Description
A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment
A. Cauwels1, S. Van Lint1, G. Garcin2, J. Bultinck1, F. Paul2, S. Gerlo1, J. Van der Heyden1, Y. Bordat2, D. Catteeuw1, L. De Cauwer1, E. Rogge1, A. Verhee1, G. Uzé2 and J. Tavernier1
1Cytokine Receptor Laboratory, VIB Medical Biotechnology Center, Ghent University, Belgium;
2CNRS UMR 5235, University Montpellier, France
Immunotherapeutic antitumor options include checkpoint inhibiting antibodies, T and Dendritic Cell (DC) based cellular therapies, and cytokines. Type I IFN has been approved for the treatment of several solid and blood cancers. However, best results are typically obtained with higher doses, and the many systemic toxic side effects of IFN are severely dose-limiting. To curtail cytokine toxicity, we develop AcTakines, Activated-by-Targeting Cytokines, improved (mutated, with reduced receptor affinity) immunocytokines fused to cell-specific targeting moieties, such as single domain antibodies (sdAbs).
As a murine AcTaferon (type I IFN AcTakine), we use hIFN2-Q124R, which is weakly active on mouse cells, about 100x less than mIFN. Fusion of AcTaferon to anti-CD20 sdAb restored full IFN activity on CD20+ cells in vitro and in vivo. In vivo treatment with CD20-targeted AcTaferon of CD20+ A20 lymphoma or B16-CD20+ melanoma tumors drastically reduced tumor growth, similar to high dose wild-type (WT) mIFN immunocytokine. In sharp contrast to the latter, however, tumor-targeted AcTaferon did not cause any systemic toxicity (evaluated via body weight, temperature, and blood cell counts). The AcTaferon effect was lost in IFNAR1- and Batf3-deficient animals, and in mice lacking IFNAR1 on CD11c+ cells, indicating the critical involvement of conventional cross-presenting DC (cDC1). Also the presence of, but not IFN signaling in, CD8+ T cells was essential. When combined with immunogenic chemotherapy, low-dose TNF, or immune checkpoint blockade strategies such as anti-PDL1, -CTLA4 or -LAG3, complete tumor regressions and subsequent immunity (memory) were observed, still without morbidity, again in sharp contrast with WT mIFN. Interestingly, the combination of tumor-targeted AcTaferon with checkpoint inhibiting antibodies indicated its ability to convert “cold” nonresponding tumors into responders. Collectively, our findings demonstrate that AcTaferon targeted to tumor-specific surface markers may provide a safe addition to cancer immunotherapies.