Enhanced Cancer Immunotherapy with Targeted IL-2 Variant Immunocytokines

The abstract discusses the development of a new type of immunocytokine for cancer treatment. IL-2 therapy has been shown to be effective but is associated with significant side effects. Previous attempts to create IL-2-based immunocytokines have not been successful due to issues such as high functional affinity, rapid clearance, and preferential activation of Tregs. The new immunocytokine described in this study is a monomeric, tumor-targeted version that uses a modified IL-2 (IL-2v) which does not bind to CD25 but retains IL-2Rbg binding. This IL-2v is fused to a tumor-specific antibody with a mutated Fc-part that prevents FcgR and C1q binding.

The immunocytokines, CEA-IL2v and FAP-IL2v, were produced and tested for their ability to activate immune cells without binding to CD25 or activating Tregs. They were found to activate NK cells and T cells, and to expand the CD8 T cell population in vivo. In mice, these immunocytokines showed improved safety and pharmacokinetics, with FAP-IL2v demonstrating effective tumor targeting with minimal uptake in normal tissues. The targeting was superior to that of a wildtype IL-2 immunocytokine. The efficacy of CEA- and FAP-IL2v was demonstrated in mouse models, showing an increase in survival rates.

In conclusion, the new immunocytokines show promise for the treatment of CEA/FAP-positive tumors due to their improved safety profile, pharmacokinetics, and tumor targeting capabilities. They activate NK and T cells through IL-2Rbg, particularly when immobilized in the tumor microenvironment. The study supports further investigation into these immunocytokines for cancer immunotherapy.