title: In vivo targeting of adoptively transferred T-cells with antibody- and cytokine-conjugated liposomes.
abstract: In adoptive cell therapy (ACT), autologous tumor-specific T-cells isolated from cancer patients are activated and expanded ex vivo, then infused back into the individual to eliminate metastatic tumors. A major limitation of this promising approach is the rapid loss of ACT T-cell effector function in vivo due to the highly immunosuppressive environment in tumors. Protection of T-cells from immunosuppressive signals can be achieved by systemic administration of supporting adjuvant drugs such as interleukins, chemotherapy, and other immunomodulators, but these adjuvant treatments are often accompanied by serious toxicities and may still fail to optimally stimulate lymphocytes in all tumor and lymphoid compartments. Here we propose a novel strategy to repeatedly stimulate or track ACT T-cells, using cytokines or ACT-cell-specific antibodies as ligands to target PEGylated liposomes to transferred T-cells in vivo. Using F(ab')2 fragments against a unique cell surface antigen on ACT cells (Thy1.1) or an engineered interleukin-2 (IL-2) molecule on an Fc framework as targeting ligands, we demonstrate that >95% of ACT cells can be conjugated with liposomes following a single injection in vivo. Further, we show that IL-2-conjugated liposomes both target ACT cells and are capable of inducing repeated waves of ACT T-cell proliferation in tumor-bearing mice. These results demonstrate the feasibility of repeated functional targeting of T-cells in vivo, which will enable delivery of imaging contrast agents, immunomodulators, or chemotherapy agents in adoptive cell therapy regimens.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Zheng
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Stephan
authors.forename: S Annie
authors.initials: SA
authors.lastname: Gai
authors.forename: Wuhbet
authors.initials: W
authors.lastname: Abraham
authors.forename: Adrianne
authors.initials: A
authors.lastname: Shearer
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016207:Cytokines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*
chemical_list: D016207:Cytokines; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D007376:Interleukin-2; D008081:Liposomes
keywords: Adoptive cell therapy; Cancer immunotherapy; Immunoliposomes; Interleukin-2 (IL-2); Melanoma; Targeted delivery