Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas

Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metas...

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Published inScience translational medicine Vol. 15; no. 698; p. eade8732
Main Authors Kanaya, Nobuhiko, Kitamura, Yohei, Lopez Vazquez, Maria, Franco, Arnaldo, Chen, Kok-Siong, van Schaik, Thijs A, Farzani, Touraj Aligholipour, Borges, Paulo, Ichinose, Toru, Seddiq, Waleed, Kuroda, Shinji, Boland, Genevieve, Jahan, Nusrat, Fisher, David, Wakimoto, Hiroaki, Shah, Khalid
Format Journal Article
LanguageEnglish
Published United States 31.05.2023
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Abstract Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1 ) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAF /PTEN and BRAF /PTEN mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell- and T cell-mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SC -releasing GM-CSF and single-chain variable fragment anti-PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.
AbstractList Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1 ) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAF /PTEN and BRAF /PTEN mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell- and T cell-mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SC -releasing GM-CSF and single-chain variable fragment anti-PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.
Author van Schaik, Thijs A
Jahan, Nusrat
Farzani, Touraj Aligholipour
Chen, Kok-Siong
Wakimoto, Hiroaki
Kitamura, Yohei
Franco, Arnaldo
Seddiq, Waleed
Shah, Khalid
Kuroda, Shinji
Kanaya, Nobuhiko
Lopez Vazquez, Maria
Borges, Paulo
Ichinose, Toru
Fisher, David
Boland, Genevieve
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  surname: Kanaya
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  organization: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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  givenname: David
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  surname: Fisher
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  givenname: Khalid
  orcidid: 0000-0002-5474-0974
  surname: Shah
  fullname: Shah, Khalid
  organization: Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
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Snippet Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the...
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StartPage eade8732
SubjectTerms Animals
Brain - pathology
Brain Neoplasms - genetics
Brain Neoplasms - pathology
Brain Neoplasms - therapy
Gene Editing
Granulocyte-Macrophage Colony-Stimulating Factor
Immunotherapy
Melanoma - pathology
Melanoma - therapy
Melanoma, Cutaneous Malignant
Mice
Oncolytic Virotherapy
Oncolytic Viruses - genetics
Proto-Oncogene Proteins B-raf
Simplexvirus - genetics
Stem Cells
Title Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas
URI https://www.ncbi.nlm.nih.gov/pubmed/37256936
Volume 15
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