Local Delivery of Topotecan Induces Immunogenic Cell Death and Associated Myeloid Response in GBM

Saturday, May 4, 2024

2:15 PM – 2:17 PM CT

Location: Booth 745 Neuro Spotlight

Presenting Author(s)

Damian E. Teasley, BS

Medical Student
Department of Neurological Surgery, Columbia University Irving Medical Center
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
Matei A. Banu, MD (he/him/his)

Neurosurgery Fellow
MD Anderson
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
Nicholas B. Dadario, BS (he/him/his)

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

Melanie H. Kristt, BS

Medical Student
Columbia Univ. Coll Phys & Surg - - New York, NY, 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
BP

Brianna Pereira, BS

Medical Student
Columbia University College of Physicians & Surgeons, 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
Anthony J. Tang, BBA BSA

Medical Student
Columbia University Vagelos College of Physicians and Surgeons
New York, NY, US
Damian E. Teasley, BS

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

Submitter(s)

Damian E. Teasley, BS

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

Co-Author(s)

JT

John F. Tuddenham, BS

Medical Student
Columbia University College of Physians & Surgeons, United States
PW

Paige E Warner, BS

Medical Student
Columbia University College of Physicians & Surgeons, United States
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: Our recently published phase 1b clinical trial of treating Glioblastoma (GBM) by delivery of Topotecan (TPT) via Convection Enhanced Delivery (CED) demonstrated significant reduction of proliferating tumor cells. Furthermore, post-treatment tissue analysis from this trial also demonstrated a robust inflammatory response. We hypothesized that TPT can induce an immunogenic cell death (ICD) response in GBM by increasing phagocytosis of dying glioma cells by local myeloid populations and ultimately activating these local immune cells towards an anti-tumor phenotype.

Methods: To characterize the induction of ICD in glioma cells, we treated tumor cells with TPT in vitro and measured surface staining of the canonical pro-phagocytic marker calreticulin (CALR) via flow cytometry. To characterize the effects of TPT-induced ICD on myeloid cells, we co-cultured myeloid cells with TPT-treated or untreated glioma cells and performed ELISA and phagocytosis assays. We also treated slice cultures generated from surgical samples of GBM with TPT and performed single-cell RNA sequencing to assess the transcriptional alterations in myeloid cell in the tumor microenvironment.

Results: TPT treatment induces ICD in glioma cells with translocation of CALR to the cellular membrane. In turn, TPT treatment of tumor cells induces significant phagocytosis of tumor cells by myeloid cells and subsequent release of pro-inflammatory cytokines. In patient-derived slice cultures, treatment with TPT induced transcriptional alterations in myeloid cells associated with migration, phagocytosis, and anti-tumor cytokine production.

Conclusion : In addition to its role in targeting proliferative tumor cells via cytotoxic topoisomerase I inhibition, TPT promotes ICD in glioma cells as well as phagocytosis and pro-inflammatory cytokine release by the surrounding myeloid populations. These results highlight important immunogenic properties of TPT treatment and its role in promoting an anti-tumor myeloid phenotype. We propose using local delivery of TPT with other immunomodulatory drugs as part of a combinatorial therapeutic approach to treat GBM.