(1) Kanaya N (2) Seddiq W (3) Chen KS (4) Kajiwara Y (5) Moreno Lama L (6) Borges P (7) Kuroda S (8) Wakimoto H (9) Shah K

Journal of the National Cancer Institute

BACKGROUND: Immune-checkpoint inhibitors have shown clinical benefit in non-small cell lung cancer (NSCLC) derived brain metastasis (BM), however, their efficacy in lung to leptomeningeal brain metastasis (LLBM) remains poor. METHODS: A paired matched RNA expression dataset of patients with NSCLCs and BMs was analyzed to idenfiy BM specific suppressive tumor microenvironment (TME) features. Next, we created immune-competent LLBM mouse models that mimic clinical LLBM. We evaluated the efficacy of intrathecal (IT) delivery of allogeneic stem cells (SCs) engineered to release single-chain variable fragment anti-PD-1 (scFvPD-1). To enhance tumor cell killing and subsequent modulation of the immune TME, we explored the therapeutic activity of dual SCs releasing oncolytic herpes simplex virus (oHSV) and scFvPD-1 and profiled immune and metabolic consequences. RESULTS: RNA sequencing analysis of primary NSCLCs and BMs revealed an immune-suppressive TME with reduced immune cells and increased PD-1+ T cells in BMs. We showed significantly decreased immune cells and increased PD-1+ T cells in the TME of LLBM compared to primary NSCLC tumors in LLBM mouse tumor models. Next, we showed that locoregional IT treatment with SC releasing scFvPD-1, but not conventional systemic injection of anti-PD-1 antibody, suppressed tumor growth and improved survival in our immune-competent LLBM models. Furthermore, dual SCs releasing oHSV and scFvPD-1 (SC-oHSV/scFvPD-1) enhanced therapeutic outcomes by inducing oHSV-mediated immunogenic cell death, activating anti-tumor T cell signaling, and disrupting oxidative phosphorylation, which sensitized tumors to cisplatin. CONCLUSION: Locoregional delivery of SC-oHSV/scFvPD-1 effectively targets the immune-suppressive TME in LLBM, providing a promising strategy for treating LLBM.

Author Info: (1) Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Brigh

Author Info: (1) Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. (2) Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. (3) Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. (4) Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. (5) Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. (6) Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. (7) Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, 700-8558, Japan. (8) Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA. (9) Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA. Harvard Stem Cell Institute, Harvard University, Cambridge, 02138, Massachusetts, USA.

Citation: J Natl Cancer Inst 2025 Jan 22 Epub01/22/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39837345

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