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Suwabe T, Shibasaki Y, Tamura S, Katagiri T, Fuse K, Ida-Kurasaki T, Ushiki T, Sone H, Narita M, Masuko M. Decade-long WT1-specific CTLs induced by WT1 peptide vaccination. Int J Hematol 2024; 119:399-406. [PMID: 38427208 DOI: 10.1007/s12185-024-03723-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 01/17/2024] [Accepted: 01/25/2024] [Indexed: 03/02/2024]
Abstract
INTRODUCTION The peptide-based cancer vaccine targeting Wilms' tumor 1 (WT1) is a promising immunotherapeutic strategy for hematological malignancies. It remains unclear how long and to what extent the WT1-specific CD8 + cytotoxic T cell (CTL) persist after WT1 peptide vaccination. METHODS The WT1 peptide vaccine was administered with written consent to a patient with CML in the chronic phase who did not respond well to imatinib, and the patient was followed for 12 years after vaccination. Immune monitoring was performed by specific amplification of WT1-specific CTLs using a mixed lymphocyte peptide culture. T-cell receptors (TCRs) of amplified WT1-specific CTLs were analyzed using next-generation sequencing. This study was approved by the Institutional Review Board of our institution. RESULT WT1-specific CTLs, which were initially detected during WT1 peptide vaccination, persisted at a frequency of less than 5 cells per 1,000,000 CD8 + T cells for more than 10 years. TCR repertoire analysis confirmed the diversity of WT1-specific CTLs 11 years after vaccination. CTLs exhibited WT1 peptide-specific cytotoxicity in vitro. CONCLUSION The WT1 peptide vaccine induced an immune response that persists for more than 10 years, even after cessation of vaccination in the CML patient.
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Affiliation(s)
- Tatsuya Suwabe
- Department of Hematopoietic Stem Cell Transplantation, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Yasuhiko Shibasaki
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, 1-754 Asahimachi-Dori, Chuo-Ku, Niigata City, Niigata, 951-8510, Japan
| | - Suguru Tamura
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, 1-754 Asahimachi-Dori, Chuo-Ku, Niigata City, Niigata, 951-8510, Japan
| | - Takayuki Katagiri
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, 1-754 Asahimachi-Dori, Chuo-Ku, Niigata City, Niigata, 951-8510, Japan
| | - Kyoko Fuse
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, 1-754 Asahimachi-Dori, Chuo-Ku, Niigata City, Niigata, 951-8510, Japan
| | - Tori Ida-Kurasaki
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, 1-754 Asahimachi-Dori, Chuo-Ku, Niigata City, Niigata, 951-8510, Japan
| | - Takashi Ushiki
- Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan
| | - Hirohito Sone
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, 1-754 Asahimachi-Dori, Chuo-Ku, Niigata City, Niigata, 951-8510, Japan
| | - Miwako Narita
- Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan
| | - Masayoshi Masuko
- Department of Hematopoietic Stem Cell Transplantation, Niigata University Medical and Dental Hospital, Niigata, Japan.
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Mun SS, Meyerberg J, Peraro L, Korontsvit T, Gardner T, Malviya M, Kyi C, O'Cearbhaill RE, Liu C, Dao T, Scheinberg DA. Dual targeting ovarian cancer by Muc16 CAR T cells secreting a bispecific T cell engager antibody for an intracellular tumor antigen WT1. Cancer Immunol Immunother 2023; 72:3773-3786. [PMID: 37635172 PMCID: PMC10991175 DOI: 10.1007/s00262-023-03529-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 08/14/2023] [Indexed: 08/29/2023]
Abstract
Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR T cell therapy in epithelial ovarian cancer and other cancers.
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Affiliation(s)
- Sung Soo Mun
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Jeremy Meyerberg
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Leila Peraro
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Tatyana Korontsvit
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Thomas Gardner
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Manish Malviya
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Chrisann Kyi
- Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Roisin E O'Cearbhaill
- Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Cheng Liu
- Eureka Therapeutics, Inc., Emeryville, CA, USA
| | - Tao Dao
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - David A Scheinberg
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
- Weill Cornell Medical College, New York, NY, USA.
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Mun SS, Peraro L, Meyerberg J, Korontsvit T, Malviya M, Gardner T, Kyi C, O'Cearbhaill RE, Liu C, Dao T, Scheinberg DA. Dual targeting ovarian cancer by Muc16 CAR-T cells secreting a bispecific T cell engager antibody for an intracellular tumor antigen WT1. RESEARCH SQUARE 2023:rs.3.rs-2887299. [PMID: 37214945 PMCID: PMC10197740 DOI: 10.21203/rs.3.rs-2887299/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR-T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR-T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR-T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR-T cell therapy in epithelial ovarian cancer and other cancers.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Tao Dao
- Memorial Sloan Kettering Cancer Center
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Alzaaqi S, Naka N, Hamada K, Hosen N, Kanegae M, Outani H, Adachi M, Imanishi R, Morii E, Iwai M, Nakata J, Fujiki F, Morimoto S, Nakajima H, Nishida S, Tsuboi A, Oka Y, Sugiyama H, Oji Y. WT1 epitope‑specific IgG and IgM antibodies for immune‑monitoring in patients with advanced sarcoma treated with a WT1 peptide cancer vaccine. Oncol Lett 2022; 23:65. [PMID: 35069874 PMCID: PMC8756391 DOI: 10.3892/ol.2022.13184] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 12/03/2021] [Indexed: 11/17/2022] Open
Abstract
The Wilms' tumor gene WT1 is highly expressed in various malignancies and may be a common target antigen for cancer immunotherapy. In our group, peptide-based cancer vaccines targeting WT1 CTL epitopes were developed as an immunotherapy for these malignancies. In the present study, WT1 epitope-specific immune responses were analyzed in 31 patients with advanced sarcoma with human leukocyte antigen-A*24:02- and WT1-expressing tumors who received the WT1-235 peptide vaccine as monotherapy. The serum levels of IgG and IgM antibodies against the target epitope WT1-235 and the non-target epitopes WT1-332 and WT1-271 were measured using ELISA. IgM antibodies against WT1-235, WT1-332 and WT1-271 were detected in three (9.6%), four (12.9%) and 20 patients (64.5%), respectively, prior to vaccine administration, indicating immune recognition of the WT1 antigen prior to administering the vaccine. Of 15 patients who had completed the 3-month treatment protocol, WT1-235 IgG was positive in five (33.3%) patients. An enzyme-linked immunospot assay revealed that WT1-235 epitope-specific IL-10 production/secretion in peripheral blood mononuclear cells declined in the first month of vaccine administration in all three patients with positivity for WT1-235 IgM at the start of the vaccine. Furthermore, positivity for both WT1-235 and WT1-271 IgM antibodies at the start of treatment was associated with unfavorable tumor control at 3 months after vaccine administration. These results suggested that WT1 epitope-specific IgG and IgM antibodies may be utilized as immune-monitoring markers for WT1 peptide cancer vaccine immunotherapy. The trials were entered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry (https://www.umin.ac.jp/ctr; no. UMIN000002001 on May 24, 2009 and no. UMIN000015997 on December 20, 2014).
