DEVELOPING IL13Rα2 SPECIFIC CHIMERIC ANTIGEN RECEPTOR T CELLS FOR GLIOBLASTOMA
The outstanding efficacy of T cells modified to express chimeric antigen receptors (CAR) for hematological malignancies promises hope that they can be programmed to target and kill solid tumors. As the current standard of care for glioblastoma (GBM) only extends patient survival minimally, CARs can provide an exciting new option for the treatment of this incurable disease.
We have generated a CAR expressing the specific single chain antibody (scFv47) against interleukin-13 receptor α 2, (IL13Rα2), a tumor associated antigen expressed highly by glioma tissues. In our recent studies, we have demonstrated that scFv47 CAR T cells are efficacious in killing human glioma cells in vitro and in vivo in athymic mice.1 Understanding how these CAR T cells behave in the GBM microenvironment and interact with the host immune system is critical for the development of successful CAR T cell therapies, and is the current focus of our investigations.
1. Krenciute G, Krebs S, Torres D, Wu MF, Liu H, Dotti G, et al. Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Ralpha2-positive Glioma. Mol Ther. 2016; 24(2): 354-63. PMID: 26514825; PMCID: PMCPMC4817815
DEVELOPING NON-INVASIVE APPROACH FOR TREATMENT OF BRAIN TUMORS USING STEM CELLS AS THERAPEUTIC CARRIERS
The effective drug delivery to brain tumors is challenging due to a lack of non-invasive methods of local delivery, and the blood-brain barrier limiting systemic delivery. Intranasal delivery of therapeutics to the brain overcomes these challenges. Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) possess natural tropism to brain tumors. Our group was a first to show that therapeutic MSCs and NSCs when delivered to the nasal cavity not only travel to intracranial tumors in mice, but also prolong the animals' survival.2, 3 Further validation of intranasal delivery of various therapeutics to the brain is of particular interest in the context of GBM. We also assess the viability of intranasal delivery of stem cells-based therapeutics for targeting a high-grade pediatric brainstem glioma, DIPG.
2. Balyasnikova IV, Prasol MS, Ferguson SD, Han Y, Ahmed AU, Gutova M, et al. Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors. Mol Ther. 2014; 22(1): 140-8. PMID: 24002694; PMCID: PMCPMC3978787
3. Dey M, Yu D, Kanojia D, Li G, Sukhanova M, Spencer DA, et al. Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma. Stem Cell Reports. 2016; 7(3): 471-82. PMID: 27594591; PMCID: PMCPMC5032402
DEVELOPING NON-INVASIVE IMAGING APPROACHES FOR TRACKING MIGRATION OF STEM CELLS TO BRAIN MALIGNANCIES
There is great interest in utilizing adult stem cells as therapeutic carriers for the treatment of brain malignancies due to their ability to migrate, carry therapeutic payload, and regenerate. Modalities for tracking the fate of stem cells are critical for the development of efficient stem cell-based therapies for glioma and other brain malignancies. However, tracking stem cells in the CNS is far from a trivial task. In our studies we often utilize MRI for detction of iron-labeled transplanted stem cells in the brain. Recently, we have reported that a nano-platform can be utilized to label NSCs with a SPECT radiotracer, 111Indium (111In). Mesoporous silica nanoparticles (MSN) were conjugated with 111In, and were used to label NSCs in non-toxic amounts. We demonstrated that the migration of radiolabeled stem cells towards intracranial glioblastoma xenografts can be tracked with SPECT imaging in the brain after both local and systemic injections in an experimental animal model of GBM.4 Our study suggests that this nanoparticle-based, non-invasive, in vivo imaging platform could be helpful in further advancing stem cells in clinical practice by improving our understanding of their behaviors in pre-clinical models of glioblastoma and other brain malignancies.
4. Cheng SH, Yu D, Tsai HM, Morshed RA, Kanojia D, Lo LW, et al. Dynamic In Vivo SPECT Imaging of Neural Stem Cells Functionalized with Radiolabeled Nanoparticles for Tracking of Glioblastoma. J Nucl Med. 2016; 57(2): 279-84. PMID: 26564318
Irina V Balyasnikova, PhD