Multiple myeloma (MM) is a genetically heterogeneous disease, with varying levels of genomic instability and intra-tumor clonal heterogeneity. Both levels of heterogeneity pose challenges for directed anti-tumor targeted therapy, which may be overcome by harnessing the power of the immune system. LCL161 is a SMAC mimetic targeting the cellular inhibitor of apoptosis proteins cIAP1 and -2 (cIAP1/2). We previously reported that bi- allelic deletions of cIAP1/2 in MM result in activation of the non canonical NFkB pathway, and consistently LCL161 has little direct anti-tumor activity, against primary MM cells, MM cell lines, or xenograft models where it induces even higher levels of NFkB. However, LCL161 has dramatic activity in vivo against MM that develops spontaneously in the immuno-competent and clinically predictive Vk*MYC mouse model, but not in vitro against these same tumor cells, suggesting an important role for the host in mediating the anti-tumor effect. Transplantation and cell depletion experiments in Vk*MYC mice implicated macrophages as mediator of LCL161 anti-MM activity that does not depend on adaptive immunity. M? are a crucial component of the MM niche and support MM growth by providing survival signals and promoting immunosuppression. However macrophages can be re-educated to acquire tumoricidal activity by CSF1R inhibition, anti-CD47 treatment or combinations of Toll-like-receptor (TLR) agonists + IFNg, TLRa + CD40 agonist or chemotherapy. We found that the SMAC mimetic compound (SMC) LCL161 also promotes macrophages M1 polarization and potent anti-MM activity in vivo. Specifically, LCL161 treatment induced M1 polarization and tumoricidal activity in BM derived macrophages co-cultures experiments, and induction of M1 cytokines in plasma from MM patients enrolled in the clinical trial. The goal of this proposal is to define the mechanisms implicated in LCL161 anti-MM activity in Vk*MYC mice and in samples obtained from MM patients enrolled in a phase II clinical trial of LCL161 at the Mayo Clinic.
Genetic heterogeneity, genomic instability and intra-tumor clonal heterogeneity pose challenges for directed anti-MM targeted therapy and emphasize the urge to harness the power of the immune system to overcome them. LCL161 represents a novel immunomodulator with a very well defined molecular target and robust anti- MM activity in a validated pre-clinical model. These reasons warrant LCL161 evaluation in the clinic and characterization of its mechanisms of action.
|Baughn, Linda B; Pearce, Kathryn; Larson, Dirk et al. (2018) Differences in genomic abnormalities among African individuals with monoclonal gammopathies using calculated ancestry. Blood Cancer J 8:96|
|Russell, Stephen J; Barber, Glen N (2018) Oncolytic Viruses as Antigen-Agnostic Cancer Vaccines. Cancer Cell 33:599-605|
|Clay-Gilmour, Alyssa I; Kumar, Shaji; Rajkumar, S Vincent et al. (2018) Risk of MGUS in relatives of multiple myeloma cases by clinical and tumor characteristics. Leukemia :|
|Sidiqi, M Hasib; Aljama, Mohammed A; Muchtar, Eli et al. (2018) Light chain type predicts organ involvement and survival in AL amyloidosis patients receiving stem cell transplantation. Blood Adv 2:769-776|
|Nair, Shiny; Sng, Joel; Boddupalli, Chandra Sekhar et al. (2018) Antigen-mediated regulation in monoclonal gammopathies and myeloma. JCI Insight 3:|
|Msaouel, Pavlos; Opyrchal, Mateusz; Dispenzieri, Angela et al. (2018) Clinical Trials with Oncolytic Measles Virus: Current Status and Future Prospects. Curr Cancer Drug Targets 18:177-187|
|Go, Ronald S; Rajkumar, S Vincent (2018) How I manage monoclonal gammopathy of undetermined significance. Blood 131:163-173|
|Kyle, Robert A; Larson, Dirk R; McPhail, Ellen D et al. (2018) Fifty-Year Incidence of Waldenström Macroglobulinemia in Olmsted County, Minnesota, From 1961 Through 2010: A Population-Based Study With Complete Case Capture and Hematopathologic Review. Mayo Clin Proc 93:739-746|
|Calcinotto, Arianna; Brevi, Arianna; Chesi, Marta et al. (2018) Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression. Nat Commun 9:4832|
|Facon, Thierry; Dimopoulos, Meletios A; Dispenzieri, Angela et al. (2018) Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood 131:301-310|
Showing the most recent 10 out of 95 publications