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Affiliation(s)
- Shouq Alzaaqi
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Norifumi Naka
- Department of Orthopaedic Surgery, Nachikatsuura Town Onsen Hospital, Nachikatsuura, Wakayama 649‑5331, Japan
| | - Kenichiro Hamada
- Hamada Orthopaedic Surgery, Kawanishi City, Hyogo 666‑0021, Japan
| | - Naoki Hosen
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Mizuki Kanegae
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Hidetatsu Outani
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Mayuko Adachi
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Rin Imanishi
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Miki Iwai
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Jun Nakata
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Fumihiro Fujiki
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Soyoko Morimoto
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Hiroko Nakajima
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Sumiyuki Nishida
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Akihiro Tsuboi
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Yoshihiro Oka
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
| | - Yusuke Oji
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
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Jain AG, Talati C, Pinilla-Ibarz J. Galinpepimut-S (GPS): an investigational agent for the treatment of acute myeloid leukemia. Expert Opin Investig Drugs 2021; 30:595-601. [PMID: 34053383 DOI: 10.1080/13543784.2021.1928635] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Acute myeloid leukemia (AML) is a disorder wherein clonal expansion of undifferentiated myeloid precursors results in compromised hematopoiesis and bone marrow failure. Even though numerous AML patients respond to induction chemotherapy, relapse is common and hence new therapeutic approaches are needed. Wild-type Wilms tumor gene (WT1) is greatly expressed in numerous blood disorders and so this has led to development of galinpepimut-S, a WT1 vaccine as a modality to maintain remission in patients with AML.Areas covered: We summarize and examine the structure, key features, safety, and efficacy data of galinpepimut-S (GPS) for AML. GPS has been shown to be safe and tolerable in phase 1 and phase 2 studies and is now being evaluated in a phase 3 study.Expert opinion: Given the unmet need in the treatment of relapsed and refractory AML, especially among the elderly and patients with comorbidities who are not fit enough to undergo traditional salvage treatments, GPS could potentially fill the gap for this subset of patients. Future clinical trials utilizing GPS in second complete remission 2 (CR2) compared to best available therapy in AML and in combination with other immunotherapeutic agents (like pembrolizumab) for treatment for various malignancies are underway.
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Affiliation(s)
| | - Chetasi Talati
- Malignant Hematology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA
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Sampaio MM, Santos MLC, Marques HS, Gonçalves VLDS, Araújo GRL, Lopes LW, Apolonio JS, Silva CS, Santos LKDS, Cuzzuol BR, Guimarães QES, Santos MN, de Brito BB, da Silva FAF, Oliveira MV, Souza CL, de Melo FF. Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review. World J Clin Oncol 2021; 12:69-94. [PMID: 33680875 PMCID: PMC7918527 DOI: 10.5306/wjco.v12.i2.69] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 12/22/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly - the presence of the Philadelphia chromosome. The advances in cytogenetic and molecular assays are of great importance to the diagnosis, prognosis, treatment, and monitoring of CML. The discovery of the breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) 1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (known as TKIs) are the standard therapy for CML and greatly increase the survival rates, despite adverse effects and the odds of residual disease after discontinuation of treatment. As therapeutic alternatives, the subsequent TKIs lead to faster and deeper molecular remissions; however, with the emergence of resistance to these drugs, immunotherapy appears as an alternative, which may have a cure potential in these patients. Against this background, this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.
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Affiliation(s)
- Mariana Miranda Sampaio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | | | - Glauber Rocha Lima Araújo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Weber Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Jonathan Santos Apolonio
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Camilo Santana Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Kauany de Sá Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Beatriz Rocha Cuzzuol
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Mariana Novaes Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Márcio Vasconcelos Oliveira
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Cláudio Lima Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Nicoli P, Calabrese C, Pellegrino RM, Rosso V, Bracco E, Signorino E, Carturan S, Petiti J, Gallo D, Gaidano V, De Gobbi M, Roetto A, Saglio G, Cilloni D. Development of cellular and humoral response against WT1 protein vaccination in mice. Am J Hematol 2015; 90:E193-4. [PMID: 26088411 PMCID: PMC5054933 DOI: 10.1002/ajh.24092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 06/17/2015] [Indexed: 12/03/2022]
Affiliation(s)
- Paolo Nicoli
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | - Chiara Calabrese
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | | | - Valentina Rosso
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | - Enrico Bracco
- Department of OncologyUniversity of TurinTurin Italy
| | | | - Sonia Carturan
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | - Jessica Petiti
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | - Daniela Gallo
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | - Valentina Gaidano
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | - Marco De Gobbi
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | - Antonella Roetto
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | - Giuseppe Saglio
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
| | - Daniela Cilloni
- Department of Clinical and Biological SciencesUniversity of TurinTurin Italy
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Yoon JH, Kim HJ, Jeon YW, Lee SE, Cho BS, Eom KS, Kim YJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Min WS. Outcome of allogeneic hematopoietic stem cell transplantation for cytogenetically normal AML and identification of high-risk subgroup using WT1 expression in association with NPM1 and FLT3-ITD mutations. Genes Chromosomes Cancer 2015; 54:489-499. [PMID: 26054017 DOI: 10.1002/gcc.22260] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 04/01/2015] [Indexed: 01/13/2023] Open
Abstract
According to recent guidelines, cytogenetically normal acute myeloid leukemia (CN AML) is divided into four molecular subgroups based on nucleophosmin-1 (NPM1) and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. All subgroups except for isolated NPM1mut are associated with poor prognosis. We retrospectively analyzed 223 patients with CN AML, 156 of whom were treated with standard chemotherapy. For postremission therapy, patients with available donors underwent allogeneic (allo) hematopoietic stem cell transplantation (HSCT) and the rest were treated with autologous HSCT or chemotherapy alone. We first compared the 4 conventional molecular subgroups, and then created another 4 subgroups based on WT1 expression: isolated NPM1mut, NPM1wt/FLT3-ITD-neg with low WT1 or high WT1, and FLT3-ITD-pos CN AML. We finally evaluated 89 patients who were treated with allo HSCT and achieved complete remission after standard chemotherapy. FLT3-ITD CN AML showed the worst outcome irrespective of NPM1mut, and isolated NPM1mut CN AML showed no significant differences compared with NPM1wt/FLT3-ITD-neg CN AML. In contrast, two newly stratified low-risk subgroups (NPM1wt/FLT3-ITD-neg with low WT1 and isolated NPM1mut CN AML) showed higher remission rates with superior overall survival (OS) compared with the other two high-risk subgroups, which showed a higher relapse rate even after allo HSCT. Further analysis showed that higher pre-HSCT expression of WT1 resulted in a higher relapse rate and poorer OS after allo HSCT. For CN AML, a risk-adapted approach using allo HSCT with novel agents should be evaluated with stratification specified by WT1. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Jae-Ho Yoon
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Hee-Je Kim
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Young-Woo Jeon
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Sung-Eun Lee
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Byung-Sik Cho
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Ki-Seong Eom
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Yoo-Jin Kim
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Seok Lee
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Chang-Ki Min
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Seok-Goo Cho
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Dong-Wook Kim
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Jong-Wook Lee
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
| | - Woo-Sung Min
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Cancer Research Institute, Seoul St. Mary's Hospital, the Catholic University of Korea, Seoul, Korea
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WT1 expression is increased in primary fibroblasts derived from Dupuytren's disease tissues. J Cell Commun Signal 2015; 9:347-52. [PMID: 26123754 DOI: 10.1007/s12079-015-0293-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 04/16/2015] [Indexed: 11/27/2022] Open
Abstract
Dupuytren's disease (DD) is a fibroproliferative and contractile fibrosis of the palmar fascia that, like all other heritable fibroses, is currently incurable. While DD is invariably benign, it exhibits some molecular similarities to malignant tumours, including increased levels of ß-catenin, onco-fetal fibronectin, periostin and insulin-like growth factor (IGF)-II. To gain additional insights into the pathogenesis of DD, we have assessed the expression of WT1, encoding Wilm's tumour 1, an established tumour biomarker that is syntenic with IGF2, the gene encoding IGF-II in humans. We found that WT1 expression is robustly and consistently up regulated in primary fibroblasts derived from the fibrotic palmar fascia of patients with DD (DD cells), whereas syngeneic fibroblasts derived from the macroscopically unaffected palmar fascia in these patients and allogeneic fibroblasts derived from normal palmar fascia exhibited very low or undetectable WT1 transcript levels. WT1 immunoreactivity was evident in a subset of cells in the fibrotic palmar fascia of patients with DD, but not in macroscopically unaffected palmar fascia. These findings identify WT1 expression as a novel biomarker of fibrotic palmar fascia and are consistent with the hypothesis that the pathogeneses of DD and malignant tumours have molecular similarities.
