Despite the recent introduction of new and effective novel therapies for multiple myeloma (MM), the disease remains incurable. For the 66,000 individuals in United States currently afflicted, an average survival of only four years from diagnosis is anticipated. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) leads to increased rates of complete remission and prolonged periods of disease free survival, but relapse remains inevitable. There is a scientifically compelling rationale for high dose radioimmunotherapy (RIT) conditioning followed by stem cell rescue for MM. High dose RIT has demonstrated efficacy when incorporated into both autologous and allogeneic stem cell transplant conditioning regimens for acute leukemia and B-cell lymphoma. Pretargeted RIT (PRIT) represents a further refinement that can effectively circumvent the major pharmacokinetic limitations of conventional one-step RIT and dramatically improve the specificity of tumor targeting. Initial studies in murine MM xenograft models have demonstrated favorable target-to-normal organ ratios with radiolabeled anti-CD38 (OKT10) monoclonal antibody and suggest that an improved therapeutic index will result with anti-CD38 streptavidin (SA) fusion protein (OKT10[scFv]4SA) PRIT. This project is designed to identify optimal regimens for OKT10 RIT (Aim 1) and OKT10 PRIT (Aim 2);compare RIT and PRIT pharmacokinetics, biodistributions and dosimetry to identify the superior method;perform therapy studies involving murine MM tumor xenograft and SCID-hu models (Aim 3);and evaluate the safety and feasibility of myeloablative OKT10 RIT or PRIT as conditioning prior to ASCT in a Phase I clinical trial. These studies will be performed by Damian J. Green, M.D., under the guidance of an outstanding mentor (Oliver W. Press, M.D., Ph.D.) who has an established and well funded research program, extensive expertise in translational RIT research and a very successful track record of guiding junior faculty to full career independence. Mentored Career Development support will provide Dr. Green expertise in the efficient translation of preclinical discovery into clinical trials for patients with MM. The project takes advantage of the exceptional resources available at the Fred Hutchinson Cancer Research Center and at the University of Washington. Together, Drs. Green and Press have formalized a career development plan that details a combination of didactic postgraduate training in statistics, epidemiology, bioethics, drug development and immunology;hands-on clinical trial design and management experience;training to establish advanced skills in a broad array of laboratory techniques;and, a process of regularly scheduled review to ensure progress in relation to established benchmarks for productivity. Dr. Green's research project represents the logical extension of his prior translational work and an exciting opportunity for this young investigator to develop new therapies for MM. Through a process of increasing autonomy, Dr. Green will proceed to full independence with the expectation that he will be in a position to apply for competitive RO1 funding for his ongoing translational research within five years and become a leader in the field of RIT, MM and stem cell transplantation within a decade.
Project Narrative: Patients diagnosed with multiple myeloma, the second most common blood cancer in the United States, live an average of only four years after diagnoses and cannot be cured with standard treatments. Stem cell or bone marrow transplant may prolong survival, but the disease almost always returns. This project is designed to develop a new approach, already proven effective for patients with leukemia and lymphoma, that directly targets multiple myeloma cells with small radioactive particles to selectively destroy them.
|Green, Damian J; O'Steen, Shyril; Lin, Yukang et al. (2018) CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies. Blood 131:611-620|
|Greenbaum, Adam M; Green, Damian J; Holmberg, Leona A et al. (2018) Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. Blood Res 53:223-226|
|Green, Damian J; Press, Oliver W (2017) Whither Radioimmunotherapy: To Be or Not To Be? Cancer Res 77:2191-2196|
|O'Steen, Shyril; Green, Damian J; Gopal, Ajay K et al. (2017) Venetoclax Synergizes with Radiotherapy for Treatment of B-cell Lymphomas. Cancer Res 77:3885-3893|
|Green, Damian J; Maloney, David G; Storer, Barry E et al. (2017) Tandem autologous/allogeneic hematopoietic cell transplantation with bortezomib maintenance therapy for high-risk myeloma. Blood Adv 1:2247-2256|
|Rufener, Gregory A; Press, Oliver W; Olsen, Philip et al. (2016) Preserved Activity of CD20-Specific Chimeric Antigen Receptor-Expressing T Cells in the Presence of Rituximab. Cancer Immunol Res 4:509-19|
|Green, Damian J; Frayo, Shani L; Lin, Yukang et al. (2016) Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers. Cancer Res 76:6669-6679|
|Green, D J; Bensinger, W I; Holmberg, L A et al. (2016) Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 51:1330-1336|
|Frost, Sofia H L; Frayo, Shani L; Miller, Brian W et al. (2015) Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models. PLoS One 10:e0120561|
|Cowan, Andrew J; Frayo, Shani L; Press, Oliver W et al. (2015) Bortezomib and fenretinide induce synergistic cytotoxicity in mantle cell lymphoma through apoptosis, cell-cycle dysregulation, and I?B? kinase downregulation. Anticancer Drugs 26:974-83|
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