?Non-Hodgkin lymphoma (NHL) is the most commonly diagnosed hematologic malignancy in the U.S. with over 70,000 new cases and about 19,000 deaths due to NHL expected in 2015. Over one third of all cases are slow-growing or indolent NHL (iNHL) which affect older adults and typically present as advanced disease. The initial treatment of iNHL consists of an anti-CD20 antibody (rituximab) alone or in combination with chemotherapy. Although first-line therapies are effective in most patients, they are not curative and long- term complications due to chemotherapy are a major concern. Thus, there is a need for effective, durable and well-tolerated treatments for iNHL. Since the antitumor activity of rituximab relies in part on the mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells, it has been suggested that immunotherapeutic agents which enhance the function of these cells may also augment rituximab therapeutic activity. Interleukin-15 (IL-15), a crucial factor for the development, proliferation and activation of effector NK cells and CD8+ memory T cells, exhibits potent antitumor activities against established tumors in animal models. Based on its properties, IL-15 is considered by NCI as the most promising immunotherapeutic product candidate that could potentially cure cancer. We have generated a novel proprietary IL-15 mutant with increased biological activity. The immunostimulatory properties of this superagonist IL-15 was further improved by creating a complex with an IL-15 receptor ?-IgG1 fusion protein. This IL-15 superagonist complex (referred to as ALT-803) is currently in four ongoing IND-supported studies in patients with hematologic and solid tumors. Initial results from these studies indicate that ALT-803 can be administered to patients at a dose capable of inducing NK cell proliferation and cytokine release without causing significant toxicity We postulate that ALT-803 in combination with rituximab will induce durable, potent antitumor immune responses, which could result in potentially curative efficacy in patients with iNHL. This approach is supported by results of our feasibility studies indicating that ALT-803 activation of human NK cells in vitro can enhance rituximab-directed ADCC against human CD20+ B cell lymphoma cell lines and primary human lymphoma cells. These results were further verified in two efficacy models showing that ALT-803 plus rituximab immunotherapy provided greater NK cell antitumor activity and longer survival than either ALT-803 or rituximab alone in mice bearing human lymphoma cells. These studies provide a strong rationale for advancing ALT-803 plus rituximab into clinical testing against relapsed or refractory (rel/ref) iNHL. Under this SBIR Phase II proposal, we plan to conduct a multicenter Phase 1/2 study to investigate the safety, pharmacokinetics, and immunostimulatory and clinical activities of ALT-803 in combination with rituximab in patients with rel/ref iNHL. Successful completion of the proposed study will pave the way for further evaluation of ALT-803 in combination with rituximab in other B cell malignancies and with other approved therapeutic antibodies in other malignancies.
Public Health Relevance Statement: Public Health Relevance: The results of our feasibility studies revealed that ALT-803, a novel interleukin-15-based immunostimulatory protein complex, is capable of enhancing the immune cell-mediated anti-lymphoma activity of the approved anti-CD20 antibody, rituximab, in vivo and in different mouse tumor models. As the results of these and our ongoing clinical studies strongly support clinical development of ALT-803 plus rituximab against non-Hodgkin lymphoma (NHL), we propose to conduct a multicenter Phase 1/2 study to investigate the safety, pharmacokinetics, and immunostimulatory and clinical activities of ALT-803 in combination with standard-of care rituximab in patients with relapsed or refractory indolent NHL. Successful completion of this study will pave the way for further clinical evaluation of ALT-803 in combination with rituximab or other approved therapeutic antibodies with the ultimate goal of developing more potent, durable or curative therapeutic options for patients with B cell malignancies and other cancers.
NIH Spending Category: Cancer; Clinical Research; Hematology; Immunization; Lymphoma; Orphan Drug; Rare Diseases; Vaccine Related
Project Terms: Activated Natural Killer Cell; Adoptive Transfer; advanced disease; Adverse effects; Affect; Age; Animal Model; Antibody -dependent cell cytotoxicity; B lymphoid malignancy; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; base; Biodistribution; Biological; Bone Marrow; Cancer Patient; Caring; CD8B1 gene; cell growth; Cell Line; Cell physiology; Cell Proliferation; Cells; Cessation of life; chemotherapy; Chimeric Proteins; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Complex; cytokine; Development; Diagnosis; Disease; Dose; Drug Kinetics; effective therapy; Effector Cell; Elderly; Evaluation; Exhibits; FDA approved; Feasibility Studies; Follicular Lymphoma; Goals; Granzyme; Hematologic Neoplasms; Human; Human Activities; IgG1; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; improved; In Vitro; in vivo; Indolent; Infusion procedures; Institutional Review Boards; Interleukin-15; interleukin-15 receptor; Laboratory Animal Models; Lymphoma; Malignant Neoplasms; Mediating; Minnesota; Modeling; MS4A1 gene; Mus; mutant; Natural Killer Cells; NK Cell Activation; Non-Hodgkin's Lymphoma; novel; Organ; Patients; perforin; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; phase 2 study; Phase II Clinical Trials; Play; Positioning Attribute; preclinical study; Property; protein complex; Proteins; public health relevance; Recurrence; Refractory; Regimen; Relapse; Reporting; Research; research clinical testing; rituximab; Role; Safety; SCID Mice; Small Business Innovation Research Grant; Solid Neoplasm; Staging; T memory cell; Therapeutic; Therapeutic antibodies; Time; tositumomab; Toxic effect; tumor; United States; Universities; Washington
