lirilumab

The clinical success of immune checkpoint inhibitors has underscored the key role of the immune system in controlling cancer. Current FDA-approved immune checkpoint inhibitors target the regulatory receptor pathways of cytotoxic T-cells to enhance their anticancer responses. Despite an abundance of evidence that natural killer (NK) cells can also mediate potent anticancer activities, there are no FDA-approved inhibitors targeting NK cell specific checkpoint pathways. Lirilumab, the most clinically advanced NK cell checkpoint inhibitor, targets inhibitory killer immunoglobulin-like receptors (KIRs), however it has yet to conclusively demonstrate clinical efficacy...

BACKGROUND AND OBJECTIVE: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. METHODS: Patients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC...

PURPOSE: Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS). PATIENTS AND METHODS: In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L...

Simultaneously targeting other pathways could increase the activity of PD-1 blockade in lymphoid malignancies not sensitive to single-agent blockade. We explored the safety and efficacy of combined PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory (R/R) lymphoid malignancies. This phase 1b trial enrolled adult patients with R/R classical Hodgkin lymphoma (cHL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM). Patients received nivolumab plus ipilimumab (nivo/ipi) or lirilumab (nivo/liri) until complete response (CR), progression, or unacceptable toxicity...

BACKGROUND: Enhancement of natural killer cell activity by blocking interactions between killer immunoglobulin (Ig)-like receptors (KIRs) and human leukocyte antigen-C (HLA-C) molecules can improve outcomes in myeloid malignancies. Lirilumab is a human IgG4 monoclonal antibody that blocks KIR/HLA-C interaction. We designed a study to evaluate the safety and efficacy of lirilumab as a single agent and in combination with azacitidine in patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Adult patients with MDS who had not received previous hypomethylating agents were included...

PURPOSE: Anti-KIR monoclonal antibodies (mAbs) can enhance the antitumor responses of natural killer (NK) cells. We evaluated the safety of the anti-KIR2D mAb lirilumab in patients with various cancers. EXPERIMENTAL DESIGN: Thirty-seven patients with hematological malignancies ( n = 22) or solid tumors ( n = 15) were included in the study. Dose escalation (0.015 to 10 mg/kg) was conducted following a 3 + 3 design. Patients were scheduled to receive four cycles of treatment...

We report here the cloning of native high affinity anti-TIM-3 and anti-KIR IgG monoclonal antibodies (mAbs) from peripheral blood mononuclear cells (PBMC) of healthy human donors. The cells that express these mAbs are rare, present at a frequency of less than one per 105 memory B-cells. Using our proprietary multiplexed screening and cloning technology CellSpot™ we assessed the presence of memory B-cells reactive to foreign and endogenous disease-associated antigens within the same individual. When comparing the frequencies of antigen-specific memory B-cells analyzed in over 20 screening campaigns, we found a strong correlation of the presence of anti-TIM-3 memory B-cells with memory B-cells expressing mAbs against three disease-associated antigens: (i) bacterial DNABII proteins that are a marker for Gram negative and Gram positive bacterial infections, (ii) hemagglutinin (HA) of influenza virus and (iii) the extracellular domain of anaplastic lymphoma kinase (ALK)...

Natural killer (NK) cells mediate antilymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of the efficacy of NK cells by spontaneous cytotoxicity. Here, using a killer-cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with major histocompatibility complex (MHC) class I antigens on lymphoma cells by anti-KIR antibodies prevents a tolerogenic interaction and augments NK-cell spontaneous cytotoxicity...