The IL-15-Based ALT-803 Complex Enhances FcγRIIIa-Triggered NK Cell Responses and In Vivo Clearance of B Cell Lymphomas

Abstract

PURPOSE Anti-CD20 monoclonal antibodies (mAbs) are an important immunotherapy for B cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ALT-803 is a super-agonist IL-15 mutant and IL-15Rα–Fc fusion complex that activates the IL-15 receptor constitutively expressed on NK cells. We hypothesized that ALT-803 would enhance anti-CD20 mAb-directed NK cell responses and antibody-dependent cellular cytotoxicity (ADCC). EXPERIMENTAL DESIGN We tested this hypothesis by adding ALT-803 immunostimulation to anti-CD20 mAb triggering of NK cells in vitro and in vivo. Cell lines and primary human lymphoma cells were utilized as targets for primary human NK cells. Two complementary in vivo mouse models were used, which included human NK cell xenografts in NOD-SCID-γc−/− mice. REULTS We demonstrate that short-term ALT-803 stimulation significantly increased degranulation, IFN-γ production, and ADCC by human NK cells against B-cell lymphoma cell lines or primary follicular lymphoma cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality. Moreover, in two distinct in vivo B cell lymphoma models, the addition of ALT-803 to anti-CD20 mAb therapy resulted in significantly reduced tumor cell burden and increased survival. Long-term ALT-803 stimulation of human NK cells induced proliferation and NK cell subset changes with preserved ADCC. CONCLUSIONS ALT-803 represents a novel immunostimulatory drug that enhances NK cell anti-lymphoma responses in vitro and in vivo, thereby supporting the clinical investigation of ALT-803 plus anti-CD20 mAbs in patients with indolent B cell lymphoma.

The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles

“…8,9,14,15 These findings have recently been extended to HIV infection, where ALT-803-activated NK cells inhibit acute HIV infection in vivo, 16 and ALT-803 also reactivates latent virus in vitro. 17 In this study, we demonstrated that ALT-803 significantly enhanced lymphocyte proliferation and activation, specifically CD16…”

“…Coupled with recent data that ALT-803 reverses viral latency in vitro, 17 it could potentially mediate both the "shock" and the "kill" in eradication strategies. Finally, given that ALT-803 also potently activates NK cells and increases their cytolytic potential, 14,16 it could also be combined with broadly neutralizing antibodies to mobilize both cytotoxic CD8 1 T-cell-and NK-mediated antibody-dependent cell-mediated cytotoxicity to clear latent virus. Cumulatively, these 3 effects suggest that ALT-803 is a formidable addition to the HIV eradication armament.…”

A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses

“…For example, ALT-803 stimulation significantly increased rituximab-mediated ADCC by human NK cells against B cell lymphoma cell lines or primary follicular lymphoma cells in vitro. Moreover, in two different B cell lymphoma mouse models, the addition of ALT-803 to anti-CD20 mAb therapy provided a significantly reduced tumor cell burden and increased survival (7). As a result, ALT-803 is currently in multiple clinical trials against solid and hematological malignancies (relapse of hematologic malignancy after allogeneic stem cell transplantation, refractory multiple myeloma, and indolent nonHodgkin's lymphoma (NCT01885897, NCT02099539, and NCT02384954, respectively)).…”

“…In various animal models, ALT-803 acts as a potent immunostimulant that is capable of simultaneously activating the innate and adaptive arms of the immune system to elicit both rapid and long-lasting protective responses against neoplastic challenges (5). Moreover, ALT-803, in combination with checkpoint blockade or therapeutic antibodies, is effective in reducing the tumor burden and prolonging survival in mouse tumor models (6,7). To make ALT-803-based molecules more specific and efficient in combating disease, we converted ALT-803 into a targeted immunotherapeutic agent by genetically fusing it with singlechain antibodies (scFv) at the N termini of IL-15N72D and IL-15R␣SuFc proteins.…”

Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes

“…65 Besides, data obtained from immunotherapies also give affirmation to NK cells in the functions of anti-lymphoma. 66 Natural killer group 2D (NKG2D), a germline-encoded receptor, plays an important role in NK-mediated immunosurveillance, while it is not only expressed on NK cells but also on activated CD8 + T cells, natural killer T (NKT) cells, and certain CD4 + T cells. NKG2D is an activating surface molecule that recognizes stress-inducible self-molecules, including major histocompatibility complex (MHC)-related ligands.…”