(UroToday.com) The 2024 IBCN annual meeting included a session on treatment response correlates, featuring a presentation by Dr. Hardev Pandha discussing oncolytic virotherapy expressing a novel TLR agonist and IL-15 for the treatment of NMIBC. The efficacy of BCG therapy in NMIBC results from direct interaction of BCG with urothelial and bladder cancer cells, and activation of innate and adaptive immune responses. The crucial role of TLR activation by BCG has been highlighted previously. Using an NF-KB reporter system coupled to the appropriate TLR receptors, Dr. Pandha and colleagues screened microbial ligands of a range of TLRs to identify a very highly potent ligand (superior to lipopolysaccharide) for expression in their backbone recombinant oncolytic herpesvirus. This has been engineered to be immunostimulatory and tumor-selective, and expresses IL-15 for proliferation of B lymphocytes and NK cells and activates CD4+ and CD8+ T cells:
The resultant virus, HSV5-15, was tested using in vitro and in vivo models. The hypothesis was that oncolytic HSV1 would be very efficient in killing cells, viral DNA activates the cGAS/STING pathway, subsequently modulating the exhausted/suppressive tumor microenvironment for delivery of key cytokines and activating/sustaining innate and adaptive immune cells.
Construction of viruses were undertaken to create variants expressing a cytokine with or without a TLR agonist, NF-κB activity assays, viral growth curves, cellular death/immunogenic cell death assays, THP-1 macrophage response assays, and an in vivo subcutaneous model of bladder cancer:
HSV5-15 had potent antitumor effects across a range of murine and human bladder cancer cell lines:
In vivo, using the subcutaneous MB49 bladder cancer model, HSV5-15 virus expressing both the cytokine and TLR agonist demonstrated selective cytotoxicity towards cancer cells while simultaneously triggering potent anti-cancer immunity to prevent recurrence:
HSV5-15 cured 40-50% of the mice, and 100% of these animals resisted rechallenge with MB49. Moreover, the virus elicited efficient cytotoxicity and activation of both innate and adaptive immune responses, with activation of TNF-α.
Dr. Pandha concluded his presentation discussing oncolytic virotherapy expressing a novel TLR agonist and IL-15 for the treatment of NMIBC with the following take-home points:
- There is a resurgent interest in oncolytic virotherapy
- The CG Oncology program confirms feasibility, safety and efficacy, which led to FDA fast track and breakthrough (BOND-003) of cretostimogene
- HSV-1 is already licensed and validated in melanoma
- oHSV-IL15-TLR5 has cytotoxic and immunomodulatory activity and was well tolerated in a murine model
Presented by: Hardev Pandha, MD, University of Surry, Guilford, UK
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 International Bladder Cancer Network (IBCN) Annual Meeting, Bern, Switzerland, Thurs, Sept 19 – Sat, Sept 21, 2024