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Shon W, Salomão DR. WT1 expression in endocrine mucin-producing sweat gland carcinoma: a study of 13 cases. Int J Dermatol 2015; 53:1228-34. [PMID: 25219513 DOI: 10.1111/ijd.12470] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND Endocrine mucin-producing sweat gland carcinoma (EMPSGC), a low-grade sweat gland carcinoma with a predilection for the eyelids, often shows areas of benign eccrine cysts, atypical intracystic proliferation and associated mucinous carcinoma, suggesting tumor progression. Wilms tumor 1 (WT1) protein, a transcription factor, is overexpressed in many tumors and plays a role in oncogenesis. METHODS A computer-based search for tumors diagnosed between 1989 and 2009 was conducted. Clinical data were obtained from pathology reports and patient records. Biopsies were reviewed for histologic features. Immunostaining was performed for WT1, chromogranin, synaptophysin, estrogen receptor (ER), epithelial membrane antigen (EMA), polyclonal carcinoembryonic antigen (P-CEA), cytokeratin 7 (CK7), cytokeratin 20 (CK20) and MIB-1. RESULTS Eight women and five men (mean age: 61.2 years; range: 40-77 years) presented with slow-growing eyelid nodules. Cases of EMPSGC were characterized by the presence of dermal nodules with various growth patterns. Adjacent eccrine cysts were present in five patients, atypical epithelial proliferation within the cyst wall in four patients, and an associated mucinous carcinoma in one patient. All tumors were positive for WT1, CK7, ER, P-CEA and EMA and negative for CK20. Tumors were positive for synaptophysin in 12 cases and chromogranin in nine cases. The MIB-1 proliferation index was low in most cases. No WT1 staining was observed in the overlying epidermis, adnexal structures or areas of benign eccrine cyst. WT1 expression was observed in areas of atypical epithelial proliferation, and the neoplastic cells. CONCLUSIONS The present study shows WT1 expression in the neoplastic epithelial cells of EMPSGC, areas of atypical intraductal proliferations, and mucinous carcinoma. The absence of WT1 expression in areas of benign eccrine cyst and cutaneous sweat glands suggests WT1 upregulation plays a role in tumor cell proliferation and progression of EMPSGC.
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Affiliation(s)
- Wonwoo Shon
- Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
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11
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Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015; 35 Suppl:S185-S198. [PMID: 25818339 DOI: 10.1016/j.semcancer.2015.03.004] [Citation(s) in RCA: 1085] [Impact Index Per Article: 108.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 03/10/2015] [Accepted: 03/13/2015] [Indexed: 12/27/2022]
Abstract
Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.
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Iranparast S, Assarehzadegan MA, Heike Y, Hossienzadeh M, Khodadadi A. Wilms' Tumor Gene (WT1) Expression Correlates with Vascular Epithelial Growth Factor (VEGF) in Newly Acute Leukemia Patients Undergoing Chemotherapy. Asian Pac J Cancer Prev 2014; 15:9217-23. [DOI: 10.7314/apjcp.2014.15.21.9217] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Iiyama T, Udaka K, Takeda S, Takeuchi T, Adachi YC, Ohtsuki Y, Tsuboi A, Nakatsuka SI, Elisseeva OA, Oji Y, Kawakami M, Nakajima H, Nishida S, Shirakata T, Oka Y, Shuin T, Sugiyama H. WT1 (Wilms' Tumor 1) Peptide Immunotherapy for Renal Cell Carcinoma. Microbiol Immunol 2013; 51:519-30. [PMID: 17579261 DOI: 10.1111/j.1348-0421.2007.tb03940.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Tumor-specific immunotherapy with a Wilms' tumor 1 (WT1) peptide has been on clinical trial for leukemia, myelodysplastic syndrome, breast and lung cancers and is producing promising results. In this study, we treated three patients with renal cell carcinoma with an anchor modified, HLA-A*2402 binding WT1 peptide which was emulsified in Freund's incomplete adjuvant. In two patients tumor growth was suppressed and clinical response was evaluated as stable disease by the RECIST criteria after 3 months of weekly immunizations. Notably, development of new metastases has stopped in these patients for a prolonged period. No deleterious side effects were observed. Peptide-specific T cells were expanded in PBMCs of the patients and a substantial fraction of them bore the surface phenotype consistent with a CD8+ cytotoxic effector population. Although established tumors did not regress further, considering the component of the vaccine, i.e. peptide alone, the stabilization effect suggested the potential of WT1 peptide to develop into a more effective vaccine. To our knowledge, this is the first report of WT1 immunotherapy for renal cell carcinoma. Hopefully, the results will stimulate more extensive clinical studies.
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Affiliation(s)
- Tatsuo Iiyama
- Department of Immunology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan
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Abstract
The targets for the immune system are antigens present on cancer cells; however, many are not cancer-specific and may also be found on normal tissues. These antigens are often products of mutated cellular genes, aberrantly expressed normal genes, or genes encoding viral proteins. Vaccines constitute an active and specific immunotherapy designed to stimulate the intrinsic antitumor immune response by presenting tumor-associated antigens expressed on normal tissues that are overexpressed on tumor cells.
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15
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Lin C, Li Y. The role of peptide and DNA vaccines in myeloid leukemia immunotherapy. Cancer Cell Int 2013; 13:13. [PMID: 23394714 PMCID: PMC3571936 DOI: 10.1186/1475-2867-13-13] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 02/06/2013] [Indexed: 12/13/2022] Open
Abstract
While chemotherapy and targeted therapy are successful in inducing the remission of myeloid leukemia as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), the disease remains largely incurable. This observation is likely due to the drug resistance of leukemic cells, which are responsible for disease relapse. Myeloid leukemia vaccines may most likely be beneficial for eradicating minimal residual disease after treatment with chemotherapy or targeted therapy. Several targeted immunotherapies using leukemia vaccines have been heavily investigated in clinical and preclinical trials. This review will focus on peptides and DNA vaccines in the context of myeloid leukemias, and optimal strategies for enhancing the efficacy of vaccines based on myeloid leukemia immunization are also summarized.
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Affiliation(s)
- Chen Lin
- Department of Microbiology and Immunology, Medical College, Jinan University, Guangzhou, 510632, China.
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Bansal H, Seifert T, Bachier C, Rao M, Tomlinson G, Iyer SP, Bansal S. The transcription factor Wilms tumor 1 confers resistance in myeloid leukemia cells against the proapoptotic therapeutic agent TRAIL (tumor necrosis factor α-related apoptosis-inducing ligand) by regulating the antiapoptotic protein Bcl-xL. J Biol Chem 2012; 287:32875-80. [PMID: 22898820 DOI: 10.1074/jbc.c112.366559] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is considered a promising cancer therapeutic agent due to its ability to induce apoptosis in a variety of cancer cells, while sparing normal cells. However, many human tumors including acute myeloid leukemia (AML) are partially or completely resistant to monotherapy with TRAIL, limiting its therapeutic utility. Therefore, identification of factors that contribute to TRAIL resistance may facilitate future development of more effective TRAIL-based cancer therapies. Here, we report a previously unknown role for WT1 in mediating TRAIL resistance in leukemia. Knockdown of WT1 with shRNA rendered TRAIL-resistant myeloid leukemia cells sensitive to TRAIL-induced cell death, and re-expression of shRNA-resistant WT1 restored TRAIL resistance. Notably, TRAIL-mediated apoptosis in WT1-silenced cells was largely due to down-regulation of the antiapoptotic protein Bcl-xL. Moreover, WT1 expression strongly correlated with overexpression of Bcl-xL in AML cell lines and blasts from AML patients. Furthermore, we found that WT1 transactivates Bcl-xL by directly binding to its promoter. We previously showed that WT1 is a novel client protein of heat shock protein 90 (Hsp90). Consistent with this, pharmacological inhibition of Hsp90 resulted in reduced WT1 and Bcl-xL expression leading to increased sensitivity of leukemia cells to TRAIL-mediated apoptosis. Collectively, our results suggest that WT1-dependent Bcl-xL overexpression contributes to TRAIL resistance in myeloid leukemias.
