EXTH-34 - Local delivery of an IL-15 superagonist using a replicating retrovirus syngerizes with temozolomide to increase lymphocyte infiltration and survival in two poorly immunogenic glioblastoma mouse models

Sunday, November 19, 2023

10:55 AM – 11:05 AM PT

Location: Room 109-110

Oral Abstract Presenter(s)

Alexander F. Haddad

Department of Neurosurgery & Division of Neuro-Oncology, University of San Francisco
San Francisco, California, United States

Author(s)

JS

Jordan Spatz

UCSF
San Francisco, California, United States
AS

Atul Saha

UCSF
San Francisco, California, United States
MM

Megan L. Montoya

UCSF
San Francisco, California, United States
Sara A. Collins

University of California, San Francisco
San Francisco, California, United States
SG

Sabraj Gill

University of California San Fransisco
San Fransisco, California, United States
EW

Elaina J. Wang

UCSF
San Francisco, Rhode Island, United States
PC

Pavlina Chuntova

Department of Neurological Surgery, University of California San Francisco
San Francisco, California, United States
DS

Diana Salha

UCSF
San Francisco, California, United States
Jacob S. Young

Department of Neurosurgery & Division of Neuro-Oncology, University of California San Francisco
San Francisco, California, United States
NK

Noriyuki Kasahara

University of California, San Francisco
San Francisco, California, United States
Manish K. Aghi

University of California, San Francisco
San Francisco, California, United States

Glioblastoma (GBM) leads to systemic and local immunosuppression and immunotherapies have had limited clinical success. We evaluated the treatment efficacy of RLI (receptor-linker-IL-15), a superagonist of T-cell activator IL-15, delivered to tumor cells using a tumor-selective retroviral replicating vector (RRV) in the syngeneic murine SB28 and Tu2449 GBM models, which are poorly immunogenic with low-mutational burden and known resistance to immunotherapy, similar to human GBM. RRV-RLI replicated and spread in cultured SB28 murine GBM cells with robust production of functional RLI (165.4 ± 5.3 ng/mL). Stereotactic injection of RRV-RLI into pre-established intracerebral Tu2449 tumors led to complete eradication of intracerebral tumors with long term survival (median not reached) in > 85% of treated mice vs. median survival of 12.5 days in control mice (p=0.001). Treated mice demonstrated significantly increased CD8 T cell infiltration. These mice also demonstrated immunologic memory to intracranial rechallenge. In SB28, RRV-RLI delivery into intracerebral tumors reduced tumor growth on bioluminescence imaging, and increased median survival compared to controls (55 vs. 19 days, p=0.002), with long-term survival in 12% of treated mice. Combining RRV-RLI treatment with systemically administered temozolomide (TMZ) in the SB28 model provided long term survival (median not reached) in >60% of treated mice. Immunologic analysis of treated tumors revealed a significant increase in CD8 T cell (2.1% to 20.5% of CD45 cells) and Natural Killer cell (1.4% to 9.6% of CD45 cells )infiltration in RLI-RRV+TMZ mice vs. PBS+TMZ mice. RLI was not detected in the blood of treated mice, and tumor-localized RRV-RLI gene delivery showed no adverse systemic immune effects. In summary, RRV-mediated RLI immunotherapy results in immunostimulatory changes that are further potentiated by systemically administered temozolomide. This tumor-localized gene therapy has the potential to synergize with standard of care treatment to reverse the immunosuppressed GBM tumor microenvironment and provide a significant treatment benefit.