Related Experiment Video
Updated: Jun 16, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Oncolytic HSV-IL27 expression improves CD8 T cell function and therapeutic activity in syngeneic glioma models
Alexia Martin1,2, Jack Hedberg1,2, Ilse Aguirre-Hernandez1,2
1Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
Background:
Malignant gliomas (MG) are the most common primary brain malignancies and are considered universally fatal. Oncolytic HSVs (oHSV) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting anti-tumor immunity, and providing local delivery of immune-activating transgenes. IL-27 is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T cell (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve anti-glioma therapeutic activity.
Methods:
We developed an oncolytic herpes simplex virus (oHSV) that expresses IL-27 (C027). The anti-glioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed in vivo cell specific depletion and IL-27 blockade alongside in vitro T cell stimulation assays. Local and systemic antitumor memory was evaluated by both orthotopic and flank tumor rechallenge of C027-treated long-term survivors.
Results:
C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector cytotoxic T lymphocytes (CTL) and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit in vivo and IL-27 enhanced CTL function in vitro. C027-treated mice that survived their initial tumors had local and systemic anti-glioma memory rejecting tumors on rechallenge.
Conclusions:
Our findings demonstrate that IL-27 expression by oHSV significantly improves anti-glioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for malignant gliomas.
Insights
This study developed an oncolytic herpes simplex virus (oHSV) expressing IL-27, which significantly improved survival in malignant glioma models. The therapy enhances cytotoxic T lymphocyte (CTL) function and induces durable anti-glioma immune memory.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Virology
Background:
- Malignant gliomas (MG) are aggressive brain tumors with poor prognoses, often resistant to current treatments.
- Oncolytic herpes simplex viruses (oHSV) show promise as immunotherapeutics for MG, enabling targeted cancer cell lysis and transgene delivery.
- Interleukin-27 (IL-27) is a cytokine with potential to boost anti-tumor T cell responses and offer neuroprotection.
Purpose of the Study:
- To engineer and evaluate an oHSV expressing IL-27 (C027) for enhanced anti-glioma efficacy.
- To investigate the mechanisms underlying C027's therapeutic effects, focusing on T cell responses.
- To assess the induction of long-term anti-tumor immunity following C027 treatment.
Main Methods:
- Development of C027, an oHSV engineered to express IL-27.
- Testing C027 efficacy in three syngeneic orthotopic glioma models (CT-2A, SB28, KR158).
- Analysis of tumor-infiltrating and systemic immune cells using spectral flow cytometry.
- In vivo cell depletion and IL-27 blockade studies to elucidate mechanisms.
- In vitro T cell stimulation assays to confirm IL-27's effect on cytotoxic T lymphocytes (CTLs).
- Evaluation of anti-tumor memory via tumor rechallenge experiments.
Main Results:
- C027 significantly prolonged survival across all tested glioma models.
- Treatment with C027 increased intratumoral multifunctional effector CTLs and systemic T cell populations.
- Both CD8 T cells and IL-27 were essential for the survival benefit, with IL-27 enhancing CTL function in vitro.
- C027-treated survivors developed robust local and systemic anti-glioma immune memory, rejecting subsequent tumor challenges.
Conclusions:
- IL-27-expressing oHSV (C027) represents a potent immunotherapeutic strategy for malignant gliomas.
- C027 enhances anti-tumor immunity by boosting CTL function and inducing durable immune memory, dependent on CD8 T cells and IL-27.
- This approach holds significant potential for improving therapeutic outcomes in patients with malignant gliomas.