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Affiliation(s)
- Hima Bansal
- Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas 78229, USA
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Mahmood MDI, Matsuo Y, Neya S, Hoshino T. Computational analysis on the binding of epitope peptide to human leukocyte antigen class I molecule A*2402 subtype. Chem Pharm Bull (Tokyo) 2012; 59:1254-62. [PMID: 21963635 DOI: 10.1248/cpb.59.1254] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Immunological response induced by small amino peptide has attracted much recent attention in the field of immunotherapy. Wilms' tumor (WT1) protein is one of the potent tumor antigens inducing immunological response in mouse and human, because WT1 is over expressed in many types of leukemia and various kinds of solid tumors. A 9-mer peptide encoded in WT1 protein (CMTWNQMNL; amino acid 235-243) is known to serve as antigenic peptide for human leukocyte antigen (HLA)-A*2402 molecule. It was reported that the replacement of the second amino residue, which is deeply responsible for the peptide binding to HLA, induced strong immunological response compared to the natural peptide. In this study, 19 kinds of single amino substitutions were introduced at position 2 of this 9-mer WT1 peptide. We performed molecular dynamics simulation on the complex of each of WT1 epitope peptides and HLA-β2 micro globulin (β2m) molecule, and subsequently estimated the binding affinity using molecular mechanics/generalized-Born surface area method combined with normal mode analysis. Our computation indicated that the peptide containing M2Y or M2W mutation showed high binding affinity to the HLA-β2m molecule as well as the natural peptide. We have also examined the role of the residue at position 2 in peptide binding to HLA-β2m. The calculation showed that van der Waals interaction between the side chain of the residue at position 2 and hydrophobic residues inside B-pocket of HLA are important. These findings will be helpful to search other potent peptides that will enhance strong immunological response specific to HLA-A*2402 molecule.
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Affiliation(s)
- M D Iqbal Mahmood
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
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Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma. Pancreas 2012; 41:195-205. [PMID: 21792083 DOI: 10.1097/mpa.0b013e31822398c6] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES In the current study, we have evaluated the clinical and immunological responses in patients with advanced pancreatic carcinoma who received dendritic cell (DC)-based immunotherapy in combination with gemcitabine and/or S-1. METHODS Dendritic cell-based immunotherapy (DC vaccine alone or DC vaccine plus lymphokine-activated killer [LAK] cell therapy) in combination with gemcitabine and/or S-1 has been carried out in 49 patients with inoperable pancreatic carcinoma refractory to standard treatment. RESULTS Of 49 patients, 2 patients had complete remission, 5 had partial remission, and 10 had stable disease. Prolongation of survival in this cohort was highly likely (median survival, 360 days). Survival of patients receiving DC vaccine and chemotherapy plus LAK cell therapy was longer than those receiving DC vaccine in combination with chemotherapy but no LAK cells. Increased numbers of cancer antigen-specific cytotoxic T cells and decreased regulatory T cells were observed in several patients on immunotherapy, but increased overall survival time tended to be associated only with the latter. None of the patients experienced grade 3 or worse adverse events during the treatment period. CONCLUSIONS Dendritic cell vaccine-based immunotherapy combined with chemotherapy was shown to be safe and possibly effective in patients with advanced pancreatic cancer refractory to standard treatment.
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Nakajima H, Oka Y, Tsuboi A, Tatsumi N, Yamamoto Y, Fujiki F, Li Z, Murao A, Morimoto S, Hosen N, Shirakata T, Nishida S, Kawase I, Isaka Y, Oji Y, Sugiyama H. Enhanced tumor immunity of WT1 peptide vaccination by interferon-β administration. Vaccine 2011; 30:722-9. [PMID: 22133512 DOI: 10.1016/j.vaccine.2011.11.074] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 11/18/2011] [Accepted: 11/19/2011] [Indexed: 10/14/2022]
Abstract
To induce and activate tumor-associated antigen-specific cytotoxic T lymphocytes (CTLs) for cancer immunity, it is important not only to select potent CTL epitopes but also to combine them with appropriate immunopotentiating agents. Here we investigated whether tumor immunity induced by WT1 peptide vaccination could be enhanced by IFN-β. For the experimental group, C57BL/6 mice were twice pre-treated with WT1 peptide vaccine, implanted with WT1-expressing C1498 cells, and treated four times with WT1 peptide vaccine at one-week intervals. During the vaccination period, IFN-β was injected three times a week. Mice in control groups were treated with WT1 peptide alone, IFN-β alone, or PBS alone. The mice in the experimental group rejected tumor cells and survived significantly longer than mice in the control groups. The overall survival on day 75 was 40% for the mice treated with WT1 peptide+IFN-β, while it was 7, 7, and 0% for those treated with WT1 peptide alone, IFN-β alone or PBS alone, respectively. Induction of WT1-specific CTLs and enhancement of NK activity were detected in splenocytes from mice in the experimental group. Furthermore, administration of IFN-β enhanced expression of MHC class I molecules on the implanted tumor cells. In conclusion, our results showed that co-administration of WT1 peptide+IFN-β enhanced tumor immunity mainly through the induction of WT1-specific CTLs, enhancement of NK activity, and promotion of MHC class I expression on the tumor cells. WT1 peptide vaccination combined with IFN-β administration can thus be expected to enhance the clinical efficacy of WT1 immunotherapy.
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Affiliation(s)
- Hiroko Nakajima
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
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Donor immunization with WT1 peptide augments antileukemic activity after MHC-matched bone marrow transplantation. Blood 2011; 118:5319-29. [PMID: 21868578 DOI: 10.1182/blood-2011-05-356238] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The curative potential of MHC-matched allogeneic bone marrow transplantation (BMT) is in part because of immunologic graft-versus-tumor (GvT) reactions mediated by donor T cells that recognize host minor histocompatibility antigens. Immunization with leukemia-associated antigens, such as Wilms Tumor 1 (WT1) peptides, induces a T-cell population that is tumor antigen specific. We determined whether allogeneic BMT combined with immunotherapy using WT1 peptide vaccination of donors induced more potent antitumor activity than either therapy alone. WT1 peptide vaccinations of healthy donor mice induced CD8(+) T cells that were specifically reactive to WT1-expressing FBL3 leukemia cells. We found that peptide immunization was effective as a prophylactic vaccination before tumor challenge, yet was ineffective as a therapeutic vaccination in tumor-bearing mice. BMT from vaccinated healthy MHC-matched donors, but not syngeneic donors, into recipient tumor-bearing mice was effective as a therapeutic maneuver and resulted in eradication of FBL3 leukemia. The transfer of total CD8(+) T cells from immunized donors was more effective than the transfer of WT1-tetramer(+)CD8(+) T cells and both required CD4(+) T-cell help for maximal antitumor activity. These findings show that WT1 peptide vaccination of donor mice can dramatically enhance GvT activity after MHC-matched allogeneic BMT.
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21
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Abstract
For the last two decades the immunotherapy of patients with solid and hematopoietic tumors has met with variable success. We have reviewed the field of tumor vaccines to examine what has worked and what has not, why this has been the case, how the anti-tumor responses were examined, and how we can make tumor immunity successful for the majority of individuals rather than for the exceptional patients who currently show successful immune responses against their tumors.
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Affiliation(s)
- Jan Joseph Melenhorst
- Stem Cell Allogeneic Transplant Section, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Ichinohasama R, Oji Y, Yokoyama H, Takeuchi K, Fujiwara T, Ishizawa K, Taniguchi O, Tsuboi A, Oka Y, Sugiyama H. Sensitive immunohistochemical detection of WT1 protein in tumors with anti-WT1 antibody against WT1 235 peptide. Cancer Sci 2010; 101:1089-92. [PMID: 20180815 PMCID: PMC11159499 DOI: 10.1111/j.1349-7006.2010.01522.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
The Wilms' tumor 1 (WT1) gene is overexpressed in leukemia and various types of solid tumor, such as lung and colorectal cancer, and plays an oncogenic role in their tumorigenesis. Recent studies have demonstrated the potential of WT1-targeting cancer immunotherapy in clinical settings. As expression of WT1 protein in tumor cells is a prerequisite for WT1-targeting immunotherapy, immunohistochemical methods to detect WT1 protein with high sensitivity and specificity are required. In the present study, we developed a rabbit polyclonal antibody (WT1-R) against the 9-mer WT1 235 peptide, which is used for vaccination. The specificity of WT1-R was confirmed by immunoprecipitation, western blotting analysis, and competitive enzyme-linked immunosorbent assay. Immunocytochemistry showed the same reactivity against five cell lines (K562, Daudi, HT-180, SW480, and PC-14), whereas levels of WT1 mRNA expression determined by real-time qPCR (RT-PCR) analysis were not equivalent. Next, we examined the reactivity of WT1-R in tissue samples compared with a previously developed anti-WT1 antibody, 6F-H2. WT1-R showed greater sensitivity for detecting WT1 protein expression in samples from four different breast cancer patients than 6F-H2 antibody. The discrepancy in WT1 expression between these methods suggested that immunohistochemical detection of WT1 peptide may be advantageous for predicting the efficacy of WT1 vaccine compared to RT-PCR, and the highly sensitive WT1 antibody, WT1-R, may be useful to detect WT1 protein in tumors.
