Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T-lymphocytes
Ignazio Caruana,Barbara Savoldo,Valentina Hoyos,Gerrit Weber,Hao Liu,Eugene S. Kim,Michael Ittmann,Dario Marchetti,Gianpietro Dotti +8 more
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TLDR
E engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity, and the use of this strategy may enhance the activity of CAR- T cells in individuals with stroma-rich solid tumors.Abstract:
Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells, functional changes in T lymphocytes after their ex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to penetrate stroma-rich solid tumors compared with lymphoid tissues. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE), which degrades heparan sulfate proteoglycans, the main components of ECM. We found that HPSE mRNA is downregulated in in vitro-expanded T cells, which may be a consequence of p53 (officially known as TP53, encoding tumor protein 53) binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity. The use of this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.read more
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Immunological hallmarks of stromal cells in the tumour microenvironment
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CAR T Cell Therapy for Solid Tumors.
TL;DR: Some of the challenges that CAR T cells have to surmount in the solid tumor microenvironment are characterized and new approaches that are being considered to overcome these hurdles are described.
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TL;DR: In this article, the authors discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CART cell therapy in both B cell leukemia or lymphoma.
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'Off-the-shelf' allogeneic CAR T cells: development and challenges.
TL;DR: This Review analyses the different sources of T cells and technological approaches to produce optimal allogeneic chimeric antigen receptor T cells with limited potential for graft-versus-host disease and increased persistence and describes the different technological approaches.
References
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Journal ArticleDOI
Functions of Cell Surface Heparan Sulfate Proteoglycans
Merton Bernfield,Martin Götte,Pyong Woo Park,Ofer Reizes,Marilyn L. Fitzgerald,John Lincecum,Masahiro Zako +6 more
TL;DR: Current analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans.
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T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia
Michael Kalos,Bruce L. Levine,David L. Porter,Sharyn I. Katz,Stephan A. Grupp,Stephan A. Grupp,Adam Bagg,Carl H. June +7 more
TL;DR: It is reported that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non–cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL).
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Immunosuppressive networks in the tumour environment and their therapeutic relevance
TL;DR: It is well known that many tumours are potentially immunogenic, as corroborated by the presence of tumour-specific immune responses in vivo, but why has tumour immunotherapy resulted in a generally poor clinical efficiency?
Journal ArticleDOI
CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia
Renier J. Brentjens,Marco L. Davila,Isabelle Riviere,Jae H. Park,Xiuyan Wang,Lindsay G. Cowell,Shirley Bartido,Jolanta Stefanski,Clare Taylor,Malgorzata Olszewska,Oriana Borquez-Ojeda,Jinrong Qu,Teresa Wasielewska,Qing He,Yvette Bernal,Ivelise Rijo,Cyrus V. Hedvat,Rachel Kobos,Kevin J. Curran,Peter G. Steinherz,Joseph G. Jurcic,Todd L. Rosenblat,Peter Maslak,Mark G. Frattini,Michel Sadelain +24 more
TL;DR: The results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.
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Matrix Proteoglycans: From Molecular Design to Cellular Function
TL;DR: The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions and additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant.
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