Viral Immunotherapy Studies Show Immune Activation in Glioblastoma
A phase I trial and a preclinical study found viral immunotherapy triggered T cell responses in glioblastoma. The clinical study enrolled 41 patients; the mouse study showed prolonged survival and immunologic memory.
Treatment with a single injection of an oncolytic virus induces persistent T cell–mediated immunity in glioblastoma, according to findings from a phase I clinical trial published in Cell. In separate preclinical research, a non-lytic replicating retrovirus that delivers an IL-15-receptor-linked fusion protein superagonist directly into glioblastoma cells dramatically suppresses tumor growth, prolongs survival, and induces lasting remission with immunologic memory in orthotopic mouse models.
Investigators conducted a first-in-human, open-label phase I clinical trial (ClinicalTrials.gov Identifier NCT03152318) evaluating a single intratumoral injection of rQNestin34.5v.2, an oncolytic herpes simplex virus engineered to selectively replicate in glioblastoma cells. The study included 41 patients with recurrent glioblastoma and led to extended survival, especially in patients with pre-existing viral antibodies. The investigators further analyzed immune activation from the oncolytic virus within the tumor microenvironment as well as spatial immune profiling and clinical outcomes.
The investigators found that the oncolytic virus treatment resulted in expansion of pre-existing T-cell clones and persistent T cell–mediated immunity against glioblastoma cells. They also found that shorter distances between cleaved caspase-3+ tumor cells and granzyme B+ T cells were associated with prolonged progression-free survival after treatment with the oncolytic virus. Additionally, when prior tumor-infiltrating T cells expand from treatment, they result in longer overall survival; although viral remnants stay in necrotic regions, T cells infiltrated live tumor regions.
Glioblastoma is a lethal brain tumor that is resistant to conventional therapies. In the preclinical study, the non-lytic replicating retrovirus creates localized immunotherapy biofactories. Mechanistically, researchers observed increased CD8+ T cell and natural killer cell infiltration and activation, alongside elevated antigen presentation pathways. Temozolomide, which is standard-of-care chemotherapy for glioblastoma, enhanced antitumor immunity when combined with the viral therapy.
T cell receptor sequencing revealed a polyclonal repertoire of T cells, enhanced by combining the retroviral therapy with temozolomide. Analysis of the T-cell repertoire suggested it to be directed against tumor rather than viral antigens, supporting the specificity and re-applicability of the approach. The findings illustrate that the therapy reprograms glioblastoma into an immunostimulatory hub, offering a viral immunotherapy against glioblastoma and potentially other therapy-resistant solid tumors.