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Affiliation(s)
- Ryo Ichinohasama
- Division of Hematopathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Narita M, Masuko M, Kurasaki T, Kitajima T, Takenouchi S, Saitoh A, Watanabe N, Furukawa T, Toba K, Fuse I, Aizawa Y, Kawakami M, Oka Y, Sugiyama H, Takahashi M. WT1 peptide vaccination in combination with imatinib therapy for a patient with CML in the chronic phase. Int J Med Sci 2010; 7:72-81. [PMID: 20428337 PMCID: PMC2860640 DOI: 10.7150/ijms.7.72] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2009] [Accepted: 04/09/2010] [Indexed: 01/13/2023] Open
Abstract
Although tyrosine kinase inhibitors is effective for dramatically reducing CML cells, it might be difficult to eradicate completely the CML stem cells. We aimed to clarify the safety and effects of WT1 peptide vaccination in combination with imatinib therapy for a CML patient. A 51 year-old male with CML in CP, who showed a resistance against imatinib therapy for 2.5 years, began to be treated with 9 mer modified-type WT1 peptides in combination with standard dose of imatinib. Although every 2-week-administration of WT1 peptides for 22 weeks did not show definite effects on the quantification of bcr-abl transcripts, by changing the administration from every 2 weeks to 4 weeks bcr-abl transcripts decreased remarkably. After 11 months of every 4-week-administration of the peptides and 12 months post cessation of the peptides bcr-abl transcripts achieved to the level below detection by RQ/RT-PCR (complete molecular response). WT1/MHC tetramer(+)CD8(+) CTLs, which appeared after the second administration of WT1 peptides and remained more than 15 in number among 10(6) CD8(+) T cells throughout the administration of WT1 peptides, are still present in the blood on 14th month post cessation of the peptides. An in vitro study as to the cytotoxicity of lymphocytes induced by mixed lymphocyte peptide culture demonstrated that cultured lymphocytes possessed cytotoxicity against WT1 expressing leukemia cells and the cytotoxicity was WT1-specific and MHC class I restricted. The present study showed that WT1 peptide vaccination in combination with TKI is feasible and effective in the therapy for imatinib-resistant CML.
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Affiliation(s)
- Miwako Narita
- Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan.
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Murao A, Oka Y, Tsuboi A, Elisseeva OA, Tanaka-Harada Y, Fujiki F, Nakajima H, Nishida S, Hosen N, Shirakata T, Hashimoto N, Myoui A, Ueda T, Takeda Y, Osaki T, Enomoto T, Yoshikawa H, Kimura T, Oji Y, Kawase I, Sugiyama H. High frequencies of less differentiated and more proliferative WT1-specific CD8+ T cells in bone marrow in tumor-bearing patients: an important role of bone marrow as a secondary lymphoid organ. Cancer Sci 2010; 101:848-54. [PMID: 20136847 PMCID: PMC11158461 DOI: 10.1111/j.1349-7006.2009.01468.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
In tumor-bearing patients, tumor-associated antigen (TAA)-specific CTLs are spontaneously induced as a result of immune response to TAAs and play an important role in anti-tumor immunity. Wilms' tumor gene 1 (WT1) is overexpressed in various types of tumor and WT1 protein is a promising pan-TAA because of its high immunogenicity. In this study, to clarify the immune response to the WT1 antigen, WT1-specific CD8(+) T cells that were spontaneously induced in patients with solid tumor were comparatively analyzed in both bone marrow (BM) and peripheral blood (PB). WT1-specific CD8(+) T cells more frequently existed in BM than in PB, whereas frequencies of naïve (CCR7(+) CD45RA(+)), central memory (CCR7(+) CD45RA-), effector-memory (CCR7- CD45RA(-)), and effector (CCR7- CD45RA(+)) subsets were not significantly different between BM and PB. However, analysis of these subsets for the expression of CD57 and CD28, which were associated with differentiation, revealed that effector-memory and effector subsets of the WT1-specific CD8(+) T cells in BM had less differentiated phenotypes and more proliferative potential than those in PB. Furthermore, CD107a/b functional assay for WT1 peptide-specific cytotoxic potential and carboxyfluorescein diacetate succinimidyl ester dilution assay for WT1 peptide-specific proliferation also showed that WT1-specific CD8(+) T cells in BM were less cytotoxic and more proliferative in response to WT1 peptide than those in PB. These results implied that BM played an important role as a secondary lymphoid organ in tumor-bearing patients. Preferential residence of WT1-specific CD8(+) T cells in BM could be, at least in part, explained by higher expression of chemokine receptor CCR5, whose ligand was expressed on BM fibroblasts on the WT1-specific CD8(+) T cells in BM, compared to those in PB. These results should provide us with an insight into WT1-specific immune response in tumor-bearing patients and give us an idea of enhancement of clinical response in WT1 protein-targeted immunotherapy.
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Affiliation(s)
- Ayako Murao
- Department of Respiratory Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
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Saitoh A, Narita M, Watanabe N, Tochiki N, Yamahira A, Nakamura T, Kaji M, Masuko M, Furukawa T, Toba K, Fuse I, Aizawa Y, Takahashi M. WT1 peptide vaccination in a CML patient: induction of effective cytotoxic T lymphocytes and significance of peptide administration interval. Med Oncol 2010; 28:219-30. [PMID: 20107936 DOI: 10.1007/s12032-010-9425-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2009] [Accepted: 01/11/2010] [Indexed: 11/26/2022]
Abstract
Although antigen-specific immune responses including cytotoxic T cells (CTLs) against antigen peptide could be enhanced after tumor antigen peptide vaccinations, the immune responses do not necessarily result in a decrease or eradication of tumor cells in the vaccination trials. We focused on whether antigen-specific CTLs could be damaged by the repeated stimulation of antigenic peptide and whether regulatory T (Treg) cells would be increased by the administration of WT1 peptide. We administered WT1 peptide 22 times over 18 months in a CML patient who was being treated with imatinib. Although WT1 peptide administration every 2 weeks did not show any beneficial effects on the minimal residual disease (copies of bcr-abl transcripts), the transcripts remarkably decreased to the level of major molecular response after changing the administration interval of WT1 peptide from 2 to 4 weeks. An ex vivo study demonstrated that re-stimulation with WT1 peptide made WT1-specific T cells less reactive to WT1 tetramers and the impaired reactivity of CTLs lasted at least for 1 week. In addition, the cytotoxicity of the T cells was hampered by re-stimulation. Treg cells increased up to more than fivefold at the end of the WT1 administration period. The present findings suggested that the administration of the peptide every 4 weeks is superior to every 2 weeks. In addition, the findings that Treg cells increased gradually in accordance with the duration of WT1 peptide administration revealed the significance of manipulating Treg cells for establishing an efficient tumor antigen peptide vaccination.
