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

Lydia Lee, Benjamin Draper, Neil Chaplin, Brian Philip, Melody Chin, Daria Galas-Filipowicz, Shimobi Onuoha, Simon Thomas, Vania Baldan, Reyisa Bughda, Paul Maciocia, Eva Kokalaki, Margarida P. Neves, Dominic Patel, Manuel Rodriguez-Justo, James Francis, Kwee Yong and Martin Pule

Key points

  • APRIL is a compact, self-protein that binds two MM antigens (BCMA and TACI) with high affinity. We present an APRIL based CAR.

  • Dual antigen targeting increases the availability of tumour binding sites and reduces the risk of antigen negative disease escape.

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.

  • Submitted May 11, 2017.
  • Accepted December 13, 2017.