Immune-stimulatory (TK/Flt3L) gene therapy opens the door to a promising new treatment strategy against brainstem gliomas
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Syed M. Faisal1,2, Flor M. Mendez1,2, Fernando Nunez1,2, Maria G. Castro1,2 and Pedro R. Lowenstein1,2
1 Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
2 Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
|Maria G. Castro,||email:||[email protected]|
|Pedro R. Lowenstein,||email:||[email protected]|
Keywords: immunotherapy; gene therapy; thymidine kinase; Flt3L; DIPG
Received: November 11, 2020 Accepted: November 18, 2020 Published: December 15, 2020
Diffuse intrinsic pontine glioma (DIPG) is a rare brainstem tumor which carries a dismal prognosis. To date. there are no effective treatments for DIPG. Transcriptomic studies have shown that DIPGs have a distinct profile compared to hemispheric high-grade pediatric gliomas. These specific genomic features coupled with the younger median age group suggest that DIPG is of developmental origin. There is a major unmet need for novel effective therapeutic approaches for DIPG. Clinical and preclinical studies have expanded our understanding of the molecular pathways in this deadly disease. We have developed a genetically engineered brainstem glioma model harboring the recurrent DIPG mutation, activin A receptor type I (ACVR1)-G328V (mACVR1) using the sleeping beauty transposon system. DIPG neurospheres isolated from the genetically engineered mouse model were implanted into the pons of immune-competent mice to assess the therapeutic efficacy and toxicity of immunostimulatory gene therapy using adenoviruses expressing thymidine kinase (TK) and fms-like tyrosine kinase 3 ligand (Flt3L). Immunostimulatory adenoviral-mediated delivery of TK/Flt3L in mice bearing brainstem gliomas resulted in antitumor immunity, recruitment of antitumor-specific T cells, and improved median survival by stimulating the host antitumor immune response. Therapeutic efficacy of the immunostimulatory gene therapy strategy will be tested in the clinical arena in a Phase I clinical trial. We also discuss immunotherapeutic interventions currently being implemented in DIPG patients and discuss the profound therapeutic implications of immunotherapy for this patient populations.
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