Adoptive Immunotherapy for Glioblastoma Multiforme

Stephen Gottschalk, M.D.

Baylor College of Medicine

Funded in September, 2011: $200000 for 3 years
LAY SUMMARY . BIOGRAPHY .

LAY SUMMARY

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Cellular imaging will reveal whether modified immune T cells better combat brain tumors

Investigators will determine in human brain tumor cells and in an animal model whether a genetically modified “immunotherapy” more effectively targets brain tumor, decreases its recurrence, and minimizes treatment complications.  

            Aggressive malignant brain tumors (gliomas) kill within two years. Conventional treatment involves surgical removal, followed by radiation and chemotherapeutic agents. This regimen has only slightly prolonged life, however, and produces serious side effects.” Immunotherapies” represent a new and potentially more effective approach. They employ strategies to strengthen a patient’s own immune response. The Baylor investigators recently developed a promising immunotherapy and now want to improve upon it. They took immune T cells from patients’ blood and genetically modified the immune T cells to recognize, attach to, and kill a specific antigen (a peptide) called, HER2 on the tumor cells’ surface. They tested the therapy in mice implanted with the patient’s tumor cells. Using cellular luminescence imaging, they found that the modified T cells killed most of the glioma cells and also glioma stem cells. But, the tumor recurred in 50 percent of the mice. The immunotherapy is now being tested in patients with glioma. The investigators hypothesize, however, that further genetic modification of T cells will improve the efficacy of their modified cell therapy approach.

They plan to undertake three aims to test this hypothesis in a glioma cell line grown in tissue culture and in mice implanted with human glioma cells. First they will see whether modifying the immune T cells to target not only HER2 but also two other antigens prevalent on the tumor cells’ surface increases the T cells’ activation, proliferation, and anti-tumor activity. Second, because tumor cells essentially suffocate immune T cell activity by reducing oxygen levels, the investigators will genetically modify the immune T cells to operate in a low oxygen environment. Third, they will further modify immune T cells to work synergistically with a chemotherapeutic agent called temozolomide (TMZ) which helps to delay tumor recurrence. Ordinarily, TMZ is toxic to immune T cells, but modifying the immune T cells to resist damage from TMZ may enable the two therapies to kill more tumor cells and prevent the tumor’s recurrence.

Significance: If this genetically modified immunotherapy effectively kills glioma cells and prevents tumor recurrence in the animal model, it would lead immediately to clinical trials in patients.

INVESTIGATOR BIOGRAPHIES

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Stephen Gottschalk, M.D.

Dr. Gottschalk received his MD in 1992 from the Georg-August University in Göttingen, Germany, followed by a research fellowship in Cell Biology at Baylor College of Medicine, Houston, Texas.  He received residency training in pediatrics at Baylor College of Medicine, where he also completed a hematology/oncology fellowship. He is currently an Associate Professor in the Department of Pediatrics and Immunology at Baylor College of Medicine and a member of the Center for Cell and Gene Therapy, Texas Children's Cancer Center, and the L Duncan Cancer Center. Dr. Gottschalk's research interest is in adoptive immunotherapies with antigen-specific and genetically modified T cells. His research is focused on Epstein-Barr virus associated malignancies such as Hodgkin’s disease and nasopharyngeal carcinoma, and HER2-positive malignancies including brain tumors and sarcomas. His group is currently conducting Phase I/II clinical studies using antigen-specific T cells and in the laboratory is investigating strategies on how to improve T-cell therapies for cancer.