SBIR-STTR Award

Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy with an estimated 20,520 newly diagnosed cases and 10,610 deaths due to MM in the United States in 2011. MM is a disease of the elderly with a median age at diagnosis of 70 years and 37% of patients older than 75 years. The number of geriatric MM patients is expected to increase over time because of the increasing life expectancy of the normal population. MM 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. Thus, 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. IL-15, a necessary factor for the development, proliferation and activation of effector NK cells and CD8* memory T cells, exhibits potent anti-tumor activities against well-established tumors in laboratory animal models and is listed by a recent NCI review as the most promising product candidate among twelve immunotherapy drugs that could potentially cure cancer. We have previously reported the isolation of a novel IL-15 mutant with a 4-fold increase in biological activity. The pharmacokinetics and biological activity of this superagonistic IL-15 (IL-15N72D) have been further improved by creating a complex with an IL-15 receptor ¿ - IgG1 fusion protein (IL-15R¿/Fc). We postulate that that intravenous administration of the IL-15N72D:IL- 15R¿/Fc fusion complex will provide a durable, potent and broad cell-mediated immune response, which would result in a highly efficacious and potentially curative immunotherapy for the treatment of patients with MM. This is supported by the data from our recent studies, indicating that this IL-15 fusion complex indeed eradicated well-established 5T33 myeloma tumors in an immunocompetent C57BL/6 mouse model. More importantly, short-term treatment provided long-lasting immunological effects that completely protected mice against subsequent tumor cell rechallenge. In this study described here, we propose to carry out experiments to reveal the mechanisms of action and to further evaluate the durability (a hallmark of immunotherapy) of IL- 15 superagonist-induced responses for 5T33 tumor-based myeloma in mice. These efforts will pave the way for pre-clinical studies, which will include additional efficacy studies to determine optimal dosing and pharmacokinetics and toxicology evaluation of the complex, as part of the SBIR Phase II project, to support clinical development. Our ultimate goal is to enter the IND phase and to conduct clinical trials using the IL- 15N72D:IL-15R¿/Fc superagonist complex to treat patients with MM.

Public Health Relevance:
In this proposal, we propose to carry out experiments to reveal the mechanisms-of-action and to evaluate the anti-tumor durability (a hallmark of immunotherapy) of a novel interleukin-15 (IL-15) superagonist complex (IL- 15N72D:IL-15R¿/Fc) in the 5T33 tumor-based multiple myeloma model in mice. Positive outcomes from this proposed study would provide justification for clinical development of this complex as a safe, durable, potent and cell-mediated immunotherapy to treat patients with multiple myeloma.

Public Health Relevance Statement:
: In this proposal, we propose to carry out experiments to reveal the mechanisms-of-action and to evaluate the anti-tumor durability (a hallmark of immunotherapy) of a novel interleukin-15 (IL-15) superagonist complex (IL- 15N72D:IL-15R¿/Fc) in the 5T33 tumor-based multiple myeloma model in mice. Positive outcomes from this proposed study would provide justification for clinical development of this complex as a safe, durable, potent and cell-mediated immunotherapy to treat patients with multiple myeloma.

Project Terms:
Adoptive Cell Transfers; Adrenal Cortex Hormones; Age; analog; Apoptosis; Apoptotic; Autologous Stem Cell Transplantation; base; Biological; Bone Diseases; Bone Marrow; Bortezomib; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Adhesion Molecules; cell growth; cell mediated immune response; Cells; Cessation of life; chemotherapy; Chimeric Proteins; Clinical; Comorbidity; Complement; Complex; Conduct Clinical Trials; cytokine; Data; Development; Dexamethasone; Diagnosis; Disease; Disease remission; Dose; Doxorubicin; Drug Kinetics; Effectiveness; Effector Cell; Elderly; Evaluation; Exhibits; Flow Cytometry; Functional disorder; Goals; Growth; Growth Factor; Hematologic Neoplasms; Hypercalcemia; IgG1; Immune response; Immunity; Immunocompetent; Immunotherapeutic agent; Immunotherapy; improved; Infusion procedures; Insulin-Like Growth Factor I; Integrins; Interleukin-15; interleukin-15 receptor; Interleukin-2; Interleukin-6; intravenous administration; Kidney Failure; Kinetics; Laboratory Animal Models; lenalidomide; Life Expectancy; Malignant Neoplasms; Mediating; Modality; Modeling; mouse model; Multiple Myeloma; Mus; mutant; Natural Killer Cells; neoplastic cell; Newly Diagnosed; novel; older patient; Outcome; Paraproteinemias; Patients; Pattern; Pharmaceutical Preparations; Phase; Plasma Cells; Play; Population; preclinical study; Production; Proteasome Inhibitor; Reporting; research study; Residual Neoplasm; Resistance; response; Role; Small Business Innovation Research Grant; standard of care; Survival Rate; T memory cell; T-Lymphocyte; Thalidomide; Therapeutic; Time; TNF gene; Toxic effect; Toxicology; treatment response; tumor; United States; Vascular Endothelial Growth Factors; Vincri

Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy with an estimated 22,350 newly diagnosed cases and 10,710 deaths due to MM in the United States in 2013. 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-15 (IL-15), a crucial factor for the development, proliferation and activation of effector NK cells and CD8+ memory T cells, exhibits potent anti-tumor activities against well-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 previously isolated a novel proprietary IL-15 mutant with increased biological activity. The immunostimulatory properties of this superagonist IL-15 (IL-15N72D) was further improved by creating a complex with an IL-15 receptor ¿ - IgG1 fusion protein. We postulate that administration of this complex (referred to as ALT-803) 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-803 indeed eradicated well- established myeloma tumors and prolonged survival of tumor-bearing mice through a novel mechanism dependent on the activation of CD8+ memory T cells and secretion of IFN-y from these T cells. Furthermore, short-term ALT-803 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-803 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-803 clinical product allowing FDA acceptance of an IND for clinical use of ALT-803 in other cancer indications. 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 patients with refractory or relapsed MM. Successful completion of this study will pave the way for further evaluation of ALT-803 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.

Thesaurus Terms:
Age;American;Animal Model;Animals;Antitumor Response;Apoptosis;Apoptotic;Autologous Stem Cell Transplantation;Base;Biological;Bone Diseases;Bone Marrow;Bone Marrow Cells;Bortezomib;Cd8b1 Gene;Cell Adhesion Molecules;Cell Growth;Cell Killing;Cell Mediated Immune Response;Cell Secretion;Cells;Cessation Of Life;Chemotherapy;Chimeric Proteins;Clinical;Clinical Trials;Comorbidity;Complement;Complex;Cyclic Gmp;Cytokine;Development;Diagnosis;Disease;Dose;Drug Kinetics;Effectiveness;Elderly;Evaluation;Exhibits;Functional Disorder;Funding Mechanisms;Goals;Growth;Growth Factor;Hematologic Neoplasms;High Dose Chemotherapy;Hypercalcemia;Igg1;Immune;Immune Response;Immunity;Immunocompetent;Immunotherapeutic Agent;Immunotherapy;Improved;Interferons;Interleukin-15;Interleukin-15 Receptor;Interleukin-2;Kidney Failure;Laboratory Animal Models;Lenalidomide;Life;Life Expectancy;Malignant Neoplasms;Memory;Metastatic Melanoma;Modality;Multiple Myeloma;Mus;Mutant;Natural Killer Cells;Neoplastic Cell;Newly Diagnosed;Next Generation;Novel;Paraproteinemias;Patients;Pharmaceutical Preparations;Phase;Phase Ii Clinical Trials;Plasma Cells;Play;Population;Preclinical Study;Production;Property;Proteasome Inhibitor;Protein Complex;Public Health Relevance;Receptor;Recording Of Previous Events;Recurrent Disease;Refractory;Refractory Disease;Relapse;Research Clinical Testing;Residual Neoplasm;Resistance;Response;Role;Safety;Small Business Innovation Research Grant;Staging;Standard Of Care;Success;Survival Rate;T Memory Cell;T-Lymphocyte;Thalidomide;Therapeutic;Time;Toxicology;Treatment Protocols;Tumor;United States