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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 2 MM antigens (BCMA and TACI) with high affinity; we present an APRIL-based CAR.

  • Dual-antigen targeting increases the availability of tumor-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 downregulation at relapse. Dual-antigen targeting increases targetable tumor 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 calcium-modulator and cyclophilin ligand (TACI). We quantified surface tumor 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 < .01 and P < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% ± 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; P < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; P < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMA+TACI and BCMATACI+ cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach.

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