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Oncolytic HSV1 targets different growth phases of breast cancer leptomeningeal metastases

Cancer Gene Therapy volume 30, pages 833–844 (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.

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

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References

  1. Chamberlain MC. Leptomeningeal metastasis. Curr Opin Oncol. 2010;22:627–35.

    Article  PubMed  Google Scholar 

  2. Chamberlain MC. Leptomeningeal metastases in the MRI era. Neurology. 2011;76:200.

    Article  PubMed  Google Scholar 

  3. Grewal J, Saria MG, Kesari S. Novel approaches to treating leptomeningeal metastases. J Neurooncol. 2012;106:225–34.

    Article  PubMed  Google Scholar 

  4. American Cancer Society. Cancer Facts & Figures 2022.

  5. Nieblas-Bedolla E, Zuccato J, Kluger H, Zadeh G, Brastianos PK. Central nervous system metastases. Hematol Oncol Clin North Am. 2022;36:161–88.

    Article  PubMed  Google Scholar 

  6. Watanabe M, Tanaka R, Takeda N. Correlation of MRI and clinical features in meningeal carcinomatosis. Neuroradiology. 1993;35:512–5.

    Article  CAS  PubMed  Google Scholar 

  7. Kesari S, Batchelor TT. Leptomeningeal metastases. Neurol Clin. 2003;21:25–66.

    Article  PubMed  Google Scholar 

  8. Franzoi MA, Hortobagyi GN. Leptomeningeal carcinomatosis in patients with breast cancer. Crit Rev Oncol Hematol. 2019;135:85–94.

    Article  PubMed  Google Scholar 

  9. Brower JV, Saha S, Rosenberg SA, Hullett CR, Ian Robins H. Management of leptomeningeal metastases: prognostic factors and associated outcomes. J Clin Neurosci. 2016;27:130–7.

    Article  PubMed  Google Scholar 

  10. Le Rhun E, Taillibert S, Chamberlain MC. Neoplastic meningitis due to lung, breast, and melanoma metastases. Cancer Control. 2017;24:22–32.

    Article  PubMed  Google Scholar 

  11. Crozier JA, Cornell LF, Rawal B, Perez EA. Breast cancer brain metastases: molecular subtype, treatment and survival. Breast Dis. 2016;36:133–41.

    Article  PubMed  Google Scholar 

  12. Niwińska A, Rudnicka H, Murawska M. Breast cancer leptomeningeal metastasis: propensity of breast cancer subtypes for leptomeninges and the analysis of factors influencing survival. Med Oncol. 2013;30:408.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kak M, Nanda R, Ramsdale EE, Lukas RV. Treatment of leptomeningeal carcinomatosis: current challenges and future opportunities. J Clin Neurosci. 2015;22:632–7.

    Article  PubMed  Google Scholar 

  14. Lee SS, Ahn JH, Kim MK, Sym SJ, Gong G, Ahn SD, et al. Brain metastases in breast cancer: prognostic factors and management. Breast Cancer Res Treat. 2008;111:523–30.

    Article  PubMed  Google Scholar 

  15. Bonneau C, Paintaud G, Trédan O, Dubot C, Desvignes C, Dieras V, et al. Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis. Eur J Cancer. 2018;95:75–84.

    Article  CAS  PubMed  Google Scholar 

  16. Venur VA, Chukwueke UN, Lee EQ. Advances in Management of Brain and Leptomeningeal Metastases. Curr Neurol Neurosci Rep. 2020;20:26.

    Article  PubMed  Google Scholar 

  17. Thakkar JP, Kumthekar P, Dixit KS, Stupp R, Lukas RV. Leptomeningeal metastasis from solid tumors. J Neurol Sci. 2020;411:116706.

    Article  PubMed  Google Scholar 

  18. Harstad L, Hess KR, Groves MD. Prognostic factors and outcomes in patients with leptomeningeal melanomatosis. Neuro Oncol. 2008;10:1010–18.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kuruppu D, Tanabe KK. Viral oncolysis by herpes simplex virus and other viruses. Cancer Biol Ther. 2005;4:524–31.

    Article  CAS  PubMed  Google Scholar 

  20. Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014;2:295–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: a new era of cancer treatment at dawn. Cancer Sci. 2016;107:1373–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lemos de Matos A, Franco LS, McFadden G. Oncolytic viruses and the immune system: the dynamic duo. Mol Ther Methods Clin Dev. 2020;17:349–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yoon SS, Carroll NM, Chiocca EA, Tanabe KK. Cancer gene therapy using a replication-competent herpes simplex virus type 1 vector. Ann Surg. 1998;228:366–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nakamura H, Kasuya H, Mullen JT, Yoon SS, Pawlik TM, Chandrasekhar S, et al. Regulation of herpes simplex virus gamma(1)34.5 expression and oncolysis of diffuse liver metastases by Myb34.5. J Clin Invest. 2002;109:871–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kuruppu D, Tanabe KK. HSV-1 as a novel therapy for breast cancer meningeal metastases. Cancer Gene Ther. 2015;22:506–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kuruppu D, Bhere D, Farrar CT, Shah K, Brownell AL, Tanabe KK. A model of breast cancer meningeal metastases: characterization with in vivo molecular imaging. Cancer Gene Ther. 2019;26:145–56.

