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.