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MESH Headings
- Antineoplastic Agents/therapeutic use
- Benzamides
- Cancer Vaccines/therapeutic use
- Combined Modality Therapy
- Fusion Proteins, bcr-abl/genetics
- Humans
- Imatinib Mesylate
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy
- Neoplasm, Residual/genetics
- Neoplasm, Residual/immunology
- Neoplasm, Residual/therapy
- Peptide Fragments/immunology
- Peptide Fragments/therapeutic use
- Piperazines/therapeutic use
- Prognosis
- Pyrimidines/therapeutic use
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Regulatory/immunology
- Vaccination
- WT1 Proteins/immunology
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Affiliation(s)
- Anri Saitoh
- Division of Hematology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
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Asgarian Omran H, Shabani M, Vossough P, Sharifian R, Tabrizi M, Khoshnoodi J, Jeddi-Tehrani M, Rabbani H, Shokri F. Cross-sectional monitoring of Wilms' tumor gene 1 (WT1) expression in Iranian patients with acute lymphoblastic leukemia at diagnosis, relapse and remission. Leuk Lymphoma 2009; 49:281-90. [DOI: 10.1080/10428190701784706] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Gu W, Hu S, Chen Z, Qiu G, Cen J, He B, He J, Wu W. High expression of WT1 gene in acute myeloid leukemias with more predominant WT1+17AA isoforms at relapse. Leuk Res 2009; 34:46-9. [PMID: 19414192 DOI: 10.1016/j.leukres.2009.04.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2009] [Revised: 04/01/2009] [Accepted: 04/03/2009] [Indexed: 10/20/2022]
Abstract
Real-time quantitative reverse transcriptase polymerase chain reaction method was established for detecting the expression levels of WT1 gene and WT1+17AA isoforms in 226 acute myeloid leukemia (AML) bone marrow (BM) cells. The results showed that WT1 gene was 2-3 logarithms expressed more in AML BM cells at initial diagnosis or relapse than in normal BM cells (p<0.001), with predominant WT1+17AA isoforms expression (the ratio of WT1+17AA/WT1 more than 0.50). Interestingly the ratio of WT1+17AA/WT1 was statistically higher in relapsed AMLs than in initially diagnosed (p=0.01), speculating that WT1+17AA isoforms might participate in AML relapse.
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Affiliation(s)
- Weiying Gu
- Department of Hematology, The First People's Hospital of Changzhou, Third Affiliated to Suzhou University, Changzhou, China.
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Ferguson AR, Nichols LA, Zarling AL, Thompson ED, Brinkman CC, Hargadon KM, Bullock TN, Engelhard VH. Strategies and challenges in eliciting immunity to melanoma. Immunol Rev 2009; 222:28-42. [PMID: 18363993 DOI: 10.1111/j.1600-065x.2008.00620.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The ability of CD8+ T cells to recognize melanoma tumors has led to the development of immunotherapeutic approaches that use the antigens CD8+ T cells recognize. However, clinical response rates have been disappointing. Here we summarize our work to understand the mechanisms of self-tolerance that limit responses to currently utilized antigens and our approach to identify new antigens directly tied to malignancy. We also explore several aspects of the anti-tumor immune response induced by peptide-pulsed dendritic cells (DCs). DCs differentially augment the avidity of recall T cells specific for self-antigens and overcome a process of aberrant CD8+ T-cell differentiation that occurs in tumor-draining lymph nodes. DC migration is constrained by injection route, resulting in immune responses in localized lymphoid tissue, and differential control of tumors depending on their location in the body. We demonstrate that CD8+ T-cell differentiation in different lymphoid compartments alters the expression of homing receptor molecules and leads to the presence of systemic central memory cells. Our studies highlight several issues that must be addressed to improve the efficacy of tumor immunotherapy.
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Affiliation(s)
- Andrew R Ferguson
- Beirne Carter Center for Immunology Research, Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA, USA
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29
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Perugorria MJ, Castillo J, Latasa MU, Goñi S, Segura V, Sangro B, Prieto J, Avila MA, Berasain C. Wilms' tumor 1 gene expression in hepatocellular carcinoma promotes cell dedifferentiation and resistance to chemotherapy. Cancer Res 2009; 69:1358-67. [PMID: 19190340 DOI: 10.1158/0008-5472.can-08-2545] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The Wilms' tumor 1 gene (WT1) encodes a transcription factor involved in cell growth and development. As we previously reported, WT1 expression is hardly detectable in normal hepatic tissue but is induced in liver cirrhosis. Although WT1 has been found to be overexpressed in a number of malignancies, the role of WT1 in hepatocarcinogenesis has not been clarified. We found that WT1 is expressed in several human hepatocellular carcinoma (HCC) cell lines, including PLC/PRF/5 and HepG2, and in HCC tumor tissue in 42% of patients. WT1 small interfering RNAs did not affect proliferation rate of HCC cells but abrogated their resistance to anoikis. Transcriptome analysis of PLC/PRF/5 cells after WT1 knockdown showed up-regulation of 251 genes and down-regulation of 321. Ninety percent of the former corresponded to metabolic genes, mostly those characterizing the mature hepatocyte phenotype. On the contrary, genes that decreased upon WT1 inhibition were mainly related to defense against apoptosis, cell cycle, and tumor progression. In agreement with these findings, WT1 expression increased the resistance of liver tumor cells to doxorubicin, a compound used to treat HCC. Interestingly, doxorubicin strongly enhanced WT1 expression in both HCC cells and normal human hepatocytes. Among different chemotherapeutics, induction of WT1 transcription was restricted to topoisomerase 2 inhibitors. When WT1 expression was prohibited, doxorubicin caused a marked increase in caspase-3 activation. In conclusion, WT1 is expressed in a substantial proportion of HCC contributing to tumor progression and resistance to chemotherapy, suggesting that WT1 may be an important target for HCC treatment.
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Affiliation(s)
- Maria J Perugorria
- Division of Hepatology and Gene Therapy,CIMA and CIBERehd, University Clinic, University of Navarra, Pamplona, Spain
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Li Z, Oka Y, Tsuboi A, Fujiki F, Harada Y, Nakajima H, Masuda T, Fukuda Y, Kawakatsu M, Morimoto S, Katagiri T, Tatsumi N, Hosen N, Shirakata T, Nishida S, Kawakami Y, Udaka K, Kawase I, Oji Y, Sugiyama H. Identification of a WT1 protein-derived peptide, WT1, as a HLA-A 0206-restricted, WT1-specific CTL epitope. Microbiol Immunol 2009; 52:551-8. [PMID: 19090835 DOI: 10.1111/j.1348-0421.2008.00069.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The Wilms' tumor gene WT1 is overexpressed in various kinds of hematopoietic malignancies as well as solid cancers, and this protein has been demonstrated to be an attractive target antigen for cancer immunotherapy. WT1-specific CTL epitopes with a restriction of HLA-A 2402 or HLA-A 0201 have been already identified. In the present study it has been demonstrated that a 9-mer WT1-derived WT1(187) peptide, which had already been shown to elicit a WT1-specific CTL response with a restriction of HLA-A 0201, can also elicit a CTL response with a restriction of HLA-A 0206. In all three different HLA-A 0206(+) healthy donors examined, WT1(187) peptide-specific CTL could be generated from peripheral blood mononuclear cells, and the CTL showed cytotoxic activity that depended on dual expression of WT1 and HLA-A 0206 molecules. The present study describes the first identification of a HLA-A 0206-restricted, WT1-specific CTL epitope. The present results should help to broaden the application of WT1 peptide-based immunotherapy from only HLA-A 0201-positive to HLA-A 0206-positive cancer patients as well.
