Engineered allogeneic stem cells orchestrate T lymphocyte driven immunotherapy in immunosuppressive leptomeningeal brain metastasis

Nobuhiko Kanaya; Waleed Seddiq; Kok-Siong Chen; Yoshinori Kajiwara; Lucia Moreno Lama; Paulo Borges; Shinji Kuroda; Hiroaki Wakimoto; Khalid Shah

doi:10.1093/jnci/djaf006

Engineered allogeneic stem cells orchestrate T lymphocyte driven immunotherapy in immunosuppressive leptomeningeal brain metastasis

J Natl Cancer Inst. 2025 Jan 22:djaf006. doi: 10.1093/jnci/djaf006. Online ahead of print.

Authors

Nobuhiko Kanaya^{1

2}, Waleed Seddiq^{1

2}, Kok-Siong Chen^{1

2}, Yoshinori Kajiwara^{1

2}, Lucia Moreno Lama^{1

2}, Paulo Borges^{1

2}, Shinji Kuroda³, Hiroaki Wakimoto^{1

2

4}, Khalid Shah^{1

2

5}

Affiliations

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

PMID: 39837345
DOI: 10.1093/jnci/djaf006

Abstract

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.