Clinical trial links oncolytic immunoactivation to survival in glioblastoma
Author:
Ling Alexander L., Solomon Isaac H.ORCID, Landivar Ana Montalvo, Nakashima Hiroshi, Woods Jared K., Santos Andres, Masud Nafisa, Fell Geoffrey, Mo XiaokuiORCID, Yilmaz Ayse S., Grant James, Zhang Abigail, Bernstock Joshua D.ORCID, Torio EricksonORCID, Ito Hirotaka, Liu Junfeng, Shono Naoyuki, Nowicki Michal O., Triggs Daniel, Halloran Patrick, Piranlioglu RaziyeORCID, Soni Himanshu, Stopa Brittany, Bi Wenya LindaORCID, 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 UgonmaORCID, Gonzalez Castro L. Nicolas, Dumont Sydney D., Batchelor Tracy, Kittelberger Kara, Tikhonova Ekaterina, Miheecheva NataliaORCID, Tabakov DmitryORCID, Shin NaraORCID, Gorbacheva Alisa, Shumskiy Artemy, Frenkel FelixORCID, Aguilar-Cordova Estuardo, Aguilar Laura K.ORCID, Krisky David, Wechuck James, Manzanera Andrea, Matheny ChrisORCID, Tak Paul P., Barone Francesca, Kovarsky Daniel, Tirosh ItayORCID, Suvà Mario L.ORCID, Wucherpfennig Kai W.ORCID, Ligon KeithORCID, Reardon David A.ORCID, Chiocca E. AntonioORCID
Abstract
AbstractImmunotherapy 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).
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference49 articles.
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