The majority of patients with multiple myeloma (MM) ultimately die of progressive disease despite high rates of initial response to novel agents. While complete response (CR) is achievable in a significant subset of patients, most of these individuals relapse as a consequence of minimal residual disease (MRD) defined by occult foci of treatment insensitive tumor cells clones. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves response, but relapse remains virtually inevitable. No modification to high dose melphalan chemotherapy conditioning regimens has further augmented the impact of ASCT on outcome over the past two decades. Unmodified CD38 monoclonal antibodies (MAbs) have demonstrated anti-MM tumor cell responses and CD38 antigen targeting with ?-emitter radioimmunotherapy (RIT) can eliminate disease in pre-clinical MM models. In clinical settings however, ?-emitter RIT has been associated with dose limiting toxicity that can prevent dose escalation to levels necessary for elimination of MRD in a substantial proportion of patients. Based on the physical characteristics of ?-emitting radionuclides and new opportunities to harness their potential, there is a compelling rationale for employing ?-emitter RIT to treat MM. The ?-emitter 211At deposits a very large amount of energy (~100 keV/?m) within a few cell diameters (50-90 ?m) resulting in irreparable double strand DNA breaks that overwhelm cellular repair mechanisms. We anticipate that this combination of high energy and short path length will confer a unique capacity to kill individual targeted MM cells and eliminate MRD with minimal radiation damage to surrounding tissues. This proposal will use 211At to functionalize an anti-CD38 monoclonal antibody ([211At]OKT10-B10) as part of a novel approach to ASCT conditioning. The goal of this project is to address three hypotheses: 1). [211At]OKT10-B10 will eliminate MRD by selectively targeting all malignant plasma cells irrespective of mutational status, 2). [211At]OKT10-B10 will disrupt the disease permissive milieu found in the bone marrow microenvironment of MM patients and 3) [211At]OKT10-B10 will demonstrate a therapeutic index sufficient to safely sterilize all occult sites of disease. First, we will generate clinical grade [211At]OKT10-B10 necessary to perform patient studies. Second, we will conduct a clinical trial to a) demonstrate that [211At]OKT10-B10 localizes to MM target cells as confirmed by direct measurement of 211At in the bone marrow and alpha camera images of target tissue; and b) evaluate the safely of [211At]OKT10-B10 dose escalation in combination with high dose melphalan. Third, we will assess the impact of [211At]OKT10-B10 on a) stringent complete response rates, b) MRD detected by high throughput next generation sequencing and multi-parameter high sensitivity flow cytometry, c) the bone marrow microenvironment, d) MM cell repopulating potential in a SCID-hu model, and e) double strand DNA injury in target cells. The successful elimination of MRD through the incorporation of [211At]OKT10-B10 into ASCT conditioning could lead to significant improvements in MM patient survival and potentially eradicate disease.

Public Health Relevance

Multiple myeloma is the second most common cancer of the blood and bone marrow and while new treatments have significantly prolonged survival, virtually all patients eventually die of disease progression. This grant proposal describes a new approach that selectively delivers a small, but powerful, radioactive payload directly to the myeloma cells by targeting a protein called CD38 found on their surface. In the short term, findings could have a significant impact on multiple myeloma patients, because the proposed treatment is designed to eliminate the disease; and in the long term, this approach could also be used to develop treatments for other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA205248-01A1
Application #
9311260
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Merritt, William D
Project Start
2017-03-08
Project End
2022-02-28
Budget Start
2017-03-08
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$697,579
Indirect Cost
$282,750
Name
Fred Hutchinson Cancer Research Center
Department
Type
Research Institutes
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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
Li, Yawen; Hamlin, Donald K; Chyan, Ming-Kuan et al. (2018) cGMP production of astatine-211-labeled anti-CD45 antibodies for use in allogeneic hematopoietic cell transplantation for treatment of advanced hematopoietic malignancies. PLoS One 13:e0205135
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
Green, Damian J; Press, Oliver W (2017) Whither Radioimmunotherapy: To Be or Not To Be? Cancer Res 77:2191-2196