Translating Guidelines and Clinical Trial Data to and ... - Amazon S3

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Candidate AgentsChemotherapy• Antipurines– Clofarabine, nelarabine• Liposomal vincristinei • Flt3 inhibitors– Lestaurtinib*, quizartinib (AC220)*• Proteosome inhibitors– Bortezomib, carfilzomib• mToR inhibitors– Temsirolimus, evrolemus• Aurora kinase inhibitors*• BCL-2 inhibitors btos– obatoclax*a• Notch inhibitors• Survivin inhibitors – EZN3042*• Epigenetic strategies– Vorinostat/decitabine• Toll-like receptor 9 agonists• CXCR4 inhibitor – plerixaforImmune directed therapies• Monoclonals– Rituximab, Epratuzumab*• Immunotoxins• Moxetumomab*, SGN3419*,Inotuzomab ozogamicin*, SAR19a*,Combotox*• Immune constructs– Blinatumomab**Investigational drug not currently FDA approved.Blinatumomabα-CD3MonoclonalAntibodyBiTE ® Single-ChainAntibodyα-CD3/ α-CD19T-cellCytotoxicGranuleCD3CD19α-CD19MonoclonalAntibodyCD19+B-cellNagorsen D, et al. Leuk Lymphoma. 2009;50(6):886-891.
Toll-Like Receptors• TLR are pattern recognition receptors– Part of our innate immunity• Perhaps T-cells are capable of recognizing otherleukemia-specific antigens– Support for a role of host immune responses in themaintenance of post-chemotherapy remission– Relapse ALL possesses changes consistent with evasion ofimmune effector mechanisms• CpG-oligodeoxynucleotide: TLR agonist for MRDpositiveleukemiaCpG = cytosine-phosphate-guanine.Kanzler H, et al. Nat Med. 2007;13(5):552-559.Another Approach:Chimeric Antigen Receptor• Autologous chimeric antigen receptor– Extracellular domain derived from an antibody combined withthe intracellular signaling domain of CD3– Allows tumor cells to be recognized in non-MHC manner• 10 patients with CLL/ALL using CD19 as target– 4 CR– 2PRinCLLMHC = major histocompatibility complex; CLL = chronic lymphocytic leukemia.Porter DL, et al. N Engl J Med. 2011;365(8):725-733. Porter DL, et al. Presented at: American Society ofHematology Annual Meeting; December 8-11, 2012; Atlanta, Georgia. Abstract 717.
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