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Affiliation(s)
- Zheyu Li
- Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan
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31
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Narita M, Tochiki N, Saitoh A, Watanabe N, Kaji M, Satoh N, Yamahira A, Nakamura T, Masuko M, Furukawa T, Toba K, Fuse I, Aizawa Y, Takahashi M. Induction of antigen-specific cytotoxic T lymphocytes by using monocyte-derived DCs transfected with in vitro-transcribed WT1 or SART1 mRNA. Med Oncol 2008; 26:429-36. [DOI: 10.1007/s12032-008-9142-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2008] [Accepted: 11/20/2008] [Indexed: 10/21/2022]
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Domfeh AB, Carley AL, Striebel JM, Karabakhtsian RG, Florea AV, McManus K, Beriwal S, Bhargava R. WT1 immunoreactivity in breast carcinoma: selective expression in pure and mixed mucinous subtypes. Mod Pathol 2008; 21:1217-23. [PMID: 18469795 DOI: 10.1038/modpathol.2008.69] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Current literature suggests that strong WT1 expression in a carcinoma of unknown origin virtually excludes a breast primary. Our previous pilot study on WT1 expression in breast carcinomas has shown WT1 expression in approximately 10% of carcinomas that show mixed micropapillary and mucinous morphology (Mod Pathol 2007;20(Suppl 2):38A). To definitively assess as to what subtype of breast carcinoma might express WT1 protein, we examined 153 cases of invasive breast carcinomas. These consisted of 63 consecutive carcinomas (contained 1 mucinous tumor), 20 cases with micropapillary morphology (12 pure and 8 mixed), 6 micropapillary 'mimics' (ductal no special type carcinomas with retraction artifacts), 33 pure mucinous carcinomas and 31 mixed mucinous carcinomas (mucinous mixed with other morphologic types). Overall, WT1 expression was identified in 33 carcinomas, that is, 22 of 34 (65%) pure mucinous carcinomas and in 11 of 33 (33%) mixed mucinous carcinomas. The non-mucinous component in these 11 mixed mucinous carcinomas was either a ductal no special type carcinoma (8 cases) or a micropapillary component (3 cases). WT1 expression level was similar in both the mucinous and the non-mucinous components. The degree of WT1 expression was generally weak to moderate (>90% cases) and rarely strong (<10% cases). None of the breast carcinoma subtype unassociated with mucinous component showed WT1 expression.
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Affiliation(s)
- Akosua B Domfeh
- Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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33
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Izumoto S, Tsuboi A, Oka Y, Suzuki T, Hashiba T, Kagawa N, Hashimoto N, Maruno M, Elisseeva OA, Shirakata T, Kawakami M, Oji Y, Nishida S, Ohno S, Kawase I, Hatazawa J, Nakatsuka SI, Aozasa K, Morita S, Sakamoto J, Sugiyama H, Yoshimine T. Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J Neurosurg 2008; 108:963-71. [PMID: 18447714 DOI: 10.3171/jns/2008/108/5/0963] [Citation(s) in RCA: 144] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT The object of this study was to investigate the safety and clinical responses of immunotherapy targeting the WT1 (Wilms tumor 1) gene product in patients with recurrent glioblastoma multiforme (GBM). METHODS Twenty-one patients with WT1/HLA-A*2402-positive recurrent GBM were included in a Phase II clinical study of WT1 vaccine therapy. In all patients, the tumors were resistant to standard therapy. Patients received intra-dermal injections of an HLA-A*2402-restricted, modified 9-mer WT1 peptide every week for 12 weeks. Tumor size, which was obtained by measuring the contrast-enhanced area on magnetic resonance images, was determined every 4 weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors (RECIST) 12 weeks after the initial vaccination. Patients who achieved an effective response continued to be vaccinated until tumor progression occurred. Progression-free survival and overall survival after initial WT1 treatment were estimated. RESULTS The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The clinical responses were as follows: partial response in 2 patients, stable disease in 10 patients, and progressive disease in 9 patients. No patient had a complete response. The overall response rate (cases with complete or partial response) was 9.5%, and the disease control rate (cases with complete or partial response as well as those in which disease was stable) was 57.1%. The median progression-free survival (PFS) period was 20.0 weeks, and the 6-month (26-week) PFS rate was 33.3%. CONCLUSIONS Although a small uncontrolled nonrandomized trial, this study showed that WT1 vaccine therapy for patients with WT1/HLA-A*2402-positive recurrent GBM was safe and produced a clinical response. Based on these results, further clinical studies of WT1 vaccine therapy in patients with malignant glioma are warranted.
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Affiliation(s)
- Shuichi Izumoto
- Department of Neurosurgery, Nagoya University, Nagoya, Japan.
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el-Shami K, Smith BD. Immunotherapy for myeloid leukemias: current status and future directions. Leukemia 2008; 22:1658-64. [PMID: 18563174 DOI: 10.1038/leu.2008.148] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Myeloid leukemias, although a heterogeneous group of hematopoietic stem cell neoplasms, are arguably among the most suited for active specific immunotherapy. Nevertheless, clinical development of myeloid leukemia vaccine lagged behind similar approaches in other solid and hematological malignancies. The recent identification of apparently specific leukemia antigens and advances in understanding the fundamentals of tumor immunology have helped initiate a number of early phase clinical studies evaluating the safety and clinical efficacy of this approach. Here we review the recently identified and characterized putative leukemia antigens, the main vaccination strategies employed by most investigators and the results of clinical studies of immunotherapy of myeloid leukemias. Although these studies are early and often difficult to interpret, they offer evidence that effective immunity to leukemia could be induced following vaccination, and that clinical benefit can sometimes be observed, thus setting the stage for future development of this strategy and in the combinatorial approaches to treatment of myeloid leukemias that incorporate immunotherapy.
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Affiliation(s)
- K el-Shami
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231-1000, USA
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35
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Neethling FA, Ramakrishna V, Keler T, Buchli R, Woodburn T, Weidanz JA. Assessing vaccine potency using TCRmimic antibodies. Vaccine 2008; 26:3092-102. [DOI: 10.1016/j.vaccine.2008.02.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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36
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Oka Y, Tsuboi A, Oji Y, Kawase I, Sugiyama H. WT1 peptide vaccine for the treatment of cancer. Curr Opin Immunol 2008; 20:211-20. [PMID: 18502632 DOI: 10.1016/j.coi.2008.04.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2007] [Revised: 04/01/2008] [Accepted: 04/25/2008] [Indexed: 12/11/2022]
Abstract
Wilms' tumor gene WT1 is expressed in various kinds of cancers. Human WT1-specific cytotoxic T lymphocytes (CTLs) were generated, and mice immunized with WT1 peptide rejected challenges by WT1-expressing cancer cells without auto-aggression to normal organs. Furthermore, WT1 antibodies and WT1-specific CTLs were detected in cancer patients, indicating that WT1 protein was immunogenic. These findings provided us with the rationale for cancer immunotherapy targeting WT1. Clinical trials of WT1 peptide vaccination for cancer patients were started, and WT1 vaccination-related immunological responses and clinical responses, including reduction of leukemic cells, reduction of M-protein amount in myeloma, and shrinkage of solid cancer, were observed. Valuable information about immune responses against tumor antigens can be obtained by the analysis of samples from the vaccinated patients, which should lead to further improvement of cancer vaccine.
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Affiliation(s)
- Yoshihiro Oka
- Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Japan.
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37
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Thomas S, Hart DP, Xue SA, Cesco-Gaspere M, Stauss HJ. T-cell receptor gene therapy for cancer: the progress to date and future objectives. Expert Opin Biol Ther 2007; 7:1207-18. [PMID: 17696819 DOI: 10.1517/14712598.7.8.1207] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
In the last decade research has begun into the use of T-cell receptor (TCR) gene therapy as a means to control and eradicate malignancies. There is now a large body of evidence to demonstrate that through the use of this technology one can redirect T-cell antigen specificity to produce both cytotoxic and helper T cells, which are functionally competent both in vitro and in vivo and show promising antitumour effects in humans. This review focuses on the means by which TCR gene transfer is achieved and the recent advances to modify the TCRs and vector delivery systems which aim to enhance the efficiency and safety of TCR gene transfer protocols.
