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Tina Chang Albershardt, David James Campbell, Andrea Jean Parsons, Megan Merrill Slough, Jan Ter Meulen, Peter Berglund
We have engineered an integration-deficient lentiviral vector, LV305, to deliver the tumor antigen NY-ESO-1 to human dendritic cells in vivo through pseudotyping with a modified Sindbis virus envelop protein. Mice immunized once with LV305 developed strong, dose-dependent, multifunctional, and cytotoxic NY-ESO-1-specific cluster of differentiation 8 (CD8) T cells within 14 days post-immunization and could be boosted with LV305 at least twice to recall peak-level CD8 T-cell responses. Immunization with LV305 protected mice against tumor growth in an NY-ESO-1-expressing CT26 lung metastasis model, with the protective effect abrogated upon depletion of CD8 T cells...
2016: Molecular Therapy Oncolytics
Michael Schmitt, Angela G Hückelhoven, Michael Hundemer, Anita Schmitt, Susanne Lipp, Martina Emde, Hans Salwender, Mathias Hänel, Katja Weisel, Uta Bertsch, Jan Dürig, Anthony D Ho, Igor Wolfgang Blau, Hartmut Goldschmidt, Anja Seckinger, Dirk Hose
BACKGROUND: Raising T-cell response against antigens either expressed on normal and malignant plasma cells (e.g. HM1.24) or aberrantly on myeloma cells only (e.g. cancer testis antigens, CTA) by vaccination is a potential treatment approach for multiple myeloma. RESULTS: Expression by GEP is found for HM1.24 in all, HMMR in 318/458 (69.4%), MAGE-A3 in 209/458 (45.6%), NY-ESO-1/2 in 40/458 (8.7%), and WT-1 in 4/458 (0.8%) of samples with the pattern being confirmed by RNA-sequencing...
August 11, 2016: Oncotarget
Mouldy Sioud, Marta Nyakas, Stein Sæbøe-Larssen, Anne Mobergslien, Steinar Aamdal, Gunnar Kvalheim
Indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells (DCs) inhibits T-cell activation and promotes T-cell differentiation into regulatory T-cells. Moreover, IDO expression promotes resistance to immunotherapies targeting immune checkpoints such as the cytotoxic T lymphocyte antigen-4 (CTLA-4). Here, a patient with metastatic melanoma pretreated with ipilimumab, an anti-CTLA-4 blocking antibody, was vaccinated with IDO-silenced DCs cotransfected with mRNA for survivin or hTERT tumour antigens. During vaccination, T-cell responses to survivin and hTERT tumour antigens were generated, and a certain degree of clinical benefit was achieved, with a significant reduction in lung, liver, and skin metastases, along with a better performance status...
2016: Case Reports in Medicine
Matthew Dallos, William D Tap, Sandra P D'Angelo
Synovial sarcoma is a rare soft tissue sarcoma characterized by a t(X;18) translocation, which results in a SYT-SSX gene fusion. In the metastatic setting, chemotherapy has limited, durable efficacy prompting the necessity for new therapeutic modalities. One emerging new strategy involves T-cell-directed therapy such as tumor-infiltrating lymphocytes or the development of T cells that are genetically engineered to express a T-cell receptor against a cancer testis antigen. Of these approaches, engineered T cells that recognize NY-ESO-1 are the furthest along in development...
September 2016: Immunotherapy
David Bernal-Estévez, Ramiro Sánchez, Rafael E Tejada, Carlos Parra-López
BACKGROUND: Experimental evidence and clinical studies in breast cancer suggest that some anti-tumor therapy regimens generate stimulation of the immune system that accounts for tumor clinical responses, however, demonstration of the immunostimulatory power of these therapies on cancer patients continues to be a formidable challenge. Here we present experimental evidence from a breast cancer patient with complete clinical response after 7 years, associated with responsiveness of tumor specific T cells...
2016: BMC Cancer
Wei Xue, Rachael L Metheringham, Victoria A Brentville, Barbara Gunn, Peter Symonds, Hideo Yagita, Judith M Ramage, Lindy G Durrant
Checkpoint blockade has demonstrated promising antitumor responses in approximately 10-40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody®: IB) results in significant tumor regression both in animal models and patients...
June 2016: Oncoimmunology
Marie-Nicole Theodoraki, Kai J Lorenz, Juliane Schneider, Julia C Thierauf, Giulio Spagnoli, Patrick J Schuler, Thomas K Hoffmann, Simon Laban
BACKGROUND: Photodynamic therapy (PDT) represents a palliative treatment resulting in induction of inflammatory reactions with importance for the development of an antitumor immunity. Cancer/testis antigens (CTAs) have been associated with poor prognosis in different types of cancer, including head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Tumor tissue samples before and after PDT were evaluated for the expression of four different CTAs by immunohistochemistry...
