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WT1 and immunotherapy

Yoichi Kato
We assessed the efficacy of WT1 class I peptide and WT1 class II peptide pulsed dendritic cell(DC)therapy for a wide range of advanced cancers. This retrospective study included 60 advanced cancer patients who were vaccinated 5times or more in this clinic between September 2013 and December 2015. The clinical response was examined. This treatment was approved by the ethics panel at this institution. Sixty patients were injected an average of 6.15times with dendritic cells(DCs) (2.6×10 / 7 cells/injection)...
October 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Leonid Dubrovsky, Elliott Joseph Brea, Dmitry Pankov, Emily Casey, Tao Dao, Cheng Liu, David A Scheinberg
Specific immunotherapy for acute leukemia remains a great unmet need. Native unmodified monoclonal antibody therapies, while promising, are inadequately effective for these malignancies, and multiple mechanisms for failure have been described. Antibody-dependent cellular cytotoxicity or phagocytosis is the primary modality of mAb-mediated cell killing in vivo, but ultimately leads to relapse of the leukemias, in model systems and in humans. By use of a T-cell receptor mimic mAb ESKM, derived against a WT1 peptide expressed in complex with HLA-A*02:01, whose only mechanism of therapeutic action is ADCC, we evaluated the mechanisms of leukemic relapse from its potent therapeutic action in mouse xenograft models of human leukemia...
2016: Oncoimmunology
Yannick Willemen, Johan M J Van den Bergh, Sarah M Bonte, Sébastien Anguille, Carlo Heirman, Barbara M H Stein, Herman Goossens, Tessa Kerre, Kris Thielemans, Marc Peeters, Viggo F I Van Tendeloo, Evelien L J Smits, Zwi N Berneman
We formerly demonstrated that vaccination with Wilms' tumor 1 (WT1)-loaded autologous monocyte-derived dendritic cells (mo-DCs) can be a well-tolerated effective treatment in acute myeloid leukemia (AML) patients. Here, we investigated whether we could introduce the receptor for hyaluronic acid-mediated motility (RHAMM/HMMR/CD168), another clinically relevant tumor-associated antigen, into these mo-DCs through mRNA electroporation and elicit RHAMM-specific immune responses. While RHAMM mRNA electroporation significantly increased RHAMM protein expression by mo-DCs, our data indicate that classical mo-DCs already express and present RHAMM at sufficient levels to activate RHAMM-specific T cells, regardless of electroporation...
September 21, 2016: Oncotarget
Masahiro Azuma, Yohei Takeda, Hiroko Nakajima, Haruo Sugiyama, Takashi Ebihara, Hiroyuki Oshiumi, Misako Matsumoto, Tsukasa Seya
Successful cancer immunotherapy necessitates T cell proliferation and infiltration into tumor without exhaustion, a process closely links optimal maturation of dendritic cells (DC), and adjuvant promotes this process as an essential prerequisite. Poly(I:C) has contributed to adjuvant immunotherapy that evokes an antitumor response through the Toll-loke receptor 3 (TLR3)/TICAM-1 pathway in DC. However, the mechanism whereby Poly(I:C) acts on DC for T cell proliferation and migration remains undetermined. Subcutaneous injection of Poly(I:C) regressed implant tumors (WT1-C1498 or OVA-EG7) in C57BL/6 mice, which coincided with tumor-infiltration of CD8(+) T cells...
August 2016: Oncoimmunology
Guilherme Cesar Martelossi Cebinelli, Nathália DE Sousa Pereira, Michelle Mota Sena, Carlos Eduardo Coral DE Oliveira, Thiago Cezar Fujita, Sérgio Paulo Dejato DA Rocha, Francisco José DE Abreu Oliveira, Poliana Camila Marinello, Maria Angelica Ehara Watanabe
The WT1 gene encodes a transcription factor involved in regulation of many cellular processes, including proliferation, differentiation, mRNA processing and apoptosis, besides acting as a transcription repressor of growth factors and their receptors' genes. This gene is expressed at high levels in several types of cancers, including acute leukemias. In this regard, many studies have identified WT1 protein as a tumor antigen, considered a target molecule for clinical application in human acute leukemias. Immunotherapy using WT1 antigen has been effective in stimulating immune responses against leukemic cells...
