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: Yiran Zheng, Matthias T Stephan, S Annie Gai, Wuhbet Abraham, Adrianne Shearer, Darrell J Irvine
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 172 Issue 2 Pg. 426-35 (Dec 10 2013) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 23770010 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Immunoconjugates
• Immunoglobulin Fab Fragments
• Interleukin-2
• Liposomes

Topics

• Animals
• Cell Proliferation
• Cytokines (administration & dosage, chemistry, immunology)
• Female
• Humans
• Immunoconjugates (administration & dosage, chemistry, immunology)
• Immunoglobulin Fab Fragments (administration & dosage, chemistry, immunology)
• Immunotherapy, Adoptive (methods)
• Interleukin-2 (administration & dosage, chemistry, immunology)
• Liposomes (administration & dosage, chemistry, immunology)
• Lymphocyte Activation
• Melanoma (immunology, pathology, secondary, therapy)
• Mice
• Mice, Inbred C57BL
• T-Lymphocytes (immunology, transplantation)