Toxicity due to IL-2 and IL-12 has limited their use in anti-cancer therapies. To improve efficacy and safety, Momin et al. evaluated intratumoral administration of IL-2 or IL-12 fused to lumican, a collagen I/IV binding protein abundant in tumors. Local retention in the tumor was prolonged and peak systemic exposure was decreased by 10-fold. Lumican-cytokine fusions enhanced antitumor efficacy in several mouse models alone and in combination with anti-PD-1, cancer vaccines, or CAR T cells without increasing toxicity. CD8+ T cells were important for efficacy, producing a systemic memory response that was active against distal, metastatic, non-injected tumors.
Contributed by Katherine Turner
The clinical application of cytokine therapies for cancer treatment remains limited due to severe adverse reactions and insufficient therapeutic effects. Although cytokine localization by intratumoral administration could address both issues, the rapid escape of soluble cytokines from the tumor invariably subverts this effort. We find that intratumoral administration of a cytokine fused to the collagen-binding protein lumican prolongs local retention and markedly reduces systemic exposure. Combining local administration of lumican-cytokine fusions with systemic immunotherapies (tumor-targeting antibody, checkpoint blockade, cancer vaccine, or T cell therapy) improves efficacy without exacerbating toxicity in syngeneic tumor models and the Braf(V600E) /Pten(fl/fl) genetically engineered melanoma model. Curative abscopal effects on noncytokine-injected tumors were also observed as a result of a protective and systemic CD8(+) T cell response primed by local therapy. Cytokine collagen-anchoring constitutes a facile, tumor-agnostic strategy to safely potentiate otherwise marginally effective systemic immunotherapies.