Combination Immunotherapy of a Novel Superagonist IL-15 Complex and Anti-CD20 Antibody for Indolent Non-Hodgkin Lymphoma

DESCRIPTION provided by applicant Non Hodgkin lymphoma NHL is the most commonly diagnosed hematologic malignancy in the U S with over new cases and about deaths due to NHL expected in 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 CD 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 IL a crucial factor for the development proliferation and activation of effector NK cells and CD memory T cells exhibits potent antitumor activities against established tumors in animal models Based on its properties IL is considered by NCI as the most promising immunotherapeutic product candidate that could potentially cure cancer We have generated a novel proprietary IL mutant with increased biological activity The immunostimulatory properties of this superagonist IL was further improved by creating a complex with an IL receptor IgG fusion protein This IL superagonist complex referred to as ALT is currently in four ongoing IND supported studies in patients with hematologic and solid tumors Initial results from these studies indicate that ALT 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 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 activation of human NK cells in vitro can enhance rituximab directed ADCC against human CD B cell lymphoma cell lines and primary human lymphoma cells These results were further verified in two efficacy models showing that ALT plus rituximab immunotherapy provided greater NK cell antitumor activity and longer survival than either ALT or rituximab alone in mice bearing human lymphoma cells These studies provide a strong rationale for advancing ALT 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 study to investigate the safety pharmacokinetics and immunostimulatory and clinical activities of ALT 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 in combination with rituximab in other B cell malignancies and with other approved therapeutic antibodies in other malignancies PUBLIC HEALTH RELEVANCE The results of our feasibility studies revealed that ALT a novel interleukin based immunostimulatory protein complex is capable of enhancing the immune cell mediated anti lymphoma activity of the approved anti CD 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 plus rituximab against non Hodgkin lymphoma NHL we propose to conduct a multicenter Phase study to investigate the safety pharmacokinetics and immunostimulatory and clinical activities of ALT 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 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