Tumor-specific antibodies fused with IFN-β effectively treat antibody-resistant tumors.

  • Major finding: Tumor-specific antibodies fused with IFN-β effectively treat antibody-resistant tumors.

  • Mechanism: The anti-EGFR–IFN-β fusion antibody leads to dendritic cell–mediated CD8+ T-cell restimulation.

  • Impact: Tumor-targeted delivery of IFN-β may increase the efficacy of antibody-based cancer therapy.

Resistance often develops after extended tumor-specific antibody treatment. Yang and colleagues explored a strategy to treat antibody-resistant tumors based on reactivation of antitumor immune responses instead of tumor-intrinsic mechanisms. The authors established that type I IFNs mediate the antitumor responses of antibody treatment by showing that the efficacy of antibody treatment on antibody-sensitive tumors could be disrupted by blocking IFN receptor signaling. Additionally, local IFN-β expression sufficiently controlled tumor growth in antibody-resistant tumors. Based on these findings, a fusion protein of IFN-β and an EGF receptor (EGFR)–specific antibody was created to deliver IFN-β directly to tumors, as systemic administration of IFN-β has problematic side effects. Not only was the fusion antibody more effective than the first-generation anti-EGFR antibody cetuximab in several models of antibody-resistant tumors, including a KRAS-mutant model, it was also effective in breaking tolerance in EGFR-tolerized hosts. However, the fusion antibody was unable to control tumor growth in tumor-bearing mice lacking CD8+ T cells, suggesting that the effectiveness of anti-EGFR–IFN-β treatment depends on adaptive immunity and not induction of tumor cell apoptosis. Anti-EGFR–IFN-β–treated antigen presenting cells induced significantly more IFN-γ production by CD8+ T cells than anti-EGFR treated cells, indicating that IFN receptor–expressing dendritic cells are the primary target cells for anti-EGFR–IFN-β treatment, which stimulates them to reactivate antitumor responses by CD8+ T cells. Anti-EGFR–IFN-β treatment significantly increased expression of the T-cell inhibitory molecule programmed death-ligand 1 (PD-L1) in tumors, providing a potential explanation for why anti-EGFR–IFN-β–treated tumors eventually relapsed and raising the possibility that PD-L1 blockade could enhance the long-term efficacy of anti-EGFR–IFN-β. Indeed, the combination of anti-EGFR–IFN-β and anti-PD-L1 completely blocked tumor growth and enhanced the antitumor T-cell response. These findings provide a framework to increase tumor-specific antibody efficacy and circumvent antibody resistance by reactivating adaptive antitumor responses.

Yang X, Zhang X, Fu ML, Weichselbaum RR, Gajewski TF, Guo Y, et al. Targeting the tumor microenvironment with interferon-β bridges innate and adaptive immune responses. Cancer Cell 2014;25:37–48.

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