Contextualizing Anti-PD-1 Cancer Immunotherapy Treatment Through Visualization of Therapeutics in vivo
Garris, Christopher S.
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CitationGarris, Christopher S. 2019. Contextualizing Anti-PD-1 Cancer Immunotherapy Treatment Through Visualization of Therapeutics in vivo. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractCancer immunotherapy using monoclonal antibodies (mAbs) targeting the immune checkpoint pathway programmed cell death protein 1 (PD-1) / programmed cell death protein 1 ligand (PD-L1) have demonstrated impressive benefits for the treatment of some cancers; however, these drugs are not always effective, and we still have a limited understanding of the mechanisms that contribute to their efficacy. I reasoned that tracking aPD-1 within the context of tumors would elucidate mechanisms of tumor rejection (or lack thereof). To do this, we designed an intravital imaging system to enable measurement of mAb drug distribution within the tumor microenvironment, and the subsequent host immune response following treatment. These investigations are partitioned into 2 primary studies by aPD-1’s pharmacokinetic (Study 1) and pharmacodynamic (Study 2) behavior.
In study 1, I found that aPD-1 mAbs initially bind to their intended targets, tumor infiltrating cytotoxic T cells, but over time aPD-1 mAbs are stripped from the surface of T cells by macrophages in an antigen independent, but Fc gamma receptor dependent manner. Concurrent blockade of mouse Fc gamma receptors with aPD-1 therapy prolonged aPD-1 mAb binding to cytotoxic T cells and enhanced immunotherapy induced tumor regression in mice, demonstrating that off-target, Fc driven antibody effects can be detrimental to aPD-1 therapy.
In study 2, I show that effective antitumor responses require a subset of tumor-infiltrating dendritic cells (DCs), which produce interleukin (IL)-12. These DCs are indirectly activated by aPD-1 through T cell-derived interferon (IFN)- . In turn, IL-12 stimulates antitumor T cell immunity. Furthermore, I find that agonizing the non-canonical NF B pathway can amplify IL-12 producing DCs and sensitize tumors to aPD-1 treatment. Contextualizing aPD-1 in the tumor microenvironment enabled discovery of off-target limiters and enhancers of aPD-1 response, as well as primary and secondary pharmacodynamic events important for therapeutic activity. This newly acquired understanding of aPD-1 pharmacology should better inform future versions of aPD-1 targeted therapeutics and combination therapies that can increase the proportion of responding cancer patients.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41121270
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