Southeastern Brain Tumors Neuro-Oncology Trainee Award: Intra-Tumoral Convection Enhanced Delivery of an Immunostimulatory Agent Extends Survival in GBM Model

Saturday, May 4, 2024

2:09 PM – 2:13 PM CT

Location: S401ab

Presenting Author(s)

Nicholas B. Dadario, BS (he/him/his)

Medical Student
Columbia University Department of Neurosurgery
New York, NY, US

Co-Author(s)

Michael G. Argenziano, MD (he/him/his)

Resident
Department of Neurological Surgery, Columbia University Irving Medical Center
New York, New York, United States
JB

Jeffrey N. Bruce, MD

Principle Investigator, Neurosurgeon
Department of Neurological Surgery, Columbia University Irving Medical Center
New York, New York, United States
PC

Peter Canoll, MD, PhD

Principle Investigator, Neuropathologist
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, United States
AD

Ana Paula Delgado, PhD

Research Scientist
Department of Systems Biology, Columbia University Irving Medical Center, United States
AD

Athanassios Dovas, PhD

Research Scientist
Department of Neurological Surgery, Columbia University Irving Medical Center, United States
JF

Julia L. Furnari, BS

Research Technician
Department of Neurological Surgery, Columbia University Irving Medical Center, United States
NH

Nelson Humala, n/a

Senior Laboratory Manager
Department of Neurological Surgery, Columbia University Irving Medical Center, United States
NI

Nkechime Ifediora, BS

Doctoral Student
Department of Neurological Surgery, Columbia University Irving Medical Center, United States
CK

Corina P. Kotidis, BS

Research Technician
Department of Neurological Surgery, Columbia University Irving Medical Center, United States
LL

Liang Lei, PhD

Research Scientist
Department of Neurological Surgery, Columbia University Irving Medical Center, United States
AM

Aayushi Mahajan, n/a

Senior Laboratory Manager
Department of Neurological Surgery, Columbia University Irving Medical Center, United States
AM

Angeliki Mela, PhD

Research Scientist
Department of Neurological Surgery, Columbia University Irving Medical Center, United States
PS

Peter A. Sims, PhD

Professor
Department of Systems Biology, Columbia University Irving Medical Center, United States
Colin P. Sperring, BS

Medical Student
Department of Neurological Surgery, Columbia University Irving Medical Center
New York, New York, United States
Damian E. Teasley, BS

Medical Student
Department of Neurological Surgery, Columbia University Irving Medical Center
New York, NY, US
NW

Nathan J. Winans, MD

Resident
Department of Neurological Surgery, Columbia University Irving Medical Center
New York, New York, United States
WZ

Wenting Zhao, PhD

Research Scientist
Department of Systems Biology, Columbia University Irving Medical Center, United States

Disclosure(s):

Nicholas B. Dadario, BS: No financial relationships to disclose

Damian E. Teasley, BS: No financial relationships to disclose

Introduction: While immunotherapy has demonstrated significant clinical impact in many cancer types, it has failed to be efficacious for glioblastoma (GBM), given the poor immunogenicity of the tumor microenvironment (TME). Convection-enhanced delivery (CED) can deliver high doses of immune modulators directly to the brain parenchyma while avoiding the systemic toxicity associated with inflammatory drugs. Here, we report that the delivery of a stimulator of interferon genes (STING) agonist by CED enhances immunogenicity and survival in GBM model.

Methods: We investigated the effects of CED of STING agonist treatment on survival and the immunological tumor microenvironment through single-cell RNA (scRNA) sequencing and histological analyses in a preclinical syngeneic mouse model. Additionally, we assessed the transcriptional response of acute human GBM slices in response to a STING agonist by scRNA sequencing.

Results: Seven-day treatment with CED of STING agonist (ADU-S100) produced a significant survival advantage in glioma-bearing mice (p < 0.001). Tissue-based assessment of treatment response demonstrated reduced glioma growth and increased myeloid cell infiltration. Single-cell transcriptional responses showed broad activation of STING-associated pathways in mouse treated tumors. Similar responses were observed in STING treated acute slices derived from human GBM specimens. Temporal analyses of varying immunomodulation treatment schedules demonstrates time-dependent changes in the TME.

Conclusion : We demonstrate the preclinical efficacy of a CED-delivered STING agonist in a GBM model and observe prolonged survival along with significant immune microenvironment remodeling. Robust STING pathway activation was found across cell types in mouse tumors and human GBM slices supporting the clinical utilization of this therapy. Temporally varying immunomodulation treatment schedules provides a potentially novel way to alter the GBM immune landscape while slowing tumor growth. CED provides us a new treatment paradigm to locally modulate the glioma immune microenvironment in a controlled fashion.