title: The safety of allogeneic innate lymphocyte therapy for glioma patients with prior cranial irradiation.
abstract: The standard treatment of high-grade glioma presents a combination of radiotherapy, chemotherapy and surgery. Immunotherapy is proposed as a potential adjunct to standard cytotoxic regimens to target remaining microscopic disease following resection. We have shown ex vivo expanded/activated γδ T cells to be a promising innate lymphocyte therapy based on their recognition of stress antigens expressed on gliomas. However, successful integration of γδ T cell therapy protocols requires understanding the efficacy and safety of adoptively transferred immune cells in the post-treatment environment. The unique features of γδ T cell product and the environment (hypoxia, inflammation) can affect levels of expression of key cell receptors and secreted factors and either promote or hinder the feasibility of γδ T cell therapy. We investigated the potential for the γδ T cells to injure normal brain tissue that may have been stressed by treatment. We evaluated γδ T cell toxicity by assessing actual and correlative toxicity indicators in several available models including: (1) expression of stress markers on normal primary human astrocytes (as surrogate for brain parenchyma) after irradiation and temozolomide treatment, (2) cytotoxicity of γδ T cells on normal and irradiated primary astrocytes, (3) microglial activation and expression of stress-induced ligands in mouse brain after whole-brain irradiation and (4) expression of stress-induced markers on human brain tumors and on normal brain tissue. The lack of expression of stress-induced ligands in all tested models suggests that γδ T cell therapy is safe for brain tumor patients who undergo standard cytotoxic therapies.
authors: Division of Hematology and Oncology, School of Medicine, University of Alabama at Birmingham (UAB), 1824 6th Ave S, WTI 510C, Birmingham, AL, 35294, USA, lpereb@uab.edu.
authors: Larisa
authors: L
authors: Pereboeva
authors: Lualhati
authors: L
authors: Harkins
authors: Shun
authors: S
authors: Wong
authors: Lawrence S
authors: LS
authors: Lamb
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D001932:Brain Neoplasms / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy / Q000009:adverse effects / Q000379:methods; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005909:Glioblastoma / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*
chemical_list: C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta