Modulating SIRP-alpha, a Myeloid-Specific Immune Checkpoint, for Immunotherapeutic Treatment of Malignancy

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dc.contributor.advisorWeissman, Irvingen
dc.contributor.committeeMemberLaccetti, Andrewen
dc.contributor.committeeMemberNijhawan, Deepaken
dc.contributor.committeeMemberWang, Richarden
dc.creatorRing, Nan Guoen
dc.date.accessioned2019-08-02T19:23:05Z
dc.date.available2019-08-02T19:23:05Z
dc.date.created2016-05
dc.date.issued2016-04-01
dc.date.submittedMay 2016
dc.date.updated2019-08-02T19:23:06Z
dc.descriptionThe general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.en
dc.descriptionPages i-iii are misnumbered as pages ii-iv.en
dc.description.abstractBACKGROUND: CD47 is a "don't-eat-me" signal upregulated by many types of cancer that signals through its receptor SIRPα to inhibit macrophage-mediated destruction. Recent studies have demonstrated the efficacy of anti-CD47 blockade in synergizing with traditional monoclonal antibodies (mAbs) to enhance phagocytosis of cancer cells. We proposed targeting SIRPα as an alternative strategy and as a bridge to creating a single format bispecific macrophage-enhancing antibody (BiME). OBJECTIVE: The focus of this project was to test the therapeutic efficacy of SIRPα-blockade in combination treatment with other anti-tumor mAbs and in a single agent format as BiMEs. METHODS: We created KWAR23, a SIRPα-blocking monoclonal antibody, and from it, we derived several BiMEs in the dual-variable-domain immunoglobulin format to target CD20, Her2, and CD70. We tested these agents in high-throughput phagocytosis assays. We have also begun testing the therapeutic efficacy of KWAR23 in combination with rituximab in a xenograft mouse model of B cell lymphoma. RESULTS: KWAR23 significantly enhanced the efficacy and potency of phagocytosis of mAb-opsonized cancer cells when compared to the mAbs alone in B cell lymphoma and breast adenocarcinoma. BiMEs resulted in greater efficacy of phagocytosis of cancer cells when compared to their parent mAbs for B cell lymphoma, breast adenocarcinoma, and renal cell carcinoma. SIRPα-blockade in combination with rituximab also appeared to significantly reduce tumor burden in mice engrafted with a B cell lymphoma cell line. CONCLUSIONS: The therapeutic role of check-point inhibitors has become increasingly apparent and important in the treatment of cancer in recent years, but the role played by macrophages remains unclear. We have now demonstrated multiple strategies for targeting the CD47-SIRPα pathway to harness macrophages in antibody-mediated cell killing. This research may further benefit the field of immunotherapy as we learn more about the intricate interplay between innate and adaptive immunity in cancer biology.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1111292128
dc.identifier.urihttps://hdl.handle.net/2152.5/7077
dc.language.isoenen
dc.subjectAntibodies, Neoplasmen
dc.subjectCD47 Antigenen
dc.subjectImmunotherapyen
dc.subjectMacrophagesen
dc.subjectNeoplasmsen
dc.subjectPhagocytosisen
dc.subjectReceptors, Immunologicen
dc.titleModulating SIRP-alpha, a Myeloid-Specific Immune Checkpoint, for Immunotherapeutic Treatment of Malignancyen
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentUT Southwestern Medical Schoolen
thesis.degree.disciplineResearchen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameM.D. with Distinctionen

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