Abstract
Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells in vitro, inducing secretion of pro-inflammatory cytokines and CAR T cell proliferation. In vivo, A3B1 CAR T cells are able to fully control disease progression in an NOD.Cg-PrkdcscidIl2rdtm1Wjl/SzJ (NSG) xenograph B-ALL mouse model. Based on the pre-clinical data, we conclude that our CART19 is clearly functional against CD19+ cells, to a level similar to other CAR19s currently being used in the clinic. Concurrently, we describe the implementation of our CAR T cell production system, using lentiviral vector and CliniMACS Prodigy, within a medium-sized academic institution. The results of the validation phase show our system is robust and reproducible, while maintaining a low cost that is affordable for academic institutions. Our model can serve as a paradigm for similar institutions, and it may help to make CAR T cell treatment available to all patients.
Highlights
Modifying autologous T cells to express chimeric antigen receptors (CARs), redirecting them to eliminate tumor cells, is a new and revolutionary therapeutic modality for cancer treatment and, in particular, for CD19+ B cell malignancies.[1,2,3,4,5,6,7,8,9]CARs are composed of an extracellular region responsible for binding to a particular antigen and an intracellular region that promotes T cell cytotoxic activity and proliferation
This paper shows the results of pre-clinical work as well as the description of our production system for ARI-0001 cells, focusing on the results of the validation phase of our clinical trial (CART19-BE-01), which has enrolled and treated more than 20 patients and is currently ongoing
Our work demonstrates the feasibility of producing CAR T cells in medium-sized academic institutions
Summary
Modifying autologous T cells to express chimeric antigen receptors (CARs), redirecting them to eliminate tumor cells, is a new and revolutionary therapeutic modality for cancer treatment and, in particular, for CD19+ B cell malignancies.[1,2,3,4,5,6,7,8,9]. CARs are composed of an extracellular region responsible for binding to a particular antigen and an intracellular region that promotes T cell cytotoxic activity and proliferation. CAR binding to the selected antigen is usually mediated by a single-chain variable fragment (scFv) of a monoclonal antibody. As a second generation CAR, this scFv is combined with an intracellular. 134 Molecular Therapy: Methods & Clinical Development Vol 12 March 2019 a 2018 The Authors.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Molecular Therapy - Methods & Clinical Development
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
