405. IL-2 and TNF-a Coding Adenoviruses Enable Adoptive T Cell Therapy in Metastatic, Solid Cancer by Systemically Activating Tumor-Reactive TILs

Abstract

Adoptive T cell therapy (ACT) using genetically modified T cells has shown exceptional efficacy in the treatment of CD19+ hematological cancers. However, far less impressive results have been achieved in the treatment of solid tumors due to local immunosuppression, rendering tumor-infiltrating T cells (TILs) hypofunctional. We have previously shown that adenovirus (Ad) infection can enhance the efficacy of ACT (Tahtinen et al, CIR 2015) and that intratumoral administration of immunostimulatory cytokines can result in favorable alteration of tumor microenvironment (Tahtinen et al, PLOS One 2015). To combine the benefits of both approaches, we studied if replication-deficient Ad5-vectors coding for interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-a) would affect the activity of adoptively transferred, TCR-transgenic TRP-2(180-188) specific T cells in vivo.To gain clinically relevant mechanism-of-action data, we chose to use ret transgenic mouse model that develops spontaneous malignant skin melanoma which metastasizes into distant organs. Following ACT and intratumoral virus injection, a significant increase in activated PD-1+ CD8+ T cells was seen in both cutaneous lesions and in metastatic lymph nodes. Interestingly, a reverse correlation between tumor weight and the number of tumor-reactive PD-1+ TILs (p=0.0015) was observed, indicating that T-cell hypofunction was overcome and successful tumor lysis was achieved. Local expression of cytokines did not affect the levels of immunosuppressive immune cell subsets such as myeloid-derived suppressor cells (MDSCs) or T regulatory cells (Tregs), latter of which has previously been associated with systemic IL-2 therapy (Ahmadzadeh and Rosenberg, Blood 2006). Instead, Ad5-IL2 treatment induced upregulation of IL-2 receptor α-chain (CD25) in conventional CD4+CD25+Foxp3-cells, suggesting that these helper T cells contributed to CD8+ TIL activation. Finally, beneficial ratios between tumor-reactive PD-1+ CD8+ TILs and Tregs was observed in primary and secondary tumor sites, indicating that IL-2 and TNF-a coding adenoviruses can modify the cellular composition of the tumor microenvironment in favor of adoptively transferred T cells.In conclusion, IL-2 and TNF-a coding adenoviruses can break tumor-associated immunotolerance and significantly increase the levels of active, tumor-reactive T-cells both in injected cutaneous lesions and in non-injected metastatic lymph nodes. Importantly, this triple modality may represent an efficient approach to achieve “CD19-like” clinical responses in the treatment of solid, metastatic cancers currently incurable by standard therapies.