Abstract
The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs and a key receptor for A proliferation-inducing ligand (APRIL), is highly expressed in MM cells from patients at all stages. The APRIL/BCMA signal cascades promote the survival and drug resistance of MM cells and further modulate immunosuppressive BM milieu. Impressively, anti-BCMA immunotherapeutic reagents, including chimeric antigen receptor (CAR), antibody-drug conjugate (ADC) and bispecific T cell engager (BiTE) have all shown high response rates in their first clinical trials in relapse and refractory patients with very limited treatment options. These results rapidly inspired numerous development of next-generation anti-BCMA biotherapeutics, i.e., bispecific molecule, bispecific or trispecific antibodies, a novel form of CAR T/NK cells and T Cell Antigen Coupler (TAC) receptors, antibody-coupled T cell receptor (ACTR) as well as a cancer vaccine. We here highlight seminal preclinical and clinical studies on novel BCMA-based immunotherapies as effective monotherapy and discuss their potential in combination with current anti-MM and novel checkpoint drugs in earlier disease stages to further achieve durable responses in patients.
Highlights
Multiple myeloma (MM), the second most hematologic malignancy, is characterized by excessive growth of malignant plasma cells in the bone marrow (BM), excessive production of monoclonal immunoglobulin, osteolytic bone lesions, impaired renal function, and immunosuppression [1].The development of novel therapies incorporating proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs, i.e., lenalidomide, pomalidomide) have significantly improved the prognosis and Cancers 2020, 12, 1473; doi:10.3390/cancers12061473 www.mdpi.com/journal/cancersCancers 2020, 12, 1473 survival of patients with MM for the last two decades
Daratumumab and elotuzumab were approved by US Food and Drug Administration (FDA) in combination with lenalidomide and dexamethasone for the treatment of refractory MM (RRMM) in 2015
T cells (Tcon), thereby decreasing the proliferation and function of Tcon. These signaling well as central immunosuppressive markers (Foxp3, IL‐10, PD‐L1, TGF‐ ) in Treg but not Tcon. This pathways contribute to the pathophysiology of MM cells and MM-induced immune suppression in the signaling pathway enhances the inhibitory effects of Treg on conventional T cells (Tcon), thereby decreasing the proliferation and function of Tcon
Summary
Multiple myeloma (MM), the second most hematologic malignancy, is characterized by excessive growth of malignant plasma cells in the bone marrow (BM), excessive production of monoclonal immunoglobulin, osteolytic bone lesions, impaired renal function, and immunosuppression [1]. BCMA is selectively expressed from the late stage of B-cell maturation to terminal differentiation of antibody-producing PCs, concomitantly with the loss of BAFF-R. These three functionally related receptors contribute to the long-term survival of B-cell during its development by binding to BAFF and/or A proliferation-inducing ligand (APRIL) [10,11,12]. Levels of BCMA transcript and proteins, either membrane or soluble forms, were not affected by certain anti-MM treatment, including PIs or IMiDs. higher sBCMA levels in patient serum is associated with higher MM disease burden and poorer clinical outcome [33,35,36]. Because of its significant pathophysiologic and clinical relevance, BCMA holds great promise for targeted immunotherapy in MM
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