Clinical trial links oncolytic immunoactivation to survival in glioblastoma

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM) 1 , 2 . Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110—an o...

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Published in:	Nature (London) Vol. 623; no. 7985; pp. 157 - 166
Main Authors:	Ling, Alexander L., Solomon, Isaac H., Landivar, Ana Montalvo, Nakashima, Hiroshi, Woods, Jared K., Santos, Andres, Masud, Nafisa, Fell, Geoffrey, Mo, Xiaokui, Yilmaz, Ayse S., Grant, James, Zhang, Abigail, Bernstock, Joshua D., Torio, Erickson, Ito, Hirotaka, Liu, Junfeng, Shono, Naoyuki, Nowicki, Michal O., Triggs, Daniel, Halloran, Patrick, Piranlioglu, Raziye, Soni, Himanshu, Stopa, Brittany, Bi, Wenya Linda, Peruzzi, Pierpaolo, Chen, Ethan, Malinowski, Seth W., Prabhu, Michael C., Zeng, Yu, Carlisle, Anne, Rodig, Scott J., Wen, Patrick Y., Lee, Eudocia Quant, Nayak, Lakshmi, Chukwueke, Ugonma, Gonzalez Castro, L. Nicolas, Dumont, Sydney D., Batchelor, Tracy, Kittelberger, Kara, Tikhonova, Ekaterina, Miheecheva, Natalia, Tabakov, Dmitry, Shin, Nara, Gorbacheva, Alisa, Shumskiy, Artemy, Frenkel, Felix, Aguilar-Cordova, Estuardo, Aguilar, Laura K., Krisky, David, Wechuck, James, Manzanera, Andrea, Matheny, Chris, Tak, Paul P., Barone, Francesca, Kovarsky, Daniel, Tirosh, Itay, Suvà, Mario L., Wucherpfennig, Kai W., Ligon, Keith, Reardon, David A., Chiocca, E. Antonio
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 02-11-2023 Nature Publishing Group
Subjects:	13 13/44 38 38/90 38/91 42 42/44 45 45/23 631/67/1922 692/308/2779/109/1940 Brain cancer Brain Neoplasms - immunology Brain Neoplasms - pathology Clinical trials Glioblastoma Glioblastoma - immunology Glioblastoma - pathology Herpes viruses Herpesvirus 1, Human - genetics Herpesvirus 1, Human - immunology Herpesvirus 1, Human - physiology Humanities and Social Sciences Humans Immune clearance Immunology Immunotherapy Lymphocytes Lymphocytes T Microenvironments multidisciplinary Nestin Nestin - genetics Neurotoxicity Neurovirulence Oncolysis Oncolytic Virotherapy - adverse effects Oncolytic Viruses - genetics Oncolytic Viruses - immunology Oncolytic Viruses - physiology Peripheral blood mononuclear cells Reproducibility of Results Science Science (multidisciplinary) Serology Survival Survival Analysis T-Lymphocytes - cytology T-Lymphocytes - immunology Treatment Outcome Tumor microenvironment Tumor Microenvironment - immunology Tumors Viruses
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Summary:	Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM) 1 , 2 . Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110—an oncolytic herpes virus (oHSV) 3 . In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue 4 . These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ). Treatment with the oncolytic herpes virus CAN-3110 is associated with improved survival responses in patients with recurrent glioblastoma, particularly in individuals who are seropositive for HSV1.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-023-06623-2