Nanoscience of `Self' 2.0: blocking CD47 recognition by phagocytes in blood & solid tumor clearance Nanoparticle coatings of PEG or other polymers have been a standard approach for prolonging circulation in order to maximize delivery to disease sites. However, particles always develop a corona of serum proteins including IgG, IgM, etc. that signal `eat me' to macrophages in the spleen, liver, and even tumors. Specific antibodies can also develop, including anti-PEG. CD47 is a protein on all of our cells that signals `Self' to macrophages and overrides `eat me' factors on the surface of our cells. We showed human-CD47 inhibits phagocytosis of IgG-coated particles and RBCs that signal at a `phagocytic synapse' through SIRPa [Tsai & Discher J Cell Biol 2008]. `Self'-nanobeads show delayed clearance from the circulation and improved delivery to tumor xenografts in NOD/SCID/? (NSG) mice with a human-compatible SIRPa [Rodriguez Science 2013]. Blocking SIRPa with antibody also eliminated `Self' signaling. Our first R01 allowed us ? among other accomplishments ? to improve gene delivery to the same xenograft model with novel nano-characterized CD47-Lentivirus [Sosale Mol Ther-MCD 2016], and we developed a safe and effective therapy with SIRPa-inhibited macrophages [Alvey Curr Biol 2017]. We propose to advance the safety and efficacy of this eng'd macrophage approach using diverse nano approaches. Phase-I clinical trials in cancer patients are already using anti-(humanCD47) for blockade because CD47 is expressed on cancer cells as on all cells. Initial reports from the anti-(humanCD47) trials are showing anemia but no efficacy. Our mouse models injected with anti-(mouseCD47) likewise show no efficacy against cancer and show anemia as well as anti-RBC IgG ? and so the model is appropriate for our new approach. Our overall hypothesis is that CD47 opposes engulfment and thereby inhibits acquired immunity. Our goal is to show an eng'd macrophage therapy can be injected systemically and prove safe (no autoimmune anemia) and sufficiently effective that mice cured of tumors acquire immunity to further injection of cancer cells. Diverse nano-tools will help test the hypothesis and achieve our goal, including nanoparticle tests of acquired immunity, nanoparticle tracking of eng'd macrophages, and new nano-Self blockade approaches.
Project Relevance to Public Health SIGNIFICANCE: Phase-I clinical trials in cancer patients are currently using antibodies that block a ubiquitously expressed membrane protein called CD47 which binds to a counter-receptor SIRPa on macrophages to signal ?Don't Eat Me!?. Initial reports from the trials show no efficacy and instead show anemia and other systemic side effects that raise concerns about autoimmunity. We will use an array of nanoparticles and nano-methods to clarify the processes in clinically relevant models and to ultimately develop a translatable approach of blocking CD47-SIRPa for safe and effective regression of tumors.
|Nair, Praful R; Alvey, Cory; Jin, Xiaoling et al. (2018) Filomicelles Deliver a Chemo-Differentiation Combination of Paclitaxel and Retinoic Acid That Durably Represses Carcinomas in Liver to Prolong Survival. Bioconjug Chem 29:914-927|
|Smith, Lucas R; Cho, Sangkyun; Discher, Dennis E (2018) Stem Cell Differentiation is Regulated by Extracellular Matrix Mechanics. Physiology (Bethesda) 33:16-25|
|Steinkühler, Jan; Ró?ycki, Bartosz; Alvey, Cory et al. (2018) Membrane fluctuations and acidosis regulate cooperative binding of 'marker of self' protein CD47 with the macrophage checkpoint receptor SIRP?. J Cell Sci 132:|
|Holle, Andrew W; Young, Jennifer L; Van Vliet, Krystyn J et al. (2018) Cell-Extracellular Matrix Mechanobiology: Forceful Tools and Emerging Needs for Basic and Translational Research. Nano Lett 18:1-8|
|Chakraborty, Kaushik; Vijayan, Kandaswamy; Brown, Andre E X et al. (2018) Glassy worm-like micelles in solvent and shear mediated shape transitions. Soft Matter 14:4194-4203|
|Pfeifer, Charlotte R; Alvey, Cory M; Irianto, Jerome et al. (2017) Genome variation across cancers scales with tissue stiffness - an invasion-mutation mechanism and implications for immune cell infiltration. Curr Opin Syst Biol 2:103-114|
|Discher, Dennis E; Dooling, Lawrence J (2017) Optimal Contractile Forces for a Mesenchymal Engine. Dev Cell 42:313-315|
|Irianto, Jerome; Xia, Yuntao; Pfeifer, Charlotte R et al. (2017) DNA Damage Follows Repair Factor Depletion and Portends Genome Variation in Cancer Cells after Pore Migration. Curr Biol 27:210-223|
|Alvey, Cory M; Spinler, Kyle R; Irianto, Jerome et al. (2017) SIRPA-Inhibited, Marrow-Derived Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors. Curr Biol 27:2065-2077.e6|
|Smith, Lucas; Cho, Sangkyun; Discher, Dennis E (2017) Mechanosensing of matrix by stem cells: From matrix heterogeneity, contractility, and the nucleus in pore-migration to cardiogenesis and muscle stem cells in vivo. Semin Cell Dev Biol 71:84-98|
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