Complex Karyotype (CK) Is Associated with Increased Cumulative Incidence of Relapse (CIR) Following Autologous Stem Cell Transplantation (ASCT) for Mantle Cell Lymphoma (MCL) in First Remission
Biology of Blood and Marrow Transplantation
GA Treatment strategies for high-grade primary brain tumors such as glioblastoma multiforme (GBM) have failed to significantly and consistently extend survival. Recently, several studies have suggested that chemotherapy-induced tumor stress may increase tumor vulnerability to the immune reaponse. We have previously shown that expanded/activated gd T cells from healthy donors recognize NKG2D ligands expressed on malignant glioma and are cytotoxic to glioma cell lines, primary GBM explants, and
... man glioma intracranial cell line xenografts placed in immunodeficient mice. In this report, we show standard therapies for GBM based on temozolomide (TMZ) increase the expression of stress-associated NKG2D ligands on TMZ-resistant glioma cells, potentially rendering them vulnerable to attack by gd T cells. As TMZ is also highly toxic to gd T cells, we genetically modified gd T cells in culture using a lentiviral vector encoding P140KMGMT, resulting in resistance to TMZ at concentrations up to 400mM. Genetic modification of gd T cells did not alter their phenotype or their ability to kill targets, as both non-modified and gene-modified gd T cells were highly cytotoxic to U87 cells and TMZ-resistant clones of SNB-19 (SNB-19 TMZ-R ) and U373 (U373 TMZ-R ) glioma cell lines in the presence of up to 400 mM TMZ. Importantly, gene modified gd T cells showed greater cytotoxicity to both U373 TMZ-R and SNB-19 TMZ-R cultures in the presence of TMZ, suggesting that TMZ exposed more targets to gd T cell lysis. These findings demonstrate that TMZ resistant gd T cells can be generated without impairing cellular functions, and the genetically modified cells efficiently kill TMZ-resistant human glioma cell lines in the presence of high concentrations of TMZ. These results provide a mechanistic basis for combining and timing chemotherapy and drug resistant cellular immunotherapy to treat GBM.