Most patients with relapsed/refractory myeloma have a high-risk gene expression profile. These patients have poor long-term outcomes with salvage strategies, including transplantation-based therapies and the application of novel drugs. We conducted a pilot trial for relapsed/refractory myeloma patients in which we infused killer cell immunoglobulin-like receptor ligand (KIR-L)-mismatched natural killer (NK) cells from haplo-identical family donors in the setting of an autologous transplant. Such cells have demonstrated remarkable antileukemic effects in the allogeneic transplant setting. Our pilot trial established that transfusions of NK cells were safe, did not cause graft-versus-host disease, and did not affect engraftment of autologous CD34+ stem cells. Additional findings lay the foundation for the work proposed in Project 2. First, we observed that inhibitory KIR-Ls on myeloma cells are down-regulated in vivo after administration of bortezomib, further sensitizing myeloma cells to alloreactive (alio-) NK cell lysis. Second, CS1-specific antibody (Ab) has significant activity against primary myeloma cells in our SCID-hu mouse model, and this activity is synergistic with bortezomib. Third, we have expanded and activated NK cells with K562 cells transfected with membrane-bound interieukin-15 (IL-15) and the costimulatory molecule 4-1 BBL, increasing the number of allo-NK cells available for killing myeloma by rendering subpopulations of previously nonalloreactive NK cells cytotoxic.
Specific Aim 1 will evaluate in a clinical trial whether the combination of bortezomib and CS1 Ab can enhance the antimyeloma activity of KIR-L-mismatched NK cells by down-regulating KIR-Ls on myeloma cells and invoking Ab-dependent cellular cytotoxicity, respectively.
Specific Aim 2 will examine the activity of human allo-NK cells activated/expanded with K562 cell transfectants in the NOD/SCID/IL2rgamma[null]-hu model, which is deficient of murine NK cells. The potential additive/synergistic effects of combinations of bortezomib, CS1 Ab, and activated/expanded allo-NK cells will be investigated in order to design highly effective allo-NK cell therapy. Once proven effective in the relapsed high-risk disease setting, such therapy could be incorporated into upfront therapy of myeloma patients and be a useful adjunct to autotransplantation and/or novel drugs. This research may also be valuable for developing more efficacious therapies for other NK cell-sensitive malignancies.

Public Health Relevance

Aggressive high-risk myeloma currently has a poor prognosis due to the presence of highly chemotherapy-refractory subpopulations that rapidly grow after elimination of drug-sensitive cells. The goal of Project 2 is to eradicate chemotherapy-refractory myeloma cells with cytotherapy using allogeneic natural killer cells, thus profoundly impacting the long-term outcome for these patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055819-18
Application #
8555167
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2000-06-05
Project End
2014-08-31
Budget Start
2012-09-11
Budget End
2013-08-31
Support Year
18
Fiscal Year
2012
Total Cost
$326,247
Indirect Cost
$101,135
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Went, Molly; Sud, Amit; Försti, Asta et al. (2018) Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nat Commun 9:3707
Mehdi, Syed J; Johnson, Sarah K; Epstein, Joshua et al. (2018) Mesenchymal stem cells gene signature in high-risk myeloma bone marrow linked to suppression of distinct IGFBP2-expressing small adipocytes. Br J Haematol :
Rasche, Leo; Angtuaco, Edgardo J; Alpe, Terri L et al. (2018) The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma. Blood 132:59-66
Went, M; Sud, A; Law, P J et al. (2017) Assessing the effect of obesity-related traits on multiple myeloma using a Mendelian randomisation approach. Blood Cancer J 7:e573
McDonald, James E; Kessler, Marcus M; Gardner, Michael W et al. (2017) Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma. Clin Cancer Res 23:1981-1987
Rasche, Leo; Weinhold, Niels; Morgan, Gareth J et al. (2017) Immunologic approaches for the treatment of multiple myeloma. Cancer Treat Rev 55:190-199
Rasche, L; Chavan, S S; Stephens, O W et al. (2017) Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat Commun 8:268
Jethava, Yogesh S; Mitchell, Alan; Epstein, Joshua et al. (2017) Adverse Metaphase Cytogenetics Can Be Overcome by Adding Bortezomib and Thalidomide to Fractionated Melphalan Transplants. Clin Cancer Res 23:2665-2672
Schinke, Carolina; Hoering, Antje; Wang, Hongwei et al. (2017) The prognostic value of the depth of response in multiple myeloma depends on the time of assessment, risk status and molecular subtype. Haematologica 102:e313-e316

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