Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy.

Autor:	Kim Y; Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Saini U; Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Kim D; Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Hernandez-Aguirre I; Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.; Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, United States.; College of Medicine, The Ohio State University, Columbus, OH, United States., Hedberg J; Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.; Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, United States.; College of Medicine, The Ohio State University, Columbus, OH, United States., Martin A; Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.; Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, United States.; College of Medicine, The Ohio State University, Columbus, OH, United States., Mo X; Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, United States., Cripe TP; Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States., Markert J; Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, United States., Cassady KA; Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States.; Department of Pediatrics, Division of Pediatric Infectious Diseases, Nationwide Children's Hospital, Columbus, OH, United States., Dhital R; Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jun 04; Vol. 15, pp. 1375413. Date of Electronic Publication: 2024 Jun 04 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1375413
Abstrakt:	Introduction: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects. To investigate oncolytic Herpes Simplex Virus (oHSV) as an immunotherapeutic approach, we compared viral replication, functional activity, and immune response between unarmed and interleukin 12 (IL-12)-armed oncolytic viruses in virus-permissive (B109) and -resistant (67C-4) murine MPNSTs. Methods: This study compared two attenuated IL-12-oHSVs with γ134.5 gene deletions (Δγ134.5) and the same transgene expression cassette. The primary difference in the IL-12-oHSVs was in their ability to counter the translational arrest response in infected cells. Unlike M002 (Δγ134.5, mIL-12), C002 (Δγ134.5, mIL-12, IRS1) expresses an HCMV IRS1 gene and evades dsRNA activated translational arrest in infected cells. Results and Discussion: Our results show that oHSV replication and gene expression results in vitro were not predictive of oHSV direct oncolytic activity in vivo. Tumors that supported viral replication in cell culture studies resisted viral replication by both oHSVs and restricted M002 transgene expression in vivo. Furthermore, two IL-12-oHSVs with equivalent transcriptional activity differed in IL-12 protein production in vivo, and the differences in IL-12 protein levels were reflected in immune infiltrate activity changes as well as tumor growth suppression differences between the IL-12-oHSVs. C002-treated tumors exhibited sustained IL-12 production with improved dendritic cells, monocyte-macrophage activity (MHCII, CD80/CD86 upregulation) and a polyfunctional Th1-cell response in the tumor infiltrates. Conclusion: These results suggest that transgene protein production differences between oHSVs in vivo, in addition to replication differences, can impact OV-therapeutic activity. Competing Interests: JM has the following relationships which may pose or be perceived as posing a financial conflict of interest: he is a board and equity holding member, in Aettis, Inc. and may receive royalties. The company holds frozen oncolytic viral stocks. Mustang Bio Tech is licensing the Intellectual Property IP of C134 an oncolytic viral Therapy. JM is blinded to the conditions for the C134 clinical trials. He is a shareholder for a privately held Small Business Innovation Research LLC, Treovir, Inc., concerning G207 oncolytic viral therapy now in clinical trial. Merck, Inc. provides industry grant support by providing Keytruda pembrolizumab for a clinical trial of M032 oncolytic virotherapy and financial support for a clinical trial. JM is a listee on Intellectual Property 1 related to a cancer immunotherapy system, and 2 to a novel immuno-virotherapeutic strategy targeting the glioma secretome. This IP has been filed by in8Bio formerly Incysus, Ltd. and has royalty earning potential. In the interest of full disclosure, KC receives licensure payments from Mustang Bio for the C134 virus, but there are no relevant financial conflicts for the technology addressed in this paper. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Kim, Saini, Kim, Hernandez-Aguirre, Hedberg, Martin, Mo, Cripe, Markert, Cassady and Dhital.)
Databáze:	MEDLINE
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