An oncolytic adenovirus shows promise in inducing immune response in prostate cancer

Intraprostatic administration of the oncolytic adenovirus ORCA-010 in treatment-naïve patients with prostate cancer showed to induce local and systemic anti-tumour immune responses in an ongoing open label, dose escalating phase I/IIa trial (NCT04097002), as discussed at the ESMO Immuno-Oncology Congress 2024 (Abstract 176MO).

Oncolytic viruses are modified viruses harnessing the immune system to attack tumours. Recent studies have disclosed the potential of this promising immunotherapy approach across a range of cancer types, but also their limitations. So far, only one oncolytic virus has been approved for its use in oncology by the European Medicines Agency (EMA), i.e. talimogene laherparepvec for melanoma (T-VSC).

The study presented in Geneva consisted in two parts. In phase I, patients received a single intraprostatic injection of ORCA-010 (3+3 trial design at increasing doses) with one-year follow-up. In phase IIa, 12 patients received two doses of 1.5x10¹² vp of ORCA-010, two weeks apart. Three patients underwent a second biopsy after one year, and nine high-risk patients had radical prostatectomy within two months of the second injection. Biopsies, prostatectomy, and blood samples were analysed for immune cell changes and tumour-specific T cells.

The immunobiological analysis in radical prostatectomy and one-year biopsies showed that intratumour administration of the oncolytic adenovirus triggered CD8 T cell activation and proliferation, leading to a shift of the tumour microenvironment from cold to hot (Figure). Peripheral blood analysis showed an increase in HLA-DR+ and Ki67+ CD8+ T cells within weeks of ORCA-010 injection. CD4+ and CD8+ T cells reactive to prostate antigens emerged post-treatment, declining after radical prostatectomy.

According to Dr Marco Donia, Copenhagen University Hospital, Herlev, Denmark, who was the invited discussant to comment on these early results in Geneva, there are still a few pending questions that need to be answered. “It is clear that an injection of ORCA-010 induces T-cell infiltration in the prostate, but is it sufficient for tumour regression/rejection, and for the prevention of metastasis development?”, he said. Donia also added that it would be crucial to understand whether ORCA-010 would be developed as monotherapy or combination therapy, and would be more effective than other oncolytic viruses currently under investigation. He concluded: “There are some T cell responses that seem to be induced by oncolytic viruses, but we do not know if an additional revival with, for instance, anti-PD-1 is required once these immune responses are fully unleashed.”