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.

Key Points Proinflammatory MKs from mice with GPS drive the extension of myelofibrosis, splenomegaly, and emperipolesis. The lack of preformed α-granules in Nbeal2−/− platelets leads to protection against cancer metastasis.

Multiple myeloma(MM) is the second commonest haematological malignancy and remains incurable. Beyond tumour biology and genomic features driving disease resistance, host factors including impaired immunity and frailty also contribute to poor outcomes. Despite reports of immune dysfunction in this cancer, clear evidence for the contribution to clinical outcomes remains lacking.We show, for the first time, that high abundance of Treg and PD-1+CD4 effector cells in bone marrow of newly diagnosed patients are independent predictors of early relapse. This work supports growing literature on the importance of CD4 effector cells in MM, and confirms a role for the PD-1/PD-L1 axis to MM pathobiology.Our work identifies Tregs and PD-1+CD4 effectors as potential therapeutic targets, and opens up avenues for further mechanistic studies into early relapse. Pending confirmation in future patient cohorts, such immune parameters may refine existing risk models, facilitating patient stratification for therapeutic strategies targeting key CD4 populations.Research.