Restoring Natural Killer Cell Immunity against Multiple Myeloma in the Era of New Drugs

Abstract

Transformed plasma cells in multiple myeloma (MM) are susceptible to natural killer (NK) cell-mediated killing via engagement of tumor ligands for NK activating receptors or “missing-self” recognition. Similar to other cancers, MM targets may elude NK cell immunosurveillance by reprogramming tumor microenvironment and editing cell surface antigen repertoire. Along disease continuum, these effects collectively result in a progressive decline of NK cell immunity, a phenomenon increasingly recognized as a critical determinant of MM progression. In recent years, unprecedented efforts in drug development and experimental research have brought about emergence of novel therapeutic interventions with the potential to override MM-induced NK cell immunosuppression. These NK-cell enhancing treatment strategies may be identified in two major groups: (1) immunomodulatory biologics and small molecules, namely, immune checkpoint inhibitors, therapeutic antibodies, lenalidomide, and indoleamine 2,3-dioxygenase inhibitors and (2) NK cell therapy, namely, adoptive transfer of unmanipulated and chimeric antigen receptor-engineered NK cells. Here, we summarize the mechanisms responsible for NK cell functional suppression in the context of cancer and, specifically, myeloma. Subsequently, contemporary strategies potentially able to reverse NK dysfunction in MM are discussed.

CAR-Expressing Natural Killer Cells for Cancer Retargeting

“…As the progression of multiple myeloma (MM) is connected to NK cell impairment by tumour escape mechanisms [51-54] and the biomolecular action of anti-myeloma agents involves NK-cell responses [also reviewed in 55], enhancing NK cell-mediated anti-tumour activity is an apparent strategy in cellular MM therapy. Although some data indicate that many primary MM tumours are insensitive to NK-92-mediated killing [54], the NK-92 cell line was investigated in a phase I clinical trial showing “some evidence of efficacy” [56].…”

“…The safety of SLAMF7 as an MM target is well supported since it is targeted by a therapeutic antibody (elotuzumab, previously known as HuLuc63), which mediates NK-cell-dependent ADCC against cells expressing the target antigen [60, 61], as well as by CAR-T and CAR-NK cells [57, 62]. Besides CD138 and SLAMF7, preclinical studies with CAR-T cells for the treatment of MM concentrated on antigens such as CD38, CD44v6, B-cell maturation antigen (BCMA, CD269), and κ-light chains [reviewed in 55], thereby holding potential for further CAR-NK cell candidates. Until now, CAR-equipped NK cells targeting MM have not entered clinical trials.…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…NK cells belong to the lymphoid branch of the immune system and account for up to 6% of circulating lymphocytes. NK cells do not express rearranged receptors and can be easily transferred across HLA barriers without causing GVHD, thus they became attractive as allogeneic effector cells (187,188). At least three different sources of NK cells are currently available: NK cell line (189), peripheral blood NK cells (189), and induced pluripotent stem cells (iPSC) NK cells (190).…”

From the “missing self” hypothesis to adaptive NK cells: Insights of NK cell-mediated effector functions in immune surveillance

“…In NK cells, PD‐1 engagement can inhibit granule polarization, dampening NK cell function . PD‐1 is up‐regulated in the NK cell surface from patients with Kaposi sarcoma, multiple myeloma (MM), and lymphoproliferative disorders, suggesting that a high expression of PD‐1 is associated with NK cell dysfunction or immune suppression. In consequence, the use of mAb's anti‐PD‐1 can restore NK cell‐mediated antitumor activity .…”