UCL logo

UCL Discovery

UCL home » Library Services » Electronic resources » UCL Discovery

Delineating the impact of binding-domain affinity and kinetic properties on Chimeric Antigen Receptor T-cell function

Kramer, AM; (2017) Delineating the impact of binding-domain affinity and kinetic properties on Chimeric Antigen Receptor T-cell function. Doctoral thesis , UCL (University College London). Green open access

[img]
Preview
Text
AMK_Thesis_20170430.pdf - ["content_typename_Accepted version" not defined]

Download (7MB) | Preview

Abstract

CD19 Chimeric Antigen Receptor (CAR) therapy represents a breakthrough in the treatment of relapsed/refractory acute lymphoblastic leukaemia and early-phase clinical trials with CAR-modified-T cells have shown unprecedented responses. A CAR is a recombinant receptor that combines a single chain variable fragment (scFv) against a tumour-associated antigen and an intracellular activation domain of the T cell receptor (TCR), recognizing membrane-bound antigen, typically with a higher affinity compared to TCR-pMHC affinity. We compared the influences of differences in on- and off-rates underlying the binding kinetics of CD19 CARs on downstream CAR T cell responses and constructed a novel CAR derived from the CAT hybridoma demonstrating a lower affinity as a result of a greater off-rate, whilst maintaining an on-rate nearly identical to FMC63, the scFv most-used in clinical trials. Using in vitro pre-clinical models we demonstrated that CAT-CAR+ T cells showed increased proliferation, higher cytotoxic responses, and increased cytokine production, as well as a greater number of interactions between CAT-CAR+ T cells and target cells and a greater motility in comparison to FMC63. In vivo CAT-CAR+ T cells showed an enhanced ability to clear disease, proliferate and produce cytokines, displaying markers characteristic for improved T cell fitness. We believe that, analogous to the natural TCR, a lower overall binding affinity might be mitigated by a relatively faster off-rate in the setting of a constant on-rate and propose that this may enhance CAR T cell function through serial triggering, where increased target:effector interaction time, may lead to exhaustion and activation induced cell death. These data have important implications for the development of future CARs.

Type: Thesis (Doctoral)
Title: Delineating the impact of binding-domain affinity and kinetic properties on Chimeric Antigen Receptor T-cell function
Event: Institute of Child Health
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Immunotherapy, Acute Lymphoblastic Leukaemia
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Development Bio and Cancer Prog
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Infect, Imm, Infla. and Physio Med
URI: http://discovery.ucl.ac.uk/id/eprint/1558284
Downloads since deposit
75Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item