Nature • 2023-10-18

Clinical trial links oncolytic immunoactivation to survival in glioblastoma

Authors

Alexander L. Ling, Isaac H. Solomon,  Ana Montalvo Landivar,  Hiroshi Nakashima,  Jared K. Woods,  Andres Santos, Nafisa Masud,  Geoffrey Fell, ...

Abstract

Immunotherapy failures can result from the highly suppressive tumourmicroenvironment that characterizes aggressive forms of cancer such as recurrentglioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in41 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 neurovirulenceICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM andother invasive tumours, but not in the adult brain or healthy differentiated tissue4.These modifications confer CAN-3110 with preferential tumour replication. Nodose-limiting toxicities were encountered. Positive HSV1 serology was significantlyassociated with both improved survival and clearance of CAN-3110 from injectedtumours. Survival after treatment, particularly in individuals seropositive for HSV1,was significantly associated with (1) changes in tumour/PBMC T cell counts and clonaldiversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and(3) tumour transcriptomic signatures of immune activation. These results providehuman validation that intralesional oHSV treatment enhances anticancer immuneresponses even in immunosuppressive tumour microenvironments, particularly inindividuals with cognate serology to the injected virus. This provides a biologicalrationale for use of this oncolytic modality in cancers that are otherwise unresponsiveto immunotherapy (ClinicalTrials.gov: NCT03152318).