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Engineered allogeneic stem cells orchestrate T lymphocyte-driven immunotherapy in immunosuppressive leptomeningeal
Nobuhiko Kanaya1,2, Waleed Seddiq1,2, Kok-Siong Chen1,2
1Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Background:
Immune checkpoint inhibitors have shown clinical benefit in non-small cell lung cancer-derived brain metastasis, but their efficacy in lung-to-leptomeningeal brain metastasis remains poor.
Methods:
A pair-matched RNA expression dataset of patients with non-small cell lung cancer and brain metastases was analyzed to identify brain metastasis-specific suppressive tumor microenvironment features. Next, we created immune-competent lung-to-leptomeningeal brain metastasis mouse models that mimic clinical lung-to-leptomeningeal brain metastasis. We evaluated the efficacy of intrathecal delivery of allogeneic stem cells engineered to release single-chain variable part of the antigen-binding fragment (scFv) anti-programmed cell death 1 protein (PD-1). To enhance tumor cell killing and subsequent modulation of the immune tumor microenvironment, we explored the therapeutic activity of dual stem cells releasing oncolytic herpes simplex virus (oHSV) and scFvPD-1 and profiled immune and metabolic consequences.
Results:
RNA sequencing analysis of primary non-small cell lung cancer and brain metastases revealed an immune-suppressive tumor microenvironment with reduced immune cells and increased PD-1-positive T cells in brain metastases. We showed decreased immune cells and increased PD-1-positive T cells in the tumor microenvironment of lung-to-leptomeningeal brain metastases compared with primary non-small cell lung cancer in lung-to-leptomeningeal brain metastasis mouse models. Next, we showed that locoregional intrathecal treatment with stem cells releasing scFvPD-1 but not conventional systemic injection of anti-PD-1 antibodies suppressed tumor growth and improved survival in our immune-competent lung-to-leptomeningeal brain metastasis models. Furthermore, dual-stem cells releasing oHSV and scFvPD-1 enhanced therapeutic outcomes by inducing oHSV-mediated immunogenic cell death, activating antitumor T-cell signaling, and disrupting oxidative phosphorylation, all of which sensitized tumors to cisplatin.
Conclusion:
Locoregional delivery of dual-stem cells releasing oHSV/scFvPD-1 effectively targets the immune-suppressive tumor microenvironment in lung-to-leptomeningeal brain metastasis, providing a promising strategy for treating lung-to-leptomeningeal brain metastases.
Insights
New stem cell therapy shows promise for treating leptomeningeal brain metastases from lung cancer. This approach targets the immune-suppressive tumor microenvironment, improving outcomes where other treatments fail.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Metastasis
Background:
- Immune checkpoint inhibitors (ICIs) show limited efficacy in lung-to-leptomeningeal brain metastasis.
- Lung cancer brain metastases often present an immune-suppressive tumor microenvironment.
Purpose of the Study:
- To investigate a novel locoregional therapy for lung-to-leptomeningeal brain metastasis.
- To evaluate the efficacy of engineered stem cells delivering anti-PD-1 agents and oncolytic viruses.
Main Methods:
- Analysis of RNA expression in non-small cell lung cancer brain metastases.
- Development of immune-competent mouse models for lung-to-leptomeningeal brain metastasis.
- Intrathecal delivery of stem cells engineered to release scFvPD-1 and/or oncolytic herpes simplex virus (oHSV).
Main Results:
- Brain metastases exhibit an immune-suppressive microenvironment with increased PD-1 expression.
- Locoregional intrathecal stem cell therapy with scFvPD-1 improved survival in mouse models.
- Dual-stem cells releasing oHSV and scFvPD-1 demonstrated enhanced therapeutic effects, inducing immunogenic cell death and sensitizing tumors to cisplatin.
Conclusions:
- Locoregional delivery of dual-stem cells (oHSV/scFvPD-1) is a promising strategy for lung-to-leptomeningeal brain metastasis.
- This therapy effectively modulates the immune-suppressive tumor microenvironment.
- The approach offers a potential new treatment avenue for refractory brain metastases.
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