A photosensitizer delivered by bispecific antibody redirected T lymphocytes enhances cytotoxicity against EpCAM-expressing carcinoma cells upon light irradiation.

Abstract

Recently conducted clinical trials have provided impressive evidence that chemotherapy resistant metastatic melanoma and several hematological malignancies can be cured using adoptive T cell therapy or T cell-recruiting bispecific antibodies. However, a significant fraction of patients did not benefit from these treatments. Here we have evaluated the feasibility of a novel combination therapy which aims to further enhance the killing potential of bispecific antibody-redirected T lymphocytes by using these cells as targeted delivery system for photosensitizing agents. For a first in vitro proof-of-concept study, ex vivo activated human donor T cells were loaded with a poly(styrene sulfonate) (PSS)-complex of the model photosensitizer 5,10,15,20-tetrakis(3-hydroxyphenyl)porphyrin (mTHPP). In the absence of light and when loading with the water-soluble PSS/mTHPP-complex occurred at a tolerable concentration, viability and cytotoxic function of loaded T lymphocytes were not impaired. When "drug-enhanced" T cells were co-cultivated with EpCAM-expressing human carcinoma cells, mTHPP was transferred to target cells. Notably, in the presence of a bispecific antibody, which cross-links effector and target cells thereby inducing the cytolytic activity of cytotoxic T lymphocytes, significantly more photosensitizer was transferred. Consequently, upon irradiation of co-cultures, redirected drug-loaded T cells were more effective in killing A549 lung and SKOV-3 ovarian carcinoma cells than retargeted unloaded T lymphocytes. Particularly, the additive approach using redirected unloaded T cells in combination with appropriate amounts of separately applied PSS/mTHPP was less efficient as well. Thus, by loading T lymphocytes with a stimulus-sensitive anti-cancer drug, we were able to enhance the cytotoxic capacity of carrier cells. Photosensitizer boosted T cells could open new perspectives for adoptive T cell therapy as well as targeted photodynamic therapy.

• Authors: André-René Blaudszun, Gerhard Moldenhauer, Marc Schneider, Anja Philippi
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 197 Pg. 58-68 (Jan 10 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 25449805 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Antibodies, Bispecific
• Antigens, Neoplasm
• Cell Adhesion Molecules
• EPCAM protein, human
• Epithelial Cell Adhesion Molecule
• Photosensitizing Agents
• Polystyrenes
• Porphyrins
• tetra(3-hydroxyphenyl)porphine
• polystyrene sulfonic acid

Topics

• Antibodies, Bispecific
• Antigens, Neoplasm (metabolism)
• Cell Adhesion Molecules (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Coculture Techniques
• Drug Delivery Systems
• Epithelial Cell Adhesion Molecule
• Humans
• Light
• Neoplasms (metabolism)
• Photosensitizing Agents (administration & dosage, chemistry, radiation effects)
• Polystyrenes (administration & dosage, chemistry)
• Porphyrins (administration & dosage, chemistry, radiation effects)
• T-Lymphocytes