August 2016: Anticancer Research
Mai Ping Tan, Garry M Dolton, Andrew B Gerry, Joanna E Brewer, Alan D Bennett, Nick Pumphrey, Bent K Jakobsen, Andrew K Sewell
CD4(+) T helper cells are a valuable component of the immune response towards cancer. Unfortunately, natural tumour-specific CD4(+) T-cells occur in low frequency, express relatively low affinity T-cell receptors (TCRs) and show poor reactivity towards cognate antigen. In addition, the lack of human leukocyte antigen (HLA) class II expression on most cancers dictates that these cells are often unable to respond to tumour cells directly. These deficiencies can be overcome by transducing primary CD4(+) T-cells with tumour-specific HLA class I-restricted TCRs prior to adoptive transfer...
June 20, 2016: Clinical and Experimental Immunology
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
Tomohide Tsukahara, Makoto Emori, Kenji Murata, Emi Mizushima, Yuji Shibayama, Terufumi Kubo, Takayuki Kanaseki, Yoshihiko Hirohashi, Toshihiko Yamashita, Noriyuki Sato, Toshihiko Torigoe
INTRODUCTION: The use of immunotherapeutic challenges for sarcoma has a long history. Despite the existence of objective responses, immunotherapy has been overshadowed by the results of chemotherapy, especially for osteosarcoma. However, the prognosis for non-responders to chemotherapy is still poor and immunotherapy is now focused on again. AREAS COVERED: We reviewed the following types of clinical trials of immunotherapy for sarcoma: (i) vaccination with autologous tumor cells, (ii) vaccination with peptides derived from tumor-associated antigens, (iii) adoptive cell transfer using engineered T cells expressing T cell receptor directed at NY-ESO-1 and (iv) immune checkpoint inhibitors targeting CTLA-4 and PD1/PDL1...
August 2016: Expert Opinion on Biological Therapy
J Brian Szender, Kevin H Eng, Junko Matsuzaki, Anthony Miliotto, Sacha Gnjatic, Takemasa Tsuji, Kunle Odunsi
OBJECTIVES: To characterize the association between major histocompatibility complex (MHC) types and spontaneous antibody development to the cancer testis (CT) antigen NY-ESO-1. METHODS: Tumor expression of NY-ESO-1 and serum antibodies to NY-ESO-1 were characterized in addition to human leukocyte antigen (HLA) type for patients with epithelial ovarian cancer. HLA types were assigned to structure-based superfamilies and statistical associations were examined. HLA types were compared to existing reference libraries of HLA frequencies in a European-Caucasian American population...
July 2016: Gynecologic Oncology
Sid P Kerkar, Zeng-Feng Wang, Jerzy Lasota, Tristen Park, Krishna Patel, Eric Groh, Steven A Rosenberg, Markku M Miettinen
Two cancer testis antigens, the New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and the melanoma-antigen family A (MAGE-A), represent promising immunotherapy targets due to the low expression of these antigens in nonmalignant tissue. To assess overexpression patterns in various cancers, we performed a systematic immunohistochemical analysis for NY-ESO-1 and MAGE-A on tissue array samples of 3668 common epithelial carcinomas (CA) and germ cell tumors of high prevalence and mortality. Here, we find significantly higher expression of MAGE-A (>50% on tumor cells) compared with NY-ESO-1 in several CAs including cutaneous squamous cell carcinomas (SCC) (52...
May 2016: Journal of Immunotherapy
Nathan Singh, Irina Kulikovskaya, David M Barrett, Gwendolyn Binder-Scholl, Bent Jakobsen, Daniel Martinez, Bruce Pawel, Carl H June, Michael D Kalos, Stephan A Grupp
The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY-ESO-1...
2016: Oncoimmunology
A Wijkhuisen, A Savatier, N Cordeiro, M Léonetti
BACKGROUND: We previously developed in vitro immunization based on a fusion protein containing the transcriptional transactivator (Tat) of human immunodeficiency virus and a double domain, called ZZ, derived from protein A of Staphylococcus aureus. In this approach, naïve human peripheral blood mononuclear cells (PBMCs) trigger a specific IgM antibody (Ab) response in the presence of ZZTat. In the present study, we attempted to raise a specific IgG Ab response. RESULTS: We found that PBMCs incubated with ZZTat and a mixture containing anti-CD40, IL4 and IL21 secrete anti-Tat IgG Abs in their supernatants, indicating that the cytokine cocktail provides an isotypic switch...
