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. 2021 Dec 6;13(23):6136. doi: 10.3390/cancers13236136

Figure 2.

Figure 2

Multiple mechanisms of action and immunomodulatory effects of current targeted immunotherapies in MM. (A) Monoclonal antibodies (MoAbs) identify and bind to specific antigens to trigger MM cell lysis via multiple immune-dependent mechanisms, including ADCC, ADCP, and CDC. (B) The single chain fragment variant of the CAR-T cell first targets the MM-specific antigen and potent MM cell lysis is induced in a major histocompatibility complex-independent manner followed by increased proliferation and activation of T effector cells, including those with central and effector memory phenotypes. (C) BiAb or BiTE, off-shelf products different from autologous CAR-T cells, simultaneously binds to specific tumor antigen on MM cells and CD3 on T cells to trigger potent MM cell killing as well as proliferation of immune effector T cells. T cells with memory phenotypes (Tcm, Tem, Tscm) and the major cytolytic T cells (CD8+ cells) are increased significantly. (D) The MoAb portion of antibody drug conjugate (ADC) binds to tumor antigen on MM cell membrane and the ADC is endocytosed followed by the release of potent cytotoxic payloads from lysosomes to directly induce MM cell apoptosis. Payloads used in ADC are typically even more potent than those used in chemotherapies to improve superior specific killing of tumors cells but not the surrounding normal tissues. Depending on the design of the ADC, NK cells and macrophages are directly or indirectly activated to induce ADCC and phagocytosis, respectively, to further augment killing of tumor cells. ADCC, antibody-dependent cellular cytotoxicity (NK cells are the predominant effector cells. Other CD16-expressing effectors including monocytes and neutrophils are also capable to induce ADCC); ADCP, antibody-dependent cellular phagocytosis (macrophage (M), especially with the M1 characteristics, are the key effector cells whereas macrophages with M2 features (TAM in Figure 1) promote tumor growth); BiAb, bispecific antibody engaging with T cells; BiTE, bispecific T cell engager; CDC, complement-dependent cytotoxicity; Tcm, central memory T cell; Tem, effector memory T cell; Tscm, stem cell-like memory T cell.