    Article  CAS  PubMed  Google Scholar 

  27. Paxinos F. The Mouse Brain In Stereotaxic Coordinates. 2008. p. 72–105. Academic Press.

  28. Kuruppu D, Brownell AL, Shah K, Mahmood U, Tanabe KK. Molecular imaging with bioluminescence and PET reveals viral oncolysis kinetics and tumor viability. Cancer Res. 2014;74:4111–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kuruppu D, Brownell AL, Zhu A, Yu M, Wang X, Kulu Y, et al. Positron emission tomography of herpes simplex virus 1 oncolysis. Cancer Res. 2007;67:3295–300.

    Article  CAS  PubMed  Google Scholar 

  30. Nigim F, Esaki S, Hood M, Lelic N, James MF, Ramesh V, et al. A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus. Neuro Oncol. 2016;18:1278–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cody JJ, Scaturro P, Cantor AB, Yancey Gillespie G, Parker JN, Markert JM. Preclinical evaluation of oncolytic δγ(1)34.5 herpes simplex virus expressing interleukin-12 for therapy of breast cancer brain metastases. Int J Breast Cancer. 2012;2012:628697.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sahin TT, Kasuya H, Nomura N, Shikano T, Yamamura K, Gewen T, et al. Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer. Cancer Gene Ther. 2012;19:229–37.

    Article  CAS  PubMed  Google Scholar 

  33. Gholami S, Chen CH, Gao S, Lou E, Fujisawa S, Carson J, et al. Role of MAPK in oncolytic herpes viral therapy in triple-negative breast cancer. Cancer Gene Ther. 2014;21:283–9.

    Article  CAS  PubMed  Google Scholar 

  34. Yang WQ, Senger D, Muzik H, Shi ZQ, Johnson D, Brasher PM, et al. Reovirus prolongs survival and reduces the frequency of spinal and leptomeningeal metastases from medulloblastoma. Cancer Res. 2003;63:3162–72.

    CAS  PubMed  Google Scholar 

  35. Yang WQ, Senger DL, Lun XQ, Muzik H, Shi ZQ, Dyck RH, et al. Reovirus as an experimental therapeutic for brain and leptomeningeal metastases from breast cancer. Gene Ther. 2004;11:1579–89.

    Article  CAS  PubMed  Google Scholar 

  36. Delhaas EM, Huygen F. Complications associated with intrathecal drug delivery systems. BJA Educ. 2020;20:51–57.

    Article  CAS  PubMed  Google Scholar 

  37. Driesse MJ, Esandi MC, Kros JM, Avezaat CJ, Vecht C, Zurcher C, et al. Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity. Gene Ther. 2000;7:1401–9.

    Article  CAS  PubMed  Google Scholar 

  38. Kuruppu D, Dorfman JD, Tanabe KK. HSV-1 viral oncolysis and molecular imaging with PET. Curr Cancer Drug Targets. 2007;7:175–80.

    Article  CAS  PubMed  Google Scholar 

  39. Groves MD. Leptomeningeal disease. Neurosurg Clin N Am. 2011;22:67–78. vii

    Article  PubMed  Google Scholar 

  40. Kokkoris CP. Leptomeningeal carcinomatosis. How does cancer reach the pia-arachnoid? Cancer. 1983;51:154–60.

    Article  CAS  PubMed  Google Scholar 

  41. Chamberlain MC. Neoplastic meningitis. Handb Clin Neurol. 2012;105:757–66.

    Article  PubMed  Google Scholar 

  42. Fowler MJ, Cotter JD, Knight BE, Sevick-Muraca EM, Sandberg DI, Sirianni RW. Intrathecal drug delivery in the era of nanomedicine. Adv Drug Deliv Rev. 2020;165-166:77–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bernardi RJ, Bomgaars L, Fox E, Balis FM, Egorin MJ, Lagattuta TF, et al. Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis. Cancer Chemother Pharmacol. 2008;62:355–61.

    Article  CAS  PubMed  Google Scholar 

  44. Salabert AS, Vaysse L, Beaurain M, Alonso M, Arribarat G, Lotterie JA, et al. Imaging grafted cells with [18F]FHBG using an optimized HSV1-TK mammalian expression vector in a brain injury rodent model. PLoS ONE. 2017;12:e0184630.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pourchet A, Fuhrmann SR, Pilones KA, Demaria S, Frey AB, Mulvey M, et al. CD8(+) T-cell immune evasion enables oncolytic virus immunotherapy. EBioMedicine. 2016;5:59–67.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Zeng J, Li X, Sander M, Zhang H, Yan G, Lin Y. Oncolytic viro-immunotherapy: an emerging option in the treatment of gliomas. Front Immunol. 2021;12:721830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jin S, Wang Q, Wu H, Pang D, Xu S. Oncolytic viruses for triple negative breast cancer and beyond. Biomark Res. 2021;9:71.

    Article  PubMed  PubMed Central  Google Scholar 

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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.

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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 30, 833–844 (2023). https://doi.org/10.1038/s41417-023-00588-0

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