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Oncolytic HSV1 targets different growth phases of breast cancer leptomeningeal metastases

Cancer Gene Therapy (2023)Cite this article

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A Correction to this article was published on 08 March 2023

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Abstract

Leptomeningeal metastasis is a fatal complication of breast cancer which results when cancer cells seed in the meninges. Currently there is no cure, limiting survival to less than four months. Treatment options are palliative. We studied a replication conditional Herpes simplex virus 1 (HSV1) in this regard and present the therapeutic efficacy of oncolytic HSV1 on different stages of breast cancer leptomeningeal metastases growth, namely the lag, intermediate, and exponential phases. These phases characterized in a murine model represent the early, intermediate, and late stages of leptomeningeal disease in patients. In this model, virus was introduced into the ventricular system by stereotactic surgery, the same path cancer cells were introduced to create leptomeningeal metastases. Tumor growth was measured with Gd-MRI and virus replication was assessed by FHBG-PET and Fluc bioluminescence. Imaging results were correlated with H&E and HSV-TK immunohistochemical staining. A remarkable growth inhibition was observed when the lag phase was targeted which was associated with multiple virus replication cycles. The onset of debilitating symptoms was delayed, and survival was lengthened by nearly 2 weeks. A growth inhibition similar to the lag phase was observed when the intermediate phase was targeted, associated with robust virus replication. The regression of existing tumor led to a reversal of neurological symptoms, extending survival by nearly one week. A modest response was observed when the lag phase was targeted lengthening survival by 3 days. Oncolytic HSV1 presents a novel treatment option for breast cancer leptomeningeal metastases with potential for targeting different disease stages where virus replication and tumor response can be monitored with molecular imaging techniques that are in the clinic.

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Fig. 1: Induction of leptomeningeal metastases and treatment with oncolytic HSV1.
Fig. 2: Tumor growth response to oncolytic HSV1 treatment of LMD studied with Gd MRI.
Fig. 3: Virus replication during oncolytic HSV1 treatment of LMD studied with bioluminescence imaging.
Fig. 4: Tumor and replicating virus identified in brains treated with oncolytic HSV1.
Fig. 5: Virus replication and accompanying tumor response studied with molecular imaging.
Fig. 6: Survival following oncolytic HSV1 therapy.

Data availability

The data generated and analyzed during this study can be found within the published article and its supplementary files.

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Acknowledgements

Department of Defense Idea Award: Award No: W81XWH-11-1-0388 (DK). NIH R21 NCI Omnibus Award: Award No:1R21CA186054-01 (DK). ESCCO-MGH Breast Cancer Research Fund (DK).

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Authors and Affiliations

  1. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA

    Darshini Kuruppu & Kenneth K. Tanabe

  2. Department of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, Columbia, SC, USA

    Deepak Bhere

  3. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA

    Christian T. Farrar & Umar Mahmood

  4. Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA

    Khalid Shah

  5. Gordon Center for Medical Imaging, Massachusetts General Hospital, Boston, MA, USA

    Anna-Liisa Brownell

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  1. Darshini Kuruppu
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Contributions

DK: provision of study material, conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, and final manuscript approval. DB: conception and design, collection, and assembly of data, data analysis and interpretation, and final manuscript approval. CTF: collection and assembly of data; final manuscript approval. KS: provision of study material; approval of manuscript. ALB: collection and assembly of data; data analyses, final manuscript approval. UM: provision of study material; final manuscript approval. KKT: conception and design, provide study material, manuscript writing, final manuscript approval.

Corresponding author

Correspondence to Darshini Kuruppu.

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Competing interests

D.B. owns equity and is consultant at AMASA Therapeutics Inc., a biotechnology company for cell-based therapeutics for cancer. The other authors declare no conflicting interests.

Ethical approval

Experiments were conducted under Institutional Animal Care and Use Committee (IACUC) for Massachusetts General Hospital (MGH) guidelines. Animal procedures were performed at an AAALAC-accredited facility and animals were cared for in accordance with the Guide for the Care and Use of Laboratory Animals. All research protocols were approved by the IACUC”.

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Kuruppu, D., Bhere, D., Farrar, C.T. et al. Oncolytic HSV1 targets different growth phases of breast cancer leptomeningeal metastases. Cancer Gene Ther (2023). https://doi.org/10.1038/s41417-023-00588-0

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