Bench to Bedside: From Laboratory to the Pharmacy
OSU-10054 – A Multicenter Phase I/II Study on the Anti-Tumor Activity, Safety and Pharmacology of IPH2101, a Human Monoclonal Anti-KIR, Combined with Lenalidomide in Patients with Multiple Myeloma Experiencing a First Relapse
Hypothesis: The combination of lenalidomide and IPH2101 is safe, and that the agents in combination show clinical activity in patients experiencing a first relapse of multiple myeloma.
Rationale: Multiple myeloma (MM) is a malignancy of plasma cells. Treatment involves chemotherapy with high-dose corticosteroids or high-dose melphalan with stem cell rescue for selected patients. Targeted drugs, including the immunomodulatory agent lenalidomide, are broadening patients’ therapeutic options. Nonetheless, MM remains incurable, with relapses invariably occurring a median of 24 to 30 months following stem cell transplant.
NK cells, large granular lymphocytes that play a crucial role in cellular innate immunity and tumor cell killing, play an important role in controlling MM, but this ability is gradually lost during disease progression. Recent data suggests that lenalidomide can help restore the ability of NK cells to kill MM cells.
Lenalidomide’s mechanism of action against MM is not understood, but evidence suggests there are several. The agent may work directly on MM cells by inducing apoptosis or arresting growth. Perhaps more significantly, lenalidomide stimulates T-cell proliferation, which leads to increased IL-2 and IFN-gamma secretion. These circulating cytokines then boost NK cell number and activity and increased MM cell death.
Cell killing by NK cells is tightly regulated by killer immunoglobulin-like receptors (KIR) displayed on the cell surface. There are both inhibitory and activating KIR. Inhibitory KIR generally outnumber, and bind cellular ligands more readily than, activating KIR, and this can prevent NK-cell killing even when activating signals are present.
IPH2101 is a novel therapy that may reduce this effect. Data suggests that this human monoclonal antibody binds to inhibitory KIR and blocks inhibitory signaling, thereby increasing MM cell killing by NK cells. Clinical studies indicate that the agent is well tolerated by patients.
Collectively, the evidence suggests that IPH2101 and lenalidomide have additive or synergistic mechanisms of action and supports their development as a promising, novel, steroid-sparing combination therapy for patients with MM. Moreover, the effect is specific to the MM tumor cell clone. NK cell cytotoxicity assays of the agents on normal peripheral blood mononuclear cells have shown no increase in killing.
At a Glance
Clinical trial OSU-10054
PI: Don M. Benson Jr., MD, PhD, assistant professor of Medicine, Division of Hematology
Eligibility: Patients with progressive or relapsed multiple myeloma after one prior therapeutic treatment with response duration of at least six months; prior treatment regimens may have included lenalidomide and thalidomide; if previously treated with lenalidomide, the subject must not have progressed during treatment and must not have discontinued the drug due to intolerance; Measurable disease; ECOG 0,1, or 2; Clinical lab values at screening; FCBP must have negative pregnancy test 10-14 days prior to and again within 24 hours of prescribing lenalidomide and agree to use 2 methods of birth control; must be registered and willing to comply with requirements of RevAssist