Faculty, Staff and Student Publications

Language

English

Publication Date

11-4-2024

Journal

Neuro-Oncology

DOI

10.1093/neuonc/noae135

PMID

39028616

PMCID

PMC11534315

PubMedCentral® Posted Date

7-19-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers.

Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs).

Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge.

Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).

Keywords

Animals, Doxorubicin, Mice, Humans, Brain Neoplasms, Blood-Brain Barrier, Programmed Cell Death 1 Receptor, Immunotherapy, CTLA-4 Antigen, Immune Checkpoint Inhibitors, Glioma, Immunoglobulin Fc Fragments, Tumor Microenvironment, Female, Combined Modality Therapy, Mice, Inbred C57BL, Glioblastoma, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols, BBB, doxorubicin, Fc-enhanced anti-CTLA-4, glioblastoma, immunotherapy

Published Open-Access

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