Adoptive T-cell based therapy can promote dramatic tumor regressions in both pre-clinical tumor models and in patients with CD19+ hematological tumors. However, in the case of human solid tumors, anti-tumor effects are limited by T-cell tolerance and the immunosuppressive tumor microenvironment. Human data from cancer patients treated with oncolytic adenovirus indicated that lymphocytes traffic to tissues following virotherapy. Therefore, we hypothesized to enable successful T-cell therapy by arming viruses with immunostimulatory cytokines which can counteract tumor immunosuppression locally.
Previously, we have identified interleukin 2 (IL-2) and Tumor Necrosis Factor alpha (TNFa) as the most promising factors to stimulate the graft used in adoptive T-cell therapy. Also, we have established that our arming approach results in long lasting, high level cytokine expression locally but low levels systemically in vivo and in patients, which is important for safety versus efficacy. One attractive aspect of this approach is the ease of combinations with standard therapies including checkpoint inhibiting antibodies (ongoing experiments).
We developed oncolytic adenoviruses expressing TNFa and/or IL2. Virus injections were given in combination with intraperitoneal adoptive transfer of OT-1 TCR transgenic T-cells to treat C57BL/6 mice bearing B16-OVA melanoma tumors. The best results were obtained when virally coded IL2 and TNFa were both used with T-cell transfer. Furthermore, in a hamster model permissive to human virus and human transgenes, oncolytic virus encoding human cytokines successfully improved the efficacy of tumor infiltrating lymphocyte therapy and protected animals from tumor rechallenge.
TILT Biotherapeutics is in the process of confirming the results in clinical trials.
Clinical trial identification
Legal entity responsible for the study
University of Helsinki
TILT Biotherapeutics Ltd
A. Hemminki: Shareholder in Targovax AS. Employee and shareholder in TILT Biotherapeutics Ltd. M. Siurala, S. Parviainen: Employee of TILT Biotherapeutics Ltd. All other authors have declared no conflicts of interest.