by Further studies to understand the determinants of response to teclistamab are required to identify which other diseases might be suitable for teclistamab targeting. == Significance: == Besides reported BCMA expression on multiple myeloma, we demonstrate BCMA can be detected and enhanced using -secretase inhibition on cell lines and main material of various B-cell malignancies. healthy donor T cells and CLL-derived T cells induced lysis of (autologous) CLL cells upon addition of teclistamab. These data show that BCMA is usually MK-2894 expressed on numerous B-cell malignancies and that lymphoma cell lines and main CLL can be targeted using teclistamab. Further studies to understand the determinants of response to teclistamab are required to identify which other diseases might be suitable for teclistamab targeting. == Significance: == Besides reported BCMA expression on multiple myeloma, we demonstrate BCMA can be detected and enhanced using -secretase inhibition on cell lines and main material of various B-cell malignancies. Furthermore, using CLL we demonstrate that low BCMA-expressing tumors can be targeted efficiently using the BCMAxCD3 DuoBody teclistamab. == Introduction == Treatment of B-cell lymphoproliferative disorders such as B-cell nonHodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL) has improved significantly over the last years. This is mostly due to a rapidly expanding treatment armamentarium of targeted brokers such as inhibitors of pivotal B-cell receptor pathway kinases BTK and PI3K, and the Bcl-2 inhibitor venetoclax (1, 2). Nevertheless, for many B-NHL subtypes, these treatments are not curative, eventually leading to disease relapse in patients, highlighting the importance of new therapies for these malignancies. From stem cell transplantations (SCT), it has become obvious that long-lived T cellmediated anticancer responses are feasible (3). However, due to severe GVHD that can occur, this mostly elderly group of patients is not eligible for SCT. Application of autologous T cellbased therapy will not lead MK-2894 to development of GVHD and therefore might be a preferable treatment modality. Different autologous T cellbased therapies have already been developed, including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells. ICB has shown to MK-2894 be effective only in a modest Epas1 quantity of B-NHL which included patients with follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL) (4). In contrast, CAR T cells proved to be more promising (4). Currently, CAR T cells are produced patient specifically, making it time-consuming and costly, and furthermore T-cell exhaustion is usually a common reason for treatment failure (5). Bispecific antibodies (BsAb) are another option to harness autologous T cells against lymphoma cells. BsAbs are off-the-shelf products that can be administered repeatedly to patients (6). BsAbs are comprised of two different antigen-recognizing arms and lead to recruitment of T cells, via the CD3-binding domain name, to tumor cells, via the tumor-associated antigen (TAA) arm. This T-cell receptorindependent acknowledgement of the tumor cells prospects to T-cell activation and eventually kills the tumor cells due to T cellmediated granzyme/perforin release (7, 8). For hematologic malignancies, the most prominent TAA has been CD19. The first BsAb to be approved by the FDA for relapsed/refractory acute lymphoblastic leukemia was the CD19-targeting bispecific T-cell engager (BiTE) blinatumomab (9, 10). The short half-life of blinatumomab and the adverse events, mainly neurotoxicity related to targeting of CD19, stress the importance of different BsAb types targeting new TAAs (11). One of these might be B-cell maturation antigen (BCMA). BCMA is normally expressed on plasmablasts (PB) and plasma cells (PC; refs.12, 13). Its expression is important for sustaining stable humoral immunity by providing prosurvival signals leading to proliferation and differentiation (13, 14). This is mediated by binding of a proliferation-inducing ligand (APRIL) or B-cellactivating factor (BAFF), which binds with lower affinity to BCMA (15). It was shown that BCMA is usually actively shed off the membrane by -secretase, resulting in release of soluble BCMA (sBCMA) which can act as a decoy for APRIL (16). In line with the expression of BCMA on PBs and PCs, BCMA is usually highly expressed on multiple myeloma cells, and is considered a validated target, based on approval of the BCMA-targeted therapies belantamab mafodotin and idecabtagene vicleucel, for treatment of advanced.
