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An APRIL based chimeric antigen receptor for dual targeting of BCMA and TACI in Multiple Myeloma

Lee, L; Draper, B; Chaplin, N; Philip, B; Chin, M; Galas-Filipowicz, D; Onuoha, S; ... Pule, M; + view all (2017) An APRIL based chimeric antigen receptor for dual targeting of BCMA and TACI in Multiple Myeloma. Blood , 2017 (5) , Article 781351. 10.1182/blood-2017-05-781351. Green open access

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Abstract

B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen down-regulation at relapse. Dual antigen targeting increases targetable tumour antigens and reduces the risk of antigen negative disease escape. 'A proliferation-inducing ligand' (APRIL) is a natural high affinity ligand for BCMA and transmembrane activator and CAML interactor (TACI). We quantified surface tumour expression of BCMA and TACI on primary MM cells (n=50). All cases tested expressed BCMA and 39(78%) of them also expressed TACI. We engineered a third generation APRIL-based CAR (ACAR), which killed targets expressing either BCMA or TACI (p<0.01 and p<0.05 respectively, cf control, E:T ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low effector to target ratios (56.2±3.9% killing of MM.1s at 48 hours, E:T ratio 1:32, p<0.01) and of primary MM cells (72.9±12.2% killing at 3 days, E:T ratio 1:1, p<0.05, n=5). Demonstrating tumour control in the absence of BCMA, cytolysis of primary tumour expressing both BCMA and TACI was maintained in the presence of a BCMA targeting antibody. Further, using an intramedullary myeloma model, ACAR T-cells caused regression of established tumour within 2 days. Finally, in an in vivo model of tumour escape, there was complete ACAR-mediated tumour clearance of BCMA+TACI- and BCMA-TACI+ cells while a scFv CAR targeting BCMA alone resulted in outgrowth of BCMA negative tumour. These results support the clinical potential of this approach.

Type: Article
Title: An APRIL based chimeric antigen receptor for dual targeting of BCMA and TACI in Multiple Myeloma
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood-2017-05-781351
Publisher version: https://doi.org/10.1182/blood-2017-05-781351
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
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 Medical Sciences > Cancer Institute > Research Department of Pathology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10041114
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