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.
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.
|Johnson, Sarah K; Stewart, James P; Bam, Rakesh et al. (2014) CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease. Blood 124:2051-60|
|Dhodapkar, Madhav V; Sexton, Rachael; Waheed, Sarah et al. (2014) Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 123:78-85|
|Lapteva, Natalia; Szmania, Susann M; van Rhee, Frits et al. (2014) Clinical grade purification and expansion of natural killer cells. Crit Rev Oncog 19:121-32|
|Bam, R; Venkateshaiah, S U; Khan, S et al. (2014) Role of Bruton's tyrosine kinase (BTK) in growth and metastasis of INA6 myeloma cells. Blood Cancer J 4:e234|
|Papanikolaou, X; Rosenbaum, E R; Tyler, L N et al. (2014) Hematopoietic progenitor cell collection after autologous transplant for multiple myeloma: low platelet count predicts for poor collection and sole use of resulting graft enhances risk of myelodysplasia. Leukemia 28:888-93|
|Sawyer, Jeffrey R; Tian, Erming; Heuck, Christoph J et al. (2014) Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease. Blood 123:2504-12|
|Tian, Erming; Sawyer, Jeffrey R; Heuck, Christoph J et al. (2014) In multiple myeloma, 14q32 translocations are nonrandom chromosomal fusions driving high expression levels of the respective partner genes. Genes Chromosomes Cancer 53:549-57|
|Waheed, Sarah; Mitchell, Alan; Usmani, Saad et al. (2013) Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data. Haematologica 98:71-8|
|Lamy, Laurence; Ngo, Vu N; Emre, N C Tolga et al. (2013) Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell 23:435-49|
|Sousa, Mirta M L; Zub, Kamila Anna; Aas, Per Arne et al. (2013) An inverse switch in DNA base excision and strand break repair contributes to melphalan resistance in multiple myeloma cells. PLoS One 8:e55493|
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