Targeted immunotherapy for myeloma and lymphoma
Monoclonal antibody (mAb)-based targeted therapy finally becomes available as a novel treatment strategy for patients with multiple myeloma (MM) following over a decade of evaluating many mAbs targeting various antigens pre-clinically and clinically. The continuous goal is to both identify more selective MM target antigens and develop more effective targeted immunotherapy to treat MM at various disease stages. Following promising pre-clinical results of my previous studies on elotuzumab targeting a new MM antigen SLAMF7/CS1 and daratumumab targeting CD38, encouraging clinical activities when combined with lenalidomide/dexamethasone have quickly moved these two Abs into multiple phase III clinical trials in MM. Specifically, daratumumab showing acceptable safety profile with signs of single agent activity in relapsed and refractory MM with diverse heterogeneity, is the first Ab approved by FDA in treating MM patients in 2015. Most recently, we further identified that the second therapeutic anti-CD38 mAb SAR650984 (SAR) directly kills p53-mutated MM cells, which represent high-risk patient subgroup, via lysosomal activation and reactive oxygen species. This is the first therapeutic mAb inducing direct tumor cell death without immune effector cells. Although caspase 3/7-dependent apoptosis plays a minor role in SAR-induced myeloma cell death, it is synergistically activated when SAR is combined with Pomalidomide, strongly supporting ongoing combination trials in resistant MM and other CD38-expressing blood cancers. However, these antigens still lack tumor specificity since they also expressed in other normal tissues including NK and T effectors, which could limit their clinical utilities. Therefore, novel therapeutic mAbs to achieve improved MM selectivity and simultaneously producing cytotoxicity against tumor cells protected by their bone marrow microenvironment are urgently needed. Very encouragingly, we reported that B cell maturation antigen is universally expressed on the MM cell surface which can be effectively targeted by a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. These studies demonstrate more potent and selective myeloma cell killing without affecting surrounding antigen-null non-tumor cells via multiple cytotoxic mechanisms even in two mice models, thus providing promising next-generation immunotherapeutics to overcome drug resistance. We are further defining molecular mechanisms regulating this signaling pathway in various aspects of myeloma pathophysiology and continuing to improve effectiveness of immunotherapies using multiple mAb- and cell-based approaches. We also characterize other novel cancer pathways, i.e., BTK and CRM1/XPO1, ligands to BCMA, and immuno-checkpoint proteins in the interaction and suppression of osteoclasts or various immune cells with myeloma cells in the immunesuppressive bone marrow microenvironment.
