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). Non-replicating adenovirus vectors coding for murine TNFa and IL-2 were used together with intraperitoneally administered OT-I TCR transgenic T-cells in the murine B16.OVA melanoma model. The best antitumor efficacy was obtained when virally coded IL-2 and TNFa were both used with T-cell transfer. Moreover, IL-2/TNFa virus combination treatment was able to attract (111)In-labelled OT-I cells into B16.OVA tumors in SPECT/CT imaging experiments. In addition to mouse studies, we developed oncolytic adenoviruses expressing human TNFa and/or human IL-2 that were used in combination with intratumoral adoptive transfer of tumor-infiltrating lymphocytes (TIL) in immunocompetent and adenovirus-permissive Syrian hamsters. These viruses improved the efficacy of TIL therapy and protected animals from tumor rechallenge. Furthermore, we have shown that adenovirally delivered IL-2 is superior to systemically administered IL-2 with regard to antitumor efficacy and safety, in both mice and hamsters. TILT Biotherapeutics is in the process of confirming the results in clinical trials.
Citation Format: Mikko Siurala, Riikka Havunen, João Santos, Siri Tähtinen, Dipongkor Saha, Markus Vähä-Koskela, Michael Behr, Dirk M. Nettelbeck, Anja Ehrhardt, Suvi Parviainen, Akseli Hemminki. Oncolytic adenoviruses armed with tumor necrosis factor alpha and interleukin-2 enable successful adoptive T cell therapy of solid tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B063.
- ©2016 American Association for Cancer Research.