August 2016: Anticancer Research
Sumiyuki Nishida, Haruo Sugiyama
There is much current excitement about the potential of cancer immunotherapy. WT1 is high on the National Cancer Institute's list of priority antigens for immune therapy. In this chapter we describe a protocol for a clinical trial using a WT1 peptide-based cancer vaccine.
2016: Methods in Molecular Biology
Keiko Naitoh, Takashi Kamigaki, Eriko Matsuda, Hiroshi Ibe, Sachiko Okada, Eri Oguma, Yoshihiro Kinoshita, Rishu Takimoto, Kaori Makita, Shun Ogasawara, Shigenori Goto
For a peptide-pulsed dendritic cell (DC) vaccine to work effectively in cancer treatment, it is significant that the target protein is expressed in cancer cells. Wilms' tumor 1 (WT1) has been identified as a molecular target for immune cell therapy of cancer. We evaluated the protein expression levels of WT1 in various solid tumors, as well as mucin 1 (MUC1) or major histocompatibility complex (MHC) class l molecules. Seven hundred and thirty-eight patients whose tissue samples were examined by immunohistochemical analysis agreed to undergo DC vaccine therapy...
July 2016: Anticancer Research
Kamila Kloudová, Hana Hromádková, Simona Partlová, Tomáš Brtnický, Lukáš Rob, Jiřina Bartůňková, Michal Hensler, Michael J Halaška, Radek Špíšek, Anna Fialová
In order to select a suitable combination of cancer cell lines as an appropriate source of antigens for dendritic cell-based immunotherapy of ovarian cancer, we analyzed the expression level of 21 tumor associated antigens (BIRC5, CA125, CEA, DDX43, EPCAM, FOLR1, Her-2/neu, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MUC-1, NY-ESO-1, PRAME, p53, TPBG, TRT, WT1) in 4 established ovarian cancer cell lines and in primary tumor cells isolated from the high-grade serous epithelial ovarian cancer tissue...
June 14, 2016: Oncotarget
Xiao-Dong Mo, Ya-Zhen Qin, Xiao-Hui Zhang, Lan-Ping Xu, Yu Wang, Chen-Hua Yan, Huan Chen, Yu-Hong Chen, Wei Han, Feng-Rong Wang, Jing-Zhi Wang, Kai-Yan Liu, Xiao-Jun Huang
This study investigated the efficacy of minimal residual disease (MRD) monitoring and MRD-directed preemptive immunotherapy in high-risk myelodysplastic syndrome (MDS) patients who received allogeneic hematopoietic stem cell transplantation (HSCT). MRD assessment consisted of Wilms' tumor gene 1 (WT1) detection with PCR and leukemia-associated immunophenotypic pattern examination with multiparameter flow cytometry (FCM). Post-HSCT, 31 patients were positive for WT1, and 8, for FCM; positivity for WT1 (18.6 vs...
August 2016: Annals of Hematology
An Coosemans, Sandra Tuyaerts, Kim Morias, Jurgen Corthals, Carlo Heirman, Kris Thielemans, Stefaan W Van Gool, Ignace Vergote, Frédéric Amant
The immune system is a crucial player in the development of cancer. Once it is in imbalance and immunosuppressive mechanisms supporting tumor growth take over control, dendritic cell immunotherapy might offer a solution to restore the balance. There are several methods to manufacture dendritic cells but none of them has yet proven to be superior to others. In this chapter, we discuss the methodology using electroporation of mRNA encoding Wilms' tumor gene 1, survivin, and TriMix (mixture of caTLR4, CD40L, and CD70) to simultaneously load and mature dendritic cells...
