IL-15 Superagonist Complex as an Immunotherapeutic for Multiple Myeloma

DESCRIPTION provided by applicant Multiple myeloma MM is the second most commonly diagnosed hematologic malignancy with an estimated newly diagnosed cases and deaths due to MM in the United States in MM typically a disease of the elderly is a malignancy of clonal plasma cells in the bone marrow BM characterized by the presence of paraproteinemia destructive bone disease hypercalcemia renal failure and or hematological dysfunction Although survival rates of MM patients have improved by recent therapeutic advances MM remains incurable due to the persistence of minimal residual disease Hence novel modalities complementing or improving current treatment options are desperately needed There is ample evidence that immunomodulatory drugs are effective against MM Thus the use of a potent immunotherapeutic is an attractive approach to provide durable immune responses to or even potentially cure patients with MM Interleukin IL a crucial factor for the development proliferation and activation of effector NK cells and CD memory T cells exhibits potent anti tumor activities against well 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 previously isolated a novel proprietary IL mutant with increased biological activity The immunostimulatory properties of this superagonist IL IL N D was further improved by creating a complex with an IL receptor IgG fusion protein We postulate that administration of this complex referred to as ALT will induce a durable potent and broad cell mediated immune response which could result in efficacious and potentially curative effects in patients with MM This approach is supported by results of our SBIR Phase I project indicating that ALT indeed eradicated well established myeloma tumors and prolonged survival of tumor bearing mice through a novel mechanism dependent on the activation of CD memory T cells and secretion of IFN y from these T cells Furthermore short term ALT treatment provided long lasting T cell dependent immunological effects that completely protected mice against subsequent tumor cell rechallenge These studies provide a strong rationale for advancing ALT into clinical testing against MM as a curative treatment In addition to the SBIR Phase I project we have completed animal toxicology studies and manufacture of ALT clinical product allowing FDA acceptance of an IND for clinical use of ALT in other cancer indications 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 patients with refractory or relapsed MM Successful completion of this study will pave the way for further evaluation of ALT either as monotherapy or in combination with chemotherapies in patients with relapsed refractory MM with the ultimate goal of developing more durable or curative therapeutic options for treatment na ve and or relapsed refractory MM patients PUBLIC HEALTH RELEVANCE The results of the SBIR Phase I project revealed that ALT a novel interleukin based immunostimulatory protein complex exhibits potent anti myeloma activity and provides protective immune responses to tumor re challenge in animal models through a novel CD memory T cell dependent mechanism As these studies strongly support clinical development of ALT against multiple myeloma MM we propose to conduct a multicenter Phase study to investigate the safety pharmacokinetics and immunostimulatory and clinical activities of ALT in patients with relapsed or refractory MM Successful completion of this study will pave the way for further evaluation of ALT either as a monotherapy or in combination with current chemotherapies in patients with relapsed refractory MM with the ultimate goal of developing more durable or curative therapeutic options for treatment na ve and or relapsed refractory MM patients