2016: BMC Biotechnology
Richard Golnik, Andrea Lehmann, Peter-Michael Kloetzel, Frédéric Ebstein
The supply of MHC class I-restricted peptides is primarily ensured by the degradation of intracellular proteins via the ubiquitin-proteasome system. Depending on the target and the enzymes involved, ubiquitination is a process that may dramatically vary in terms of linkages, length, and attachment sites. Here we identified the unique lysine residue at position 124 of the NY-ESO-1 cancer/testis antigen as the acceptor site for the formation of canonical Lys-48-linkages. Interestingly, a lysine-less form of NY-ESO-1 was as efficient as its wild-type counterpart in supplying the HLA-A*0201-restricted NY-ESO-1157-165 antigenic peptide...
April 15, 2016: Journal of Biological Chemistry
Kengo Miyauchi, Takahiro Tsuchikawa, Masataka Wada, Takehiro Abiko, Noriaki Kyogoku, Toshiaki Shichinohe, Yoshihiro Miyahara, Shinichi Kageyama, Hiroaki Ikeda, Hiroshi Shiku, Satoshi Hirano
AIM: To investigate the antigen spreading pattern in the CHP-MAGE-A4-vaccinated patients and analyze the clinical relevance of antigen spreading pattern as a surrogate marker of patient survival. MATERIALS & METHODS: 12 patients who had been injected with 300 μg of CHP-MAGE-A4 and 0.5 Klinische Einheit of OK-432 in more than five vaccinations were analyzed. RESULTS: Increases in the anti-MAGE-A4-specific antibody response were observed in eight patients (66...
May 2016: Immunotherapy
Katherine Woods, Ashley J Knights, Matthew Anaka, Ralf B Schittenhelm, Anthony W Purcell, Andreas Behren, Jonathan Cebon
BACKGROUND: A current focus in cancer treatment is to broaden responses to immunotherapy. One reason these therapies may prove inadequate is that T lymphocytes fail to recognize the tumor due to differences in immunogenic epitopes presented by the cancer cells under inflammatory or non-inflammatory conditions. The antigen processing machinery of the cell, the proteasome, cleaves proteins into peptide epitopes for presentation on MHC complexes. Immunoproteasomes in inflammatory melanomas, and in antigen presenting cells of the immune system, are enzymatically different to standard proteasomes expressed by tumors with no inflammation...
2016: Journal for Immunotherapy of Cancer
Pragya Srivastava, Benjamin E Paluch, Junko Matsuzaki, Smitha R James, Golda Collamat-Lai, Nadja Blagitko-Dorfs, Laurie Ann Ford, Rafeh Naqash, Michael Lübbert, Adam R Karpf, Michael J Nemeth, Elizabeth A Griffiths
Cancer testis antigens (CTAs) are promising cancer associated antigens in solid tumors, but in acute myeloid leukemia, dense promoter methylation silences their expression. Leukemia cell lines exposed to HMAs induce expression of CTAs. We hypothesized that AML patients treated with standard of care decitabine (20mg/m2 per day for 10 days) would demonstrate induced expression of CTAs. Peripheral blood blasts serially isolated from AML patients treated with decitabine were evaluated for CTA gene expression and demethylation...
March 15, 2016: Oncotarget
Johannes A Veit, Daniela Heine, Julia Thierauf, Jochen Lennerz, Subasch Shetty, Patrick J Schuler, Theresa Whiteside, Dirk Beutner, Moritz Meyer, Inga Grünewald, Gerd Ritter, Sacha Gnjatic, Andrew G Sikora, Thomas K Hoffmann, Simon Laban
BACKGROUND: Adenoid cystic carcinoma (ACC) of the head and neck is a rare but highly malignant tumor. Cancer-testis antigens (CTAs) represent an immunogenic family of cancer-specific proteins and thus represent an attractive target for immunotherapy. METHODS: Eighty-four cases of ACC were identified, the CTAs pan-Melanoma antigen (pan-MAGE; M3H67) and New York esophageal squamous cell carcinoma (NY-ESO-1; E978) were detected immunohistochemically (IHC) and correlated with clinical data...
July 2016: Head & Neck
Qingda Meng, Zhenjiang Liu, Elena Rangelova, Thomas Poiret, Aditya Ambati, Lalit Rane, Shanshan Xie, Caroline Verbeke, Ernest Dodoo, Marco Del Chiaro, Matthias Löhr, Ralf Segersvärd, Markus J Maeurer
Generation of T lymphocytes with reactivity against cancer is a prerequisite for effective adoptive cellular therapies. We established a protocol for tumor-infiltrating lymphocytes (TILs) from patients with pancreatic ductal adenocarcinoma. Tumor samples from 17 pancreatic cancer specimens were cultured with cytokines (IL-2, IL-15, and IL-21) to expand TILs. After 10 days of culture, TILs were stimulated with an anti-CD3 antibody (OKT3) and irradiated allogeneic peripheral blood mononuclear cells. Reactivity of TILs against tumor-associated antigens (mesothelin, survivin, or NY-ESO-1) was detected by intracellular cytokine production by flow cytometry...
February 2016: Journal of Immunotherapy
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