title: 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.affiliation: Environment and Bio Group, Korea Institute of Science and Technology (KIST) Europe Forschungsgesellschaft mbH, Saarland University, Campus E7 1, Saarbrücken D-66123, Germany. Electronic address: a.blaudszun@kist-europe.de.
authors.forename: André-René
authors.initials: AR
authors.lastname: Blaudszun
authors.affiliation: Department of Translational Immunology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg D-69120, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Moldenhauer
authors.affiliation: Department of Pharmaceutics and Biopharmacy, Philipps-University, Ketzerbach 63, Marburg D-35037, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Environment and Bio Group, Korea Institute of Science and Technology (KIST) Europe Forschungsgesellschaft mbH, Saarland University, Campus E7 1, Saarbrücken D-66123, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Philippi
mesh_terms: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D016503:Drug Delivery Systems; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D008027:Light; D009369:Neoplasms / Q000378:metabolism; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000528:radiation effects; D011137:Polystyrenes / Q000008:administration & dosage / Q000737:chemistry; D011166:Porphyrins / Q000008:administration & dosage* / Q000737:chemistry / Q000528:radiation effects; D013601:T-Lymphocytes
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D017319:Photosensitizing Agents; D011137:Polystyrenes; D011166:Porphyrins; C437342:tetra(3-hydroxyphenyl)porphine; C003321:polystyrene sulfonic acid
keywords: Adoptive T cell therapy; Cell-mediated drug delivery; Targeted photodynamic therapy; Tumor targeting; mTHPP