On November 21, 2016 Mustang Bio, Inc. ("Mustang"), a Fortress Biotech (NASDAQ: FBIO) Company, reported that Phase 1 clinical data and pre‐clinical data on its MB‐101 (IL13Rα2‐specific Chimeric Antigen Receptor–engineered CAR T cells (CAR T cells)) product candidate in development for the treatment of glioblastoma were presented by investigators from the City of Hope ("COH") in oral sessions at the 21st Annual Meeting and Education Day of the Society for Neuro‐Oncology ("SNO") in Scottsdale, AZ (Press release, Fortress Biotech, NOV 21, 2016, View Source;FID=1500093635 [SID1234516780]).
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Dr. Lindsay A. Rosenwald, Fortress Biotech’s Chairman, President and Chief Executive Officer commented, "CAR T cell therapy has shown promise in treating certain forms of hematological cancers. However, translating that activity into solid tumors has been challenging to date. The clinical data presented at SNO by the investigators from COH suggest MB‐101 is safe and well‐tolerated, and capable of eliciting a potent anti‐tumor response in patients with glioblastoma (GBM), a disease that is almost universally fatal. We believe this is the first evidence of activity of CAR T cells in the treatment of GBM. We are very encouraged by the early evidence of anti‐tumor activity with MB‐101 with five of seven post‐surgical resection patients showing stable disease for >8 weeks and, in particular, one patient showing complete response for 7.5 months. Interestingly, this patient was the only patient of the seven to receive, on a compassionate use basis, the dual delivery of CAR T cells by both intracavitary and via intraventricular administration, which provides systemic CNS delivery of the CAR T cells. We look forward to continuing to advance MB‐101 in Phase 1 studies and further exploring the dual delivery approach beyond this single patient experience."
The following summarizes the oral presentations on November 18, 2016 at SNO:
Phase I Study of Chimeric Antigen Receptor–Engineered T cells Targeting IL13Rα2 for the Treatment of Glioblastoma
Presenter: Christine E. Brown, PhD, Heritage Provider Network Professor of Immunotherapy, Associate Director, T Cell Therapeutics Research Laboratory, City of Hope National Medical Center/Beckman Research Institute
The Phase I study presented showed early clinical data evaluating IL13Rα2‐targeted CAR T cell therapy for the treatment of glioblastoma. On this study, patients are treated on a four‐week therapeutic regimen consisting of three weekly intracranial infusions of IL13Rα2‐specific CAR T cells followed by one rest week for toxicity and disease assessment. To date, seven patients have been treated with local intracavitary delivery of the CAR T cells following surgical resection.
Some highlights from the presentation included:
The treatment was well‐tolerated in all patients treated – with No DLTs or therapy‐related SAEs
No grade 3 or higher toxicities attributed to the therapy were observed
No CRS or Neurotoxicity was observed
Only grade < 2 fevers, headaches, myalgia, chills
Best Response: 2 PD, 4 SD for >8‐weeks, 1 SD CR following intraventricular CAR T therapy for 7.5 months
Development of murine IL13Rα2‐targeted CAR T cells (mIL13BBζ) for assessment of CAR T cell therapy in syngeneic glioma models
Presenter: Darya Alizadeh, PhD, City of Hope National Medical Center/Beckman Research Institute
The pre‐clinical research program presented discussed a murine IL13Rα2‐targeted CAR T cell platform that was developed to evaluate parameters that impact the efficacy of CAR T cell therapy. Overall, the development of mIL13BBζ CAR T cells and its applications will allow researchers to assess factors that may impact the efficacy of CAR T cells and provide invaluable information critical for combination therapies and clinical trial design. These studies may also provide important insights for improving therapeutic outcomes for patients with glioblastoma.
About Glioblastoma multiforme (GBM)
Glioblastomas (GBM) are tumors that arise from astrocytes cells that make up the supportive tissue of the brain. These tumors are usually highly malignant (cancerous) because the cellsreproduce quickly and they are supported by a large network of blood vessels. GBM isthe most common brain and central nervoussystem (CNS) malignancy, accounting for 15.1 percent of all primary brain tumors and 55.1 percent of all gliomas. There will be an estimated 12,120 new glioblastoma casesin the U.S. in 2016. Malignant brain tumors are the most common cause of cancer‐ related deaths in adolescents and young adults aged 15‐39, and the most common cancer occurring among 15‐19 year olds in the U.S. (Brain Tumor Statistics. American Brain Tumor Association. December 2015). While GBM is a rare disease (2‐3 cases per 100,000 person life years in the U.S. and EU), it is quite lethal with five‐year survival rates historically lessthan 10 percent. Chemotherapy with temozolomide and radiation are shown to extend mean survival from approximately 12 to 15 months, while surgery remains the standard of care. GBM remains difficult to treat due to the inherent resistance of the tumor to conventional therapies. Treatment is further complicated by the susceptibility of the brain to damage, difficulty of the brain to repair itself and limitation to drugs crossing the blood brain barrier. Immunotherapy approaches targeting brain tumors offer promise over conventional treatments.
About MB‐101 (IL13Rα2‐specific CAR T cells)
IL13Rα2 is an attractive target for CAR T therapy as it has limited expression in normal tissue but is over‐expressed on the surface of the majority of GBM. CAR T cells are designed to express a membrane‐tethered IL‐13 receptor ligand (IL‐13) incorporating a single point mutation that provides high affinity for IL13Rα2 and reduces binding to IL13Rα1 in order to reduce healthy tissue targeting.
Mustang is developing an optimized CAR T product incorporating enhancements in CAR design and T cell engineering to improve antitumor potency and T cell persistence. We include a second‐generation hinge optimized CAR containing mutations in the IgG4 linker to reduce off‐target Fc interactions, as well as the 41BB (CD137) co‐stimulatory signaling domain forimproved persistence of CAR T cells, and extracellular domain of CD19 as a selection/safety marker. In order to further improve persistence, central memory T cells are enriched and genetically engineered using a manufacturing process that limits ex vivo expansion in order to reduce T cell exhaustion and maintain a memory T cell phenotype.