Clinical trial links oncolytic immunoactivation to survival in glioblastoma

Rákkutatás · Glioblastoma

Intralesional injection of the oncolytic herpes virus CAN‑3110 induces antitumour immune activation and improves overall survival in patients with recurrent glioblastoma, especially in those seropositive for HSV1.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterises aggressive forms of cancer such as recurrent glioblastoma (rGBM). Here we report the results of a first‑in‑human phase I trial in 41 patients with rGBM who were injected with CAN‑3110—a modified oncolytic herpes simplex virus (oHSV). In contrast to other clinical oHSVs, CAN‑3110 retains the viral neurovirulence ICP34.5 gene under a nestin promoter; nestin is over‑expressed in GBM and other invasive tumours, but not in adult brain or healthy differentiated tissue. These modifications confer CAN‑3110 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, providing a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318).

This first‑in‑human trial demonstrates that a neuro‑virulent oncolytic HSV can safely reach and replicate in recurrent glioblastoma, stimulating robust anti‑tumour T‑cell responses and translating into improved survival, especially for patients with prior HSV1 exposure. The findings support further clinical development of oncolytic virotherapy as a strategy to overcome the innate immunosuppressive environment of glioblastoma, a cancer with limited effective systemic therapies.

Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.

Eredeti forrás

Kapcsolódó jelek