With current therapy multiple myeloma (MM) is an incurable disease with approximately 16,000 new cases per year in the USA. New approaches and new tumor targeting modalities for therapy are urgently required. In this proposal we will evaluate the tolerability, efficacy, biodistribution and tumor targeting of a novel oncolytic virus delivery system in patients with relapsed or refractory MM. MV-NIS is a recombinant measles virus capable of concentrating radioactive iodine using the thyroid sodium iodide symporter. This grant builds upon years of pre-clinical work by Dr. Russell and his colleagues. This work is now culminating in a therapeutic trial, which is the focus of this grant application.
The specific aims of this project follow:
Aim 1. Evaluate the safety and maximum tolerated dose level of MV-NIS administered intravenously with and without cyclophosphamide to patients with advanced multiple myeloma and obtain preliminary data on clinical outcome in the context of a Phase I clinical trial. Hypothesis: MV-NIS administered with and without cyclophosphamide to patients with advanced multiple myeloma will safely and selectively target & propagate in myeloma deposits throughout the body leading to tumor cell killing and reduction of tumor burden.
Aim 2 : To characterize MV-NIS gene expression using 123-I, gamma camera imaging, and SPECT/CT imaging and to determine whether it correlates with disease distribution and/or disease response. Hypothesis: We predict that our ability to track MV-NIS using 123-I will be dependent on the pattern and extent of a patient's disease. One would anticipate that patients with high tumor burden disease and/or focal lesions would be most easily imaged and would have the best hematologic responses.
Aim 3 : To characterize the time course of expression, replication, biodistribution, and shedding of MV-NIS and to correlate these parameters with CD46 receptor expression in myeloma cells, dose level, and toxicity. Hypothesis: There will be self-limited expression, replication, and shedding of MV-NIS, which will correlate with both CD46 receptor status in myeloma cells and dose level and will be influenced by cyclophosphamide Aim 4: To determine humoral and cellular immune response to the injected virus in the peripheral blood and correlate it with toxicity, viremia, MV-NIS expression and response. Hypothesis: There will be an inverse correlation between early immune response and viral persistence. This unique strategy using MV-NIS (a genetically modified measles virus) to treat patients with relapsed, refractory myeloma has the potential to change the way cancer is treated. MV-NIS, given by vein, should kill myeloma cells. Using simple scans, we should be able to track where MV-NIS goes in the body. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125614-02
Application #
7293546
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Merritt, William D
Project Start
2006-09-29
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$246,400
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Dispenzieri, A; Tong, C; LaPlant, B et al. (2017) Phase I trial of systemic administration of Edmonston strain of measles virus genetically engineered to express the sodium iodide symporter in patients with recurrent or refractory multiple myeloma. Leukemia 31:2791-2798
Russell, Stephen J; Federspiel, Mark J; Peng, Kah-Whye et al. (2014) Remission of disseminated cancer after systemic oncolytic virotherapy. Mayo Clin Proc 89:926-33
Penheiter, A R; Griesmann, G E; Federspiel, M J et al. (2012) Pinhole micro-SPECT/CT for noninvasive monitoring and quantitation of oncolytic virus dispersion and percent infection in solid tumors. Gene Ther 19:279-87
Dispenzieri, Angela (2012) POEMS syndrome: update on diagnosis, risk-stratification, and management. Am J Hematol 87:804-14
Dispenzieri, Angela (2012) How I treat POEMS syndrome. Blood 119:5650-8
Dispenzieri, Angela; Gertz, Morie A; Buadi, Francis (2012) What do I need to know about immunoglobulin light chain (AL) amyloidosis? Blood Rev 26:137-54
Dispenzieri, Angela; Armitage, James O; Loe, Matt J et al. (2012) The clinical spectrum of Castleman's disease. Am J Hematol 87:997-1002
Liu, Y-P; Tong, C; Dispenzieri, A et al. (2012) Polyinosinic acid decreases sequestration and improves systemic therapy of measles virus. Cancer Gene Ther 19:202-11
Dispenzieri, Angela (2011) POEMS syndrome: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 86:591-601
Dispenzieri, Angela; Dingli, David; Kumar, Shaji K et al. (2010) Discordance between serum cardiac biomarker and immunoglobulin-free light-chain response in patients with immunoglobulin light-chain amyloidosis treated with immune modulatory drugs. Am J Hematol 85:757-9

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