2016: Methods in Molecular Biology
Norihiro Ueda, Rong Zhang, Minako Tatsumi, Tian-Yi Liu, Shuichi Kitayama, Yutaka Yasui, Shiori Sugai, Tatsuaki Iwama, Satoru Senju, Seiji Okada, Tetsuya Nakatsura, Kiyotaka Kuzushima, Hitoshi Kiyoi, Tomoki Naoe, Shin Kaneko, Yasushi Uemura
The advent of tyrosine kinase inhibitor (TKI) therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia (CML). However, the poor prognosis of patients with advanced-phase CML and the lifelong dependency on TKIs are remaining challenges; therefore, an effective therapeutic has been sought. The BCR-ABL p210 fusion protein's junction region represents a leukemia-specific neoantigen and is thus an attractive target for antigen-specific T-cell immunotherapy. BCR-ABL p210 fusion-region-specific CD4(+) T-helper (Th) cells possess antileukemic potential, but their function remains unclear...
May 16, 2016: Cellular & Molecular Immunology
Akinori Miyazono, Yasuhiro Okamoto, Hironobu Nagasako, Yuko Hamasaki, Seiichiro Shishido, Takako Yoshioka, Yoshifumi Kawano
Posttransplantation lymphoproliferative disorder (PTLD) is associated with significant mortality in kidney transplant recipients. PTLD cases associated with poor prognostic factors that are refractory to reduction of immunosuppression generally require chemotherapy and immunotherapy. We present a patient with PTLD who achieved complete remission after reduction of immunosuppression alone despite having a poor prognosis. A boy with a mutation in the WT1 gene developed bilateral Wilms tumor at 15 months and received a kidney transplant at the age of 4 years...
September 2016: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
A L Van de Velde, P Beutels, E L Smits, V F Van Tendeloo, G Nijs, S Anguille, A Verlinden, A P Gadisseur, W A Schroyens, S Dom, I Cornille, H Goossens, Z N Berneman
The advent of new cell-based immunotherapies for leukemia offers treatment possibilities for certain leukemia subgroups. The wider acceptability of these new technologies in clinical practice will depend on its impact on survival and costs. Due to the small patient groups who have received it, these aspects have remained understudied. This non-randomized single-center study evaluated medical costs and survival for acute myeloid leukemia between 2005 and 2010 in 50 patients: patients treated with induction and consolidation chemotherapy (ICT) alone; patients treated with ICT plus allogeneic hematopoietic stem cell transplantation (HCT), which is the current preferred post-remission therapy in patients with intermediate- and poor-risk AML with few co-morbidities, and patients treated with ICT plus immunotherapy using autologous dendritic cells (DC) engineered to express the Wilms' tumor protein (WT1)...
July 2016: Leukemia Research
Evelien L J M Smits, Barbara Stein, Griet Nijs, Eva Lion, Viggo F Van Tendeloo, Yannick Willemen, Sébastien Anguille, Zwi N Berneman
First described in the 1970s, dendritic cells (DC) are currently subjects of intense investigation to exploit their unique antigen-presenting and immunoregulatory capacities. In cancer, DC show promise to elicit or amplify immune responses directed against cancer cells by activating natural killer (NK) cells and tumor antigen-specific T cells. Wilms' tumor 1 (WT1) protein is a tumor-associated antigen that is expressed in a majority of cancer types and has been designated as an antigen of major interest to be targeted in clinical cancer immunotherapy trials...
2016: Methods in Molecular Biology
Carmen Di Grazia, Sarah Pozzi, Simona Geroldi, Raffaella Grasso, Maurizio Miglino, Nicoletta Colombo, Elisabetta Tedone, Silvia Luchetti, Teresa Lamparelli, Francesca Gualandi, Adalberto Ibatici, Stefania Bregante, Maria Teresa Van Lint, Anna Maria Raiola, Alida Dominietto, Riccardo Varaldo, Federica Galaverna, Anna Ghiso, Simona Sica, Andrea Bacigalupo
Minimal residual disease (MRD) was monitored by Wilms tumor 1 (WT1) expression in 207 patients with acute myeloid leukemia (AML) after an allogeneic hemopoietic stem cell transplantation (HSCT) as a trigger to initiate pre-emptive immunotherapy (IT) with cyclosporin discontinuation and/or donor lymphocyte infusion. The trigger for IT was WT1 ≥ 180 copies/10(4) Abelson cells in marrow cells in the first group of 122 patients (WT1-180) and ≥ 100 copies in a subsequent group of 85 patients (WT1-100). Forty patients received IT...
