An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma

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 ( < .01 and < .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; < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; < .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 BCMATACI 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.

Dynamic Profiling of Antitumor Activity of CAR T Cells Using Micropatterned Tumor Arrays

“…[22] Our assay shows that APRIL-based T cells can efficiently eliminate both BCMA positive and negative MM.1s tumor cells (Figure 5a,b-i,c-e). "A proliferation-inducing ligand" (APRIL) is a soluble ligand that can bind BCMA and the transmembrane activator and calciummodulator and cyclophilin ligand (TACI), two antigens highly expressed on MM cells.…”

BAFF inhibition in SLE—Is tolerance restored?

“…23,24 In addition, APRIL supports the survival of long-loved plasma cells (LLPC) in the bone marrow, especially during neonatal development. 18 Although currently restricted to oncology trials, these therapies could potentially be used to target B cell subsets in SLE TACI and BCMA both shed soluble forms that can act as decoy receptors and human TACI has an intracellular short form that preferentially interacts with TLR9.…”

“…Specifically, anti-BAFF-R 16 and anti-BCMA 17 CARs are being developed for the treatment of B cell leukemia/lymphoma and multiple myeloma, respectively, while APRILexpressing CARs target TACI and BCMA expressing cells. 18 Although currently restricted to oncology trials, these therapies could potentially be used to target B cell subsets in SLE…”

Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis

“…Although the vast majority of CAR-T-cell trials for hematologic diseases have focused on CD19redirected T cells, there are a number of new trials targeting other B-cell antigens (including CD20, CD22, CD30, and B-cell maturation antigen [109][110][111][112], T-cell antigens, as well as early trials targeting antigens associated with acute myeloid leukemia. [113][114][115][116][117][118][119][120][121][122][123][124] The elements of success with CAR-T therapies As with HCT, CAR-T-cell therapies are composed of multiple stages, and at each stage, critical elements exist that contribute to success or failure. It is useful to divide CAR-T cellular therapies into 4 distinct stages: (1) patient selection and cell manufacturing;…”