Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity.
Marianela Candolfi,Kader Yagiz,David Foulad,Gabrielle E. Alzadeh,Matthew Tesarfreund,A.K.M. Ghulam Muhammad,Mariana Puntel,Kurt M. Kroeger,Chunyan Liu,Sharon Lee,James F. Curtin,Gwendalyn D. King,Jonathan Lerner,Katsuaki Sato,Yohei Mineharu,Weidong Xiong,Pedro R. Lowenstein,Maria G. Castro +17 more
TLDR
The results indicate that Ad-TK+GCV+Ad-Flt3L exhibit the highest efficacy and safety profile among the several proapoptotic approaches tested.Abstract:
Purpose: In preparation for a phase I clinical trial using a combined cytotoxic/immunotherapeutic strategy with adenoviruses (Ad) expressing Flt3L (Ad-Flt3L) and thymidine kinase (Ad-TK) to treat glioblastoma (GBM), we tested the hypothesis that Ad-TK+GCV would be the optimal tumor-killing agent in relation to efficacy and safety when compared with other proapoptotic approaches. Experimental Design: The efficacy and neurotoxicity of Ad-TK+GCV was compared with Ads encoding the proapoptotic cytokines [tumor necrosis factor-α, tumor necrosis factor–related apoptosis-inducing factor (TRAIL), and Fas ligand (FasL)], alone or in combination with Ad-Flt3L. In rats bearing small GBMs (day 4), only Ad-TK+GCV or Ad-FasL improved survival. Results: In rats bearing large GBMs (day 9), the combination of Ad-Flt3L with Ad-FasL did not improve survival over FasL alone, whereas Ad-Flt3L combined with Ad-TK+GCV led to 70% long-term survival. Expression of FasL and TRAIL caused severe neuropathology, which was not encountered when we used Ad-TK+/−Ad-Flt3L. In vitro, all treatments elicited release of high mobility group box 1 protein (HMGB1) from dying tumor cells. In vivo, the highest levels of circulating HMGB1 were observed after treatment with Ad-TK+GCV+Ad-Flt3L; HMGB1 was necessary for the therapeutic efficacy of AdTK+GCV+Ad-Flt3L because its blockade with glycyrrhizin completely blocked tumor regression. We also showed the killing efficacy of Ad-TK+GCV in human GBM cell lines and GBM primary cultures, which also elicited release of HMGB1. Conclusions: Our results indicate that Ad-TK+GCV+Ad-Flt3L exhibit the highest efficacy and safety profile among the several proapoptotic approaches tested. The results reported further support the implementation of this combined approach in a phase I clinical trial for GBM.read more
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Consensus guidelines for the detection of immunogenic cell death
Oliver Kepp,Laura Senovilla,Ilio Vitale,Erika Vacchelli,Sandy Adjemian,Patrizia Agostinis,Lionel Apetoh,Fernando Aranda,Vincenzo Barnaba,Norma Bloy,Laura Bracci,Karine Breckpot,David Brough,Aitziber Buqué,Maria G. Castro,Mara Cirone,María Isabel Colombo,Isabelle Cremer,Sandra Demaria,Luciana Dini,Aristides G. Eliopoulos,Alberto Faggioni,Silvia C. Formenti,Jitka Fucikova,Lucia Gabriele,Udo S. Gaipl,Jérôme Galon,Abhishek D. Garg,François Ghiringhelli,Nathalia A. Giese,Zong Sheng Guo,Akseli Hemminki,Martin Herrmann,James W. Hodge,Stefan Holdenrieder,Jamie Honeychurch,Hong-Min Hu,Xing Huang,Timothy M Illidge,Koji Kono,Mladen Korbelik,Dmitri V. Krysko,Sherene Loi,Pedro R. Lowenstein,Enrico Lugli,Yuting Ma,Frank Madeo,Angelo A. Manfredi,Isabelle Martins,Domenico Mavilio,Laurie Menger,Nicolò Merendino,Michael Michaud,Grégoire Mignot,Karen L. Mossman,Gabriele Multhoff,Rudolf Oehler,Fabio Palombo,Theocharis Panaretakis,Jonathan Pol,Enrico Proietti,Jean-Ehrland Ricci,Chiara Riganti,Patrizia Rovere-Querini,Anna Rubartelli,Antonella Sistigu,Mark J. Smyth,Juergen Sonnemann,Radek Spisek,John Stagg,Abdul Qader Sukkurwala,Eric Tartour,Andrew Thorburn,Stephen H. Thorne,Peter Vandenabeele,Francesca Velotti,Samuel T Workenhe,Haining Yang,Wei-Xing Zong,Laurence Zitvogel,Guido Kroemer,Lorenzo Galluzzi +81 more
TL;DR: Strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative I CD inducers are outlined, based on a high-content, high-throughput platform that was recently developed.
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Detection of immunogenic cell death and its relevance for cancer therapy
Jitka Fucikova,Oliver Kepp,Lenka Kasikova,Giulia Petroni,Takahiro Yamazaki,Peng Liu,Liwei Zhao,Radek Spisek,Guido Kroemer,Lorenzo Galluzzi,Lorenzo Galluzzi +10 more
TL;DR: Qualitative approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer are outlined.
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Glioblastoma multiforme: State of the art and future therapeutics
TL;DR: Treatment of Glioblastoma multiforme remains extremely challenging, and continued research and development of targeted therapies, based on a detailed understanding of molecular pathogenesis can reasonably be expected to yield improved outcomes for patients with GBM.
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Targeting the Fas/FasL signaling pathway in cancer therapy
TL;DR: The success of the Fas/FasL system targeting for therapeutics will require a better understanding of the alterations conferring resistance, in order to use the most appropriate sensitizing chemotherapeutic or radiotherAPEutic agents in combination with effective targeted therapies.
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Immunosuppressive Myeloid Cells' Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy.
Neha Kamran,Padma Kadiyala,Meghna Saxena,Marianela Candolfi,Youping Li,Mariela A. Moreno-Ayala,Nicholas Raja,Diana Shah,Pedro R. Lowenstein,Maria G. Castro +9 more
TL;DR: Testing whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy indicates that blocking MDSCs-mediated immunosuppression holds great promise for increasing the efficacy for gene therapy-mediated Immunotherapies for GBM.
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