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38
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Stauss HJ, Thomas S, Cesco-Gaspere M, Hart DP, Xue SA, Holler A, King J, Wright G, Perro M, Pospori C, Morris E. WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells. Blood Cells Mol Dis 2007; 40:113-6. [PMID: 17855129 DOI: 10.1016/j.bcmd.2007.06.018] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2007] [Revised: 06/30/2007] [Accepted: 06/30/2007] [Indexed: 11/23/2022]
Abstract
Adoptive transfer of antigen-specific T lymphocytes is an attractive form of immunotherapy for haematological malignancies and cancer. The difficulty of isolating antigen-specific T lymphocytes for individual patients limits the more widespread use of adoptive T cell therapy. The demonstration that cloned T cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy. The first trial in humans demonstrated that TCR gene-modified T cells persisted for an extended time period and reduced tumor burden in some patients. The WT1 protein is an attractive target for immunotherapy of leukemia and solid cancer since elevated expression has been demonstrated in AML, CML, MDS and in breast, colon and ovarian cancer. In the past, we have isolated high avidity CTL specific for a WT1-derived peptide presented by HLA-A2 and cloned the TCR alpha and beta genes of a WT1-specific CTL line. The genes were inserted into retroviral vectors for transduction of human peripheral blood T lymphocytes of leukemia patients and normal donors. The treatment of leukemia-bearing NOD/SCID mice with T cells transduced with the WT1-specific TCR eliminated leukemia cells in the bone marrow of most mice, while treatment with T cells transduced with a TCR of irrelevant specificity did not diminish the leukemia burden. In order to improve the safety and efficacy of TCR gene therapy, we have developed lentiviral TCR gene transfer. In addition, we employed strategies to enhance TCR expression while avoiding TCR mis-pairing. It may be possible to generate dominant TCR constructs that can suppress the expression of the endogenous TCR on the surface of transduced T cells. The development of new TCR gene constructs holds great promise for the safe and effective delivery of TCR gene therapy for the treatment of malignancies.
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Affiliation(s)
- Hans J Stauss
- Department of Immunology and Molecular Pathology, University College London, Hampstead Campus, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, United Kingdom.
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39
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Ariyaratana S, Loeb DM. The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis. Expert Rev Mol Med 2007; 9:1-17. [PMID: 17524167 DOI: 10.1017/s1462399407000336] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
In addition to its loss playing a pivotal role in the development of a childhood kidney malignancy, the Wilms tumour 1 gene (WT1) has emerged as an important factor in normal and malignant haematopoiesis. Preferentially expressed in CD34+ haematopoietic progenitors and down-regulated in more-differentiated cells, the WT1 transcription factor has been implicated in regulation of apoptosis, proliferation and differentiation. Putative target genes, such as BCL2, MYC, A1 and cyclin E, may cooperate with WT1 to modulate cell growth. However, the effects of WT1 on target gene expression appear to be isoform-specific. Certain WT1 isoforms are over-represented in leukaemia, but the exact mechanisms underlying the role of WT1 in transformation remain unclear. The ubiquity of WT1 in haematological malignancies has led to efforts to exploit it as a marker for minimal residual disease and as a prognostic factor, with conflicting results. In vitro killing of tumour cells by WT1-specific CD8+ cytotoxic T lymphocytes facilitated design of Phase I vaccine trials that showed clinical regression of WT1-positive tumours. Alternative methods employing WT1-specific immunotherapy are being investigated and might ultimately be used to optimise multimodal therapy of haematological malignancies.
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Affiliation(s)
- Suzie Ariyaratana
- Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
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40
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Abstract
Several clinical observations demonstrate that immunologic effects are important in chronic myeloid leukemia (CML). The characteristic BCR-ABL fusion protein is a leukemia-specific antigen, and it has therefore received much immunologic attention, especially regarding the amino acid sequences that span the e14a2 junction. Other attractive targets are the Wilms' tumor 1 antigen and the PR1 epitope from proteinase 3, a granule protein overexpressed in CML. Imatinib may modulate several components of the immune response, although the clinical relevance of this effect is uncertain. In clinical trials, peptide vaccination appears safe and undoubtedly produces clinical effects, but randomized trials are now required to see if these are distinct from the effects of other concurrent therapy. These trials will be difficult to orchestrate in the competitive environment of novel therapies for CML.
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MESH Headings
- Antigens, Neoplasm/chemistry
- Antigens, Neoplasm/immunology
- Benzamides
- Cancer Vaccines/immunology
- Cancer Vaccines/therapeutic use
- Clinical Trials as Topic
- Clonal Anergy
- Dendritic Cells/drug effects
- Dendritic Cells/immunology
- Epitopes/chemistry
- Epitopes/immunology
- Fusion Proteins, bcr-abl/chemistry
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/immunology
- Humans
- Imatinib Mesylate
- Immunotherapy/methods
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy
- Myeloblastin/chemistry
- Myeloblastin/immunology
- Neoplasm Proteins/chemistry
- Neoplasm Proteins/genetics
- Neoplasm Proteins/immunology
- Peptide Fragments/chemistry
- Peptide Fragments/immunology
- Piperazines/pharmacology
- Piperazines/therapeutic use
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Pyrimidines/pharmacology
- Pyrimidines/therapeutic use
- T-Lymphocyte Subsets/immunology
- Vaccination
- Vaccines, Subunit/immunology
- Vaccines, Subunit/therapeutic use
- WT1 Proteins/chemistry
- WT1 Proteins/immunology
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Affiliation(s)
- Richard E Clark
- Department of Haematology, Royal Liverpool University Hospital, Prescot St., Liverpool L7 8XP, UK.
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41
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Epling-Burnette PK, Painter JS, Rollison DE, Ku E, Vendron D, Widen R, Boulware D, Zou JX, Bai F, List AF. Prevalence and clinical association of clonal T-cell expansions in Myelodysplastic Syndrome. Leukemia 2007; 21:659-67. [PMID: 17301813 DOI: 10.1038/sj.leu.2404590] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Selected patients with Myelodysplastic Syndromes (MDS) are responsive to immunosuppressive therapy, suggesting that hematopoietic suppressive T cells have a pathogenic role in ineffective hematopoiesis. We assessed T-cell receptor (TCR) clonality through combined flow cytometry and molecular analysis of the complementarity determining region (CDR)-3 of the T-cell receptor-Vbeta gene. We identified clonal T cells in 50% of MDS patients (n=52) compared to 5% of age-matched normal controls (n=20). The presence of T-cell clones was not associated with features linked previously to immunosuppression response, including WHO diagnostic category, karyotype, marrow cellularity, IPSS category, sex or age <or=60. Using flow cytometry to identify expanded Vbeta-families, we found that T cells showed greater expansion in the bone marrow compared with peripheral blood, and were characterized as CD8(+)/CD57(+)/CD28(-) effector T cells. Expanded effector T cell were CD62L negative and expressed the natural killer C-lectin-family receptor NKG2D and CD244 (2B4). We conclude that clonal T-cell expansion is common among all MDS prognostic subgroups.
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Affiliation(s)
- P K Epling-Burnette
- Immunology Program, H Lee Moffitt Cancer Center, Department of Interdisciplinary Oncology, University of South Florida, Tampa, FL 33612, USA.
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Abstract
When connective tissue undergoes malignant transformation, glioblastomas and sarcomas arise. However, the ancient biochemical mechanisms, which are now operational in sarcomas distorted by mutations and gene fusions in misaligned chromosomes, were originally acquired by those cells that emerged during the Cambrian explosion. Preserved throughout evolution up to the genus Homo, these mechanisms dictate the apoptosis- and senescence-resistant immortality of malignant cells. A 'retroviral paradox' distinguishes human sarcomas from those of the animal world. In contrast to the retrovirally induced sarcomatous transformation of animal (avian, murine, feline and simian) cells, human sarcomas have so far failed to yield a causative retroviral isolate. However, the proto-oncogenes/oncogenes transduced from their host cells by retroviruses of animals are the same that are active in human sarcomas. Since the encoded oncoproteins arise after birth, they are recognized frequently by the immune system of the host. Immune lymphocytes that kill autologous sarcoma cells in vitro commonly fail to do so in vivo. Sarcoma vaccines generate immune T- and natural killer cell reactions; even when vaccinated patients do not show a clinical response, their tumors become more sensitive to chemotherapy. The aim of this review is to lay a solid molecular biological foundation for the conclusion that targeting the sarcoma oncogenes will result in regression of the disease.
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Affiliation(s)
- Joseph G Sinkovics
- Cancer Institute of St. Joseph's Hospital Affiliated with the HL Moffitt Cancer Center, The University of South Florida College of Medicine, Department of Medical Microbiology and Immunology, Tampa, Florida, USA.
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