Other important immune system checkpoints include T-cell immunoglobulin (TIM)-3 and T-cell immunoreceptor with Ig and ITIM (TIGIT) domains which are currently being studied as potential targets for therapy18. Treg-mediated immune suppression in MM Tregs are involved in the maintenance of self-tolerance and prevention of autoimmunity by exerting an inhibitory effect on immune response through various mechanisms, including release of inhibitory interleukins (IL) like IL-10, TGF-, and IL-35 that leads to a state of T-cell anergy and immune paresis19,20. the rationale for use of immune-based therapies in MM and summarize the currently available literature for common antibodies and CAR-T therapies that are utilized in MM. Subject terms: Myeloma, Therapeutics Introduction Multiple myeloma (MM) is a disorder of clonal plasma cells with a median age at diagnosis of around 67 years and accounts for ~10% of all newly diagnosed hematologic malignancies1. The incorporation of novel agents into upfront therapy and the introduction of maintenance approaches have led Andarine (GTX-007) to a sustained improvement in the overall survival (OS) of patients with MM over the past two decades2. Unfortunately, MM remains incurable and relapse of the disease is common. The improvement in outcomes of patients with MM has also presented the challenge of treating Andarine (GTX-007) an increasingly elderly population at relapse, making it important to have drugs with a better efficacy and safety profile to minimize toxicities3. A host of new agents have been approved for use in relapsed/refractory MM (RRMM) and potentially the most revolutionary class of therapeutics that have been introduced in the treatment paradigm of MM in the Andarine (GTX-007) past few years include immune-based therapies targeting the malignant cell clone4,5. Immune-based therapy for treatment of MM is not a new concept. Allogenic stem cell transplant has been utilized as a treatment strategy in MM and the presence of a graft versus myeloma effect points toward the efficacy of this approach6. The high rates of transplant-related mortality associated with allogenic transplant have made it a less preferred modality, but the potentially curative nature of this treatment makes it unique in the treatment landscape for MM7. Immune dysregulation is postulated to be centrally involved in the pathogenesis and disease progression in MM8. In this review, we discuss the rationale, targets, and evidence for immune-based therapies in treating MM. Immune dysregulation in MM Role of immune checkpoints in pathogenesis of MM A Andarine (GTX-007) normal cell-mediated immune response is driven by the interaction between antigen presenting cells (APC) and effector T cells, and is orchestrated by the dynamic balance between the activating and inhibitory signaling molecules and cytokines9. The B7-CD28 family of proteins, especially cytotoxic tumor lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) are important co-inhibitory molecules that are expressed on T-cells, B-cells, and natural killer (NK) cells10. These serve as important immune checkpoints and regulate the production of antigen-specific T-cells thus playing are an important role in maintaining immune tolerance11. Programmed cell death-ligand 1 (PD-L1), the ligand for PD-1 receptor, is expressed on APCs and its binding to PD-1 leads to suppression of T-cell activation and immune response. Cytotoxic tumor lymphocyte antigen-4 competes with the co-stimulatory molecule CD28 in binding to CD80 and CD86 thereby limiting the production of antigen-specific T cells11. Similarly, the binding of PD-L1 to PD-1 leads to immune inhibition and escape of tumor cells from immune surveillance11. Both CTLA-4 and PD-L1 are shown to have increased expression in bone marrow milieu of patients with MM12,13. Another important player involved in the immune regulation of T cells in MM is lymphocyte activation gene-3 (LAG3; CD223). The role of LAG3 as an immune checkpoint was identified in relation to its role in enhancing the function of regulatory T cells (Tregs) and inhibition of CD8 T-cells14. Like PD-1/PD-L1, LAG3 expression can prevent the development of autoimmunity but sustained LAG3 stimulation can be associated with T-cell exhaustion which can potentially contribute to immune escape10. Increased expression of LAG3 on T cells in the tumor milieu of MM has been noted in murine models and there is preclinical evidence of synergy between PD-1 and LAG3 inhibition, which could represent an important dual immune targeting strategy15. In a small Gdf11 study performed on 16 bone marrow specimens, patients with faster progression of smoldering MM had an expression of negative immune regulatory mediators including LAG3 expression on the T cells in the microenvironment and PD-L1 on the plasma cells16. A recent study also demonstrated that increased LAG3 transcript expression in T-cells postautologous transplant was associated with a worse outcome in patients with MM, suggesting potential.
