Research Perspectives:

Immune-stimulatory (TK/Flt3L) gene therapy opens the door to a promising new treatment strategy against brainstem gliomas

Syed M. Faisal, Flor M. Mendez, Fernando Nunez, Maria G. Castro _ and Pedro R. Lowenstein _

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Oncotarget. 2020; 11:4607-4612. https://doi.org/10.18632/oncotarget.27834

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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

Correspondence to:

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

Copyright: © 2020 Faisal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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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