Classical approaches to immunotherapy that show promise in some malignancies have generally been disappointing when applied to high-grade brain tumors such as glioblastoma multiforme (GBM). We recently showed that ex vivo expanded/activated cd T cells recognize NKG2D ligands expressed on malignant glioma and are cytotoxic to glioma cell lines and primary GBM explants. In addition, cd T cells extend survival and slow tumor progression when administered to immunodeficient mice with intracranial human glioma xenografts. We now show that temozolomide (TMZ), a principal chemotherapeutic agent used to treat GBM, increases the expression of stress-associated NKG2D ligands on TMZ-resistant glioma cells, potentially rendering them vulnerable to cd T cell recognition and lysis. TMZ is also highly toxic to cd T cells, however, and to overcome this cytotoxic effect cd T cells were genetically modified using a lentiviral vector encoding the DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) from the O(6)-methylguanine methyltransferase (MGMT) cDNA, which confers resistance to TMZ. Genetic modification of cd T cells did not alter their phenotype or their cytotoxicity against GBM target cells. Importantly, gene modified cd T cells showed greater cytotoxicity to two TMZ resistant GBM cell lines, U373TMZ-R and SNB-19TMZ-R cells, in the presence of TMZ than unmodified cells, suggesting that TMZ exposed more receptors for cd T cell-targeted lysis. Therefore, TMZ resistant cd T cells can be generated without impairing their anti-tumor functions in the presence of high concentrations of TMZ. These results provide a mechanistic basis for combining chemotherapy and cd T cell-based drug resistant cellular immunotherapy to treat GBM.
Dr. Lamb's primary research interest can be broadly defined as cell-based immunotherapy of cancer. His group was the first to describe an association between gamma/delta T cell recovery and disease-free survival in allogeneic bone marrow transplantation patients as well homeostatic reconstitution of a dominant infused allogeneic T cell population in an ablated host. Team members also were the first to report gamma/delta T cell receptor CDR3 conservation in leukemia patients. Group’s current focus is the biology of gamma/delta T cell interaction with high-grade gliomas, therapeutic gamma/delta T cell manufacturing strategies, and translation of innate cell-based therapies for high-grade gliomas into clinical trials. Group receives or has received funding from NINDS, NCI, NCRR, Elsa U. Pardee Foundation, Southeastern Brain Tumor Foundation, and the National Brain Tumor Society for which he had the honor of holding Samuel Gerson Leadership Chair for Glioblastoma Research from 2007-2009. He also direct the UAB Cell Therapy Laboratory, an advanced collection and processing facility which is comprised of an apheresis facility, a bone marrow transplant cell processing facility, a cGMP advanced cell manufacturing facility, and an immunodiagnostics laboratory