title: Enhancing Adoptive Cell Therapy of Cancer through Targeted Delivery of Small-Molecule Immunomodulators to Internalizing or Noninternalizing Receptors.
abstract: Adoptive cell therapy (ACT) has achieved striking efficacy in B-cell leukemias, but less success treating other cancers, in part due to the rapid loss of ACT T-cell effector function in vivo due to immunosuppression in solid tumors. Transforming growth factor-β (TGF-β) signaling is an important mechanism of immune suppression in the tumor microenvironment, but systemic inhibition of TGF-β is toxic. Here we evaluated the potential of targeting a small molecule inhibitor of TGF-β to ACT T-cells using PEGylated immunoliposomes. Liposomes were prepared that released TGF-β inhibitor over ∼3 days in vitro. We compared the impact of targeting these drug-loaded vesicles to T-cells via an internalizing receptor (CD90) or noninternalizing receptor (CD45). When lymphocytes were preloaded with immunoliposomes in vitro prior to adoptive therapy, vesicles targeted to both CD45 and CD90 promoted enhanced T-cell expression of granzymes relative to free systemic drug administration, but only targeting to CD45 enhanced accumulation of granzyme-expressing T-cells in tumors, which correlated with the greatest enhancement of T-cell antitumor activity. By contrast, when administered i.v. to target T-cells in vivo, only targeting of a CD90 isoform expressed exclusively by the donor T-cells led to greater tumor regression over equivalent doses of free systemic drug. These results suggest that in vivo, targeting of receptors uniquely expressed by donor T-cells is of paramount importance for maximal efficacy. This immunoliposome strategy should be broadly applicable to target exogenous or endogenous T-cells and defines parameters to optimize delivery of supporting (or suppressive) drugs to these important immune effectors.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology (MIT) , Cambridge, Massachusetts 02139, United States.|Koch Institute for Integrative Cancer Research, MIT , Cambridge, Massachusetts 02139, United States.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Koch Institute for Integrative Cancer Research, MIT , Cambridge, Massachusetts 02139, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.affiliation: Koch Institute for Integrative Cancer Research, MIT , Cambridge, Massachusetts 02139, United States.
authors.forename: Llian
authors.initials: L
authors.lastname: Mabardi
authors.affiliation: Koch Institute for Integrative Cancer Research, MIT , Cambridge, Massachusetts 02139, United States.
authors.forename: Sudha
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology (MIT) , Cambridge, Massachusetts 02139, United States.|Koch Institute for Integrative Cancer Research, MIT , Cambridge, Massachusetts 02139, United States.|Department of Material Science and Engineering, MIT , Cambridge, Massachusetts 02139, United States.|Ragon Institute of Massachusetts General Hospital, MIT and Harvard University , Cambridge, Massachusetts 02139, United States.|Howard Hughes Medical Institute , Chevy Chase, Maryland 20815, United States.
authors.forename: Darrell J
authors.identifier: 0000-0002-8637-1405
authors.initials: DJ
authors.lastname: Irvine
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D005260:Female; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D017493:Leukocyte Common Antigens / Q000037:antagonists & inhibitors / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D018800:Thy-1 Antigens / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007155:Immunologic Factors; D054852:Small Molecule Libraries; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse
keywords: TGF-β receptor inhibitor; adoptive cell therapy; cancer immunotherapy; immunoliposomes; melanoma; targeted delivery