaccinia-NY-ESO-1 followed by recombinant fowlpox-NY-ESO-1. The vaccines were well tolerated either individually or together. NY-ESO-1-specific antibody responses and/or specific CD8 and CD4 T cell responses directed against a broad range of NY-ESO-1 epitopes were induced by a course of at least four vaccinations at monthly intervals in a high proportion of patients. CD8 T cell clones derived from five vaccinated patients were shown to lyse NY-ESO-1-expressing melanoma target cells. In several patients with melanoma, there was a strong impression that the natural course of the disease was favorably influenced by vaccination.Proceedings of the National Academy of Sciences 10/2006; 103(39):14453-8. · 9.68 Impact Factor
Top co-authors
Top Journals
Institutions
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2011
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Tokyo Medical University
Tokyo, Tokyo-to, Japan -
Kawasaki Medical University
- Department of Respiratory Medicine
Kurashiki, Okayama-ken, Japan -
Osaka City University
- Graduate School of Medicine
Ōsaka-shi, Osaka-fu, Japan
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2007–2011
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The Ludwig Institute for Cancer Research USA
New York City, NY, USA
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2006–2007
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Memorial Sloan-Kettering Cancer Center
New York City, NY, USA
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