Dual Targeting of Multiple Myeloma Stem Cells and Myeloid-Derived Suppressor Cells for Treatment of Chemotherapy-Resistant Multiple Myeloma

Abstract

Here we review the insights and lessons learned from early clinical trials of T-cell engaging bispecific antibodies (BsABs) as a new class of biotherapeutic drug candidates with clinical impact potential for the treatment of multiple myeloma (MM). BsABs are capable of redirecting host T-cell cytotoxicity in an MHC-independent manner to malignant MM clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC). T-cell engaging BsAB targeting the BCMA antigen may help delay disease progression in MM by destroying the MM cells. T-cell engaging BsAB targeting the CD38 antigen may help delay disease progression in MM by depleting both the malignant MM clones and the MDSC in the bone marrow microenvironment (BMME). BsABs may facilitate the development of a new therapeutic paradigm for achieving improved survival in MM by altering the immunosuppressive BMME. T-cell engaging BsiABs targeting the CD123 antigen may help delay disease progression in MM by depleting the MDSC in the BMME and destroying the MM stem cells that also carry the CD123 antigen on their surface.

Hypermethylation of the Promoter Region of miR-23 Enhances the Metastasis and Proliferation of Multiple Myeloma Cells via the Aberrant Expression of uPA

“…The progress of human malignancies represented by the MM complex is often affected by the ECM or microenvironment ( 1 – 6 ). One sign of malignant transformation of these malignant tumor cells is metastasis and invasion, in which cells destroy the ECM/basal membrane of the primary site through MMPs and achieve invasive growth and migration to other tissues and organs ( 21 ).…”

“…Multiple myeloma (MM) is a clonal malignant plasma cell disease that accumulates in bone marrow, leading to bone destruction and marrow failure as well as out-bone injury for the whole body at advanced stages ( 1 – 3 ). Increasing data have been indicated that the MM is often accompanied by the multiple osteolytic lesions, hypercalcemia, or kidney damage ( 1 – 5 ).…”

“…Multiple myeloma (MM) is a clonal malignant plasma cell disease that accumulates in bone marrow, leading to bone destruction and marrow failure as well as out-bone injury for the whole body at advanced stages ( 1 – 3 ). Increasing data have been indicated that the MM is often accompanied by the multiple osteolytic lesions, hypercalcemia, or kidney damage ( 1 – 5 ). Although therapeutic approaches to MM have been rapidly evolving, and MM is typically sensitive to a variety of cytotoxic chemotherapies, the prognosis of patients with distal metastasis (the extra-bone MM, at an advanced stage of the disease) is still poor ( 4 – 6 ).…”

Cancer drug resistance in multiple myeloma

“…Precision medicines as well as biotherapeutic agents, including therapeutic monoclonal antibodies such as the anti-CD38 MoAb Daratumumab and isatuximab, and the anti-signaling lymphocyte activation marker F7, antibody elotuzumab, antibody-drug conjugates, and bispecific antibodies (BiAb) have been developed to damage drug-resistant MM clones as well as alter the immunosuppressive bone marrow microenvironment with some very promising clinical data regarding their clinical impact potential [ 1 , 4 , 39 ] . T-cell redirecting BiAb and bispecific T-cell engagers (BiTES) targeting CD38, the orphan G protein-coupled receptor GPRC5D, and the B-cell maturation antigen (BCMA)/CD269 on MM cells and CD3 antigen on T-cells facilitate the CTL-mediated destruction of drug-resistant MM cells in cytolytic synapses [ 4 , 40 ] . They showed promising single-agent activity in early clinical trials of R/R MM patients, and risk mitigation strategies have been identified for their potentially serious side effects such as cytokine release syndrome and neurotoxicity [ 4 , 40 ] .…”

“…T-cell redirecting BiAb and bispecific T-cell engagers (BiTES) targeting CD38, the orphan G protein-coupled receptor GPRC5D, and the B-cell maturation antigen (BCMA)/CD269 on MM cells and CD3 antigen on T-cells facilitate the CTL-mediated destruction of drug-resistant MM cells in cytolytic synapses [ 4 , 40 ] . They showed promising single-agent activity in early clinical trials of R/R MM patients, and risk mitigation strategies have been identified for their potentially serious side effects such as cytokine release syndrome and neurotoxicity [ 4 , 40 ] . BCMA-targeting cellular immunotherapy platforms using chimeric antigen receptor (CAR)-T cells or NK cells have also been developed with documented objective clinical responses in single-agent trials [ 1 , 4 , 6 - 9 , 40 ] .…”