Introduction: Glioblastoma (GBM) is a fatal tumor with a median survival of only 14 months. In a first-in-human pilot safety trial, we previously demonstrated that autologous anti-IL13Ra chimeric antigen receptor (CAR) T cell therapy was safe and demonstrated bioactivity in three patients with recurrent GBM. The clinical utility of this strategy, however, may be hampered by the autologous T-cell manufacturing timeframe and the use of glucocorticoids that induce T-cell apoptosis. To overcome these limitations, we generated "off the shelf" allogeneic CD8 T-cells (SB-313-T) that (1) were steroid resistant through the disruption of the glucocorticoid receptor (GR) gene by Zinc Finger Nucleases (ZFNs); (2) expressed the IL13-zetakine to target GBM; and (3) encoded an HSV thymidine kinase reporter/suicide gene for in vivo imaging.
Methods: Six subjects with recurrent GBM receiving steroids were enrolled. After insertion of a Rickham cathether, SB-313 (108 cells) was infused into the tumor on days 1, 3, 8, and 10. In addition, a total of 35,000 IU of IL-2 was infused into the tumor in divided doses on days 2-5 and 8-12. MRI, 18FDG, and 18FHBG PETs were performed at baseline and then every 2 weeks.
Results: Local intratumoral injection of SB-313 CAR T cells and IL-2 was generally safe and well tolerated. Two unrelated SAEs (dehydration and stroke) occurred in one subject. Antitumor activity was demonstrated by necrosis (by MRI/MRS) and decreased metabolic activity (by 18FDG PET) in 4 of the 6 treated subjects. In another subject, who underwent surgical resection ~7 weeks after T-cell infusion, histologic examination revealed ~70% necrosis in the SB-313-T injected tumor. By comparison, only ~20% necrosis was observed in an adjacent uninjected tumor. Median survival was 76 days but 2 subjects survived for 205 and 337 days.
Conclusions: Intratumoral infusion of SB-313-T and IL-2 in subjects with recurrent GBM is generally safe and well tolerated. SB-313-T cells demonstrated resistance to steroid evidenced by T-cell migration and proliferation in the tumor following infusion. Antitumor activity was observed in 4 of the 6 treated patients. These preliminary data are encouraging and support further development of this therapeutic approach.
Patient Care: Potentially lead to the development of a new therapy for glioblastoma.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the mechanism of CAR T-Cell therapy for glioblastoma, 2) Identify limitations of cell delivery technologies for glioma therapy.