Clinical trial links oncolytic immunoactivation to survival in glioblastoma

Alexander L. Ling, Isaac H. Solomon, Ana Montalvo Landivar, Hiroshi Nakashima, Jared K. Woods, Andres Santos, Nafisa Masud, Geoffrey Fell, Xiaokui Mo, Ayse S. Yilmaz, James Grant, Abigail Zhang, Joshua D. Bernstock, Erickson Torio, Hirotaka Ito, Junfeng Liu, Naoyuki Shono, Michal O. Nowicki, Daniel Triggs, Patrick Halloran, Raziye Piranlioglu, Himanshu Soni, Brittany Stopa, Wenya Linda Bi, Pierpaolo Peruzzi, Ethan Chen, Seth W. Malinowski, Michael C. Prabhu, Yu Zeng, Anne Carlisle, Scott J. Rodig, Patrick Y. Wen, Eudocia Quant Lee, Lakshmi Nayak, Ugonma Chukwueke, L. Nicolas Gonzalez Castro, Sydney D. Dumont, Tracy Batchelor, Kara Kittelberger, Ekaterina Tikhonova, Natalia Miheecheva, Dmitry Tabakov, Nara Shin, Alisa Gorbacheva, Artemy Shumskiy, Felix Frenkel, Estuardo Aguilar-Cordova, Laura K. Aguilar, David Krisky, James Wechuck, Andrea Manzanera, Chris Matheny, Paul P. Tak, Francesca Barone, Daniel Kovarsky, Itay Tirosh, Mario L. Suvà, Kai W. Wucherpfennig, Keith Ligon, David A. Reardon and E. Antonio Chiocca ()
Additional contact information
Alexander L. Ling: Brigham and Women’s Hospital
Isaac H. Solomon: Brigham and Women’s Hospital
Ana Montalvo Landivar: Brigham and Women’s Hospital
Hiroshi Nakashima: Brigham and Women’s Hospital
Jared K. Woods: Brigham and Women’s Hospital
Andres Santos: Brigham and Women’s Hospital
Nafisa Masud: Brigham and Women’s Hospital
Geoffrey Fell: Dana-Farber Cancer Institute
Xiaokui Mo: The Ohio State University
Ayse S. Yilmaz: The Ohio State University
James Grant: Brigham and Women’s Hospital
Abigail Zhang: Brigham and Women’s Hospital
Joshua D. Bernstock: Brigham and Women’s Hospital
Erickson Torio: Brigham and Women’s Hospital
Hirotaka Ito: Brigham and Women’s Hospital
Junfeng Liu: Brigham and Women’s Hospital
Naoyuki Shono: Brigham and Women’s Hospital
Michal O. Nowicki: Brigham and Women’s Hospital
Daniel Triggs: Brigham and Women’s Hospital
Patrick Halloran: Brigham and Women’s Hospital
Raziye Piranlioglu: Brigham and Women’s Hospital
Himanshu Soni: Brigham and Women’s Hospital
Brittany Stopa: Brigham and Women’s Hospital
Wenya Linda Bi: Brigham and Women’s Hospital
Pierpaolo Peruzzi: Brigham and Women’s Hospital
Ethan Chen: Brigham and Women’s Hospital
Seth W. Malinowski: Brigham and Women’s Hospital
Michael C. Prabhu: Brigham and Women’s Hospital
Yu Zeng: Brigham and Women’s Hospital
Anne Carlisle: Dana-Farber Cancer Institute
Scott J. Rodig: Brigham and Women’s Hospital
Patrick Y. Wen: Dana-Farber Cancer Institute
Eudocia Quant Lee: Dana-Farber Cancer Institute
Lakshmi Nayak: Dana-Farber Cancer Institute
Ugonma Chukwueke: Dana-Farber Cancer Institute
L. Nicolas Gonzalez Castro: Dana-Farber Cancer Institute
Sydney D. Dumont: Massachusetts General Hospital
Tracy Batchelor: Brigham and Women’s Hospital
Kara Kittelberger: ClearPoint Neuro
Ekaterina Tikhonova: BostonGene
Natalia Miheecheva: BostonGene
Dmitry Tabakov: BostonGene
Nara Shin: BostonGene
Alisa Gorbacheva: BostonGene
Artemy Shumskiy: BostonGene
Felix Frenkel: BostonGene
Estuardo Aguilar-Cordova: Candel Therapeutics
Laura K. Aguilar: Candel Therapeutics
David Krisky: Candel Therapeutics
James Wechuck: Candel Therapeutics
Andrea Manzanera: Candel Therapeutics
Chris Matheny: Candel Therapeutics
Paul P. Tak: Candel Therapeutics
Francesca Barone: Candel Therapeutics
Daniel Kovarsky: Weizmann Institute of Medical Sciences
Itay Tirosh: Weizmann Institute of Medical Sciences
Mario L. Suvà: Massachusetts General Hospital
Kai W. Wucherpfennig: Dana Farber Cancer Institute
Keith Ligon: Brigham and Women’s Hospital
David A. Reardon: Dana-Farber Cancer Institute
E. Antonio Chiocca: Brigham and Women’s Hospital

Nature, 2023, vol. 623, issue 7985, 157-166

Abstract: Abstract 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 tissue4. 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 ).

Date: 2023
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DOI: 10.1038/s41586-023-06623-2

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