July 2016: Biology of Blood and Marrow Transplantation
Adnan Jaigirdar, Steven A Rosenberg, Maria Parkhurst
Wilms tumor gene 1 (WT1) is an attractive target antigen for cancer immunotherapy because it is overexpressed in many hematologic malignancies and solid tumors but has limited, low-level expression in normal adult tissues. Multiple HLA class I and class II restricted epitopes have been identified in WT1, and multiple investigators are pursuing the treatment of cancer patients with WT1-based vaccines and adoptively transferred WT1-reactive T cells. Here we isolated an HLA-A*0201-restricted WT1-reactive T-cell receptor (TCR) by stimulating peripheral blood lymphocytes of healthy donors with the peptide WT1:126-134 in vitro...
April 2016: Journal of Immunotherapy
Yuho Najima, Mariko Tomizawa-Murasawa, Yoriko Saito, Takashi Watanabe, Rintaro Ono, Toshiki Ochi, Nahoko Suzuki, Hiroshi Fujiwara, Osamu Ohara, Leonard D Shultz, Masaki Yasukawa, Fumihiko Ishikawa
Induction of specific immune response against therapy-resistant tumor cells can potentially improve clinical outcomes in malignancies. To optimize immunotherapy in the clinic, we aimed to create an in vivo model enabling us to analyze human cytotoxic T-lymphocyte (CTL) responses against human malignancies. To this end, we developed NOD/SCID/IL2rgKO (NSG) mice expressing the HLA class I molecules HLA-A*0201 and A*2402. In the bone marrow (BM) and spleen of HLA class I transgenic (Tg) NSG mice transplanted with cord blood hematopoietic stem cells (HSCs), we found human memory CD8(+) T cells and antigen-presenting cells...
February 11, 2016: Blood
Niloufar Ataie, Jingyi Xiang, Neal Cheng, Elliott J Brea, Wenjie Lu, David A Scheinberg, Cheng Liu, Ho Leung Ng
Antibody therapies currently target only extracellular antigens. A strategy to recognize intracellular antigens is to target peptides presented by immune HLA receptors. ESK1 is a human, T-cell receptor (TCR)-mimic antibody that binds with subnanomolar affinity to the RMF peptide from the intracellular Wilms tumor oncoprotein WT1 in complex with HLA-A*02:01. ESK1 is therapeutically effective in mouse models of WT1(+) human cancers. TCR-based therapies have been presumed to be restricted to one HLA subtype. The mechanism for the specificity and high affinity of ESK1 is unknown...
January 16, 2016: Journal of Molecular Biology
Rosaely Casalegno-Garduño, Anita Schmitt, Alf Spitschak, Jochen Greiner, Lei Wang, Inken Hilgendorf, Carsten Hirt, Anthony D Ho, Mathias Freund, Michael Schmitt
Wilms' tumor gene 1 (WT1) is overexpressed in leukemia and WT1-derived CD8(+) T-cell epitopes for immunotherapies targeting WT1 have been defined. Here, we analyzed expression of WT1 in 226 peripheral blood and bone marrow samples from patients with acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) before and after allogeneic stem cell transplantation (SCT). Transcripts were assessed by quantitative polymerase chain reaction, and WT1-specific CD8+ cytotoxic T cells (CTL) were monitored by tetramer staining and enzyme-linked immunospot (ELISPOT) assays...
April 1, 2016: International Journal of Cancer. Journal International du Cancer
Omran Rezai, Ali Khodadadi, Yuji Heike, Ali Mostafai, Nader Dashti Gerdabi, Mohammad Rashno, Zahra Abdoli
BACKGROUND: Leukemia is a common cancer among children and adolescents. Wilms' tumor gene (WT1) is highly expressed in patients with acute leukemia. It is found as a tumor associated antigen (TAA) in various types of hematopoietic malignancies and can be employed as a useful marker for targeted immunotherapy and monitoring of minimal residual disease (MRD). In this regard, WT1 is a transcription factor that promotes gene activation or repression depending on cellular and promoter context...
2015: Asian Pacific Journal of Cancer Prevention: APJCP
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