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    Kipp Weiskopf.
    Cancer cells develop mechanisms to avoid detection by the immune system, and therapeutic approaches aimed at overcoming these mechanisms form the basis of cancer immunotherapy. In this dissertation, I employed macrophages as effector cells by targeting the CD47/SIRPa axis, which is a critical regulator of macrophage activation. CD47 is highly expressed on many different types of cancer, and it transduces inhibitory signals through SIRPa, a receptor on macrophages and other myeloid cells. Thus, the CD47/SIRPa axis serves as a myeloid-specific immune checkpoint. To create next-generation CD47 antagonists, we engineered high-affinity SIRPa variants that exhibited ~50,000-fold higher affinity for human CD47 relative to wild-type SIRPa. When produced as high-affinity SIRPa-Fc fusion proteins, these therapeutics acted as single agents for cancer with moderate on-target toxicity to normal cells expressing CD47. When produced as 14 kDa high-affinity SIRPa monomers, the therapeutics had minimal activity as single agents but instead acted as universal adjuvants to anti-cancer antibodies. Therefore, CD47 blockade is not sufficient to induce macrophage phagocytosis, but instead lowers the threshold for phagocytosis in the presence of a separate, tumor-opsonizing antibody. I demonstrated these principles could be extended to models of small cell lung cancer (SCLC), and I identified additional therapeutic targets on the surface of SCLC cells. Last, I generated anti-SIRPa antibodies and characterized KWAR23 as a clone that binds and antagonizes SIRPa directly on macrophages. Therapies targeting the CD47/SIRPa axis are now under investigation in clinical trials. These agents may differ in their pharmacokinetic, pharmacodynamic, and toxicity profiles, raising important considerations for further development and clinical evaluation. Overall, the therapies developed in this dissertation could be broadly applied to cancer and may benefit many patients suffering from disease.
    Digital Access   2016