Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies

Effective antitumor immunity in mice requires activation of the type I interferon (IFN) response pathway. IFN alpha and IFN beta therapies have proven promising in humans, but suffer from limited efficacy and high toxicity. Intratumoral IFN retention ameliorates systemic toxicity, but given the complexity of IFN signaling, it was unclear whether long-term intratumoral retention of type I IFNs would promote or inhibit antitumor responses. To this end, we compared the efficacy of IFN alpha and IFN beta that exhibit either brief or sustained retention after intratumoral injection in syngeneic mouse tumor models. Significant enhancement in tumor retention, mediated by anchoring these IFNs to coinjected aluminum-hydroxide (alum) particles, greatly improved both their tolerability and efficacy. The improved efficacy of alum-anchored IFNs could be attributed to sustained pleiotropic effects on tumor cells, immune cells, and nonhematopoietic cells. Alum-anchored IFNs achieved high cure rates of B16F10 tumors upon combination with either anti-PD-1 antibody or interleukin-2. Interestingly however, these alternative combination immunotherapies yielded disparate T cell phenotypes and differential resistance to tumor rechallenge, highlighting important distinctions in adaptive memory formation for combinations of type I IFNs with other immunotherapies.

Automated summary

The study found that anchoring IFNs to aluminum-hydroxide particles can improve their retention and efficacy in tumors, significantly enhancing the cure rate of B16F10 tumors. Additionally, alum-anchored IFNs in combination with anti-PD-1 antibody or interleukin-2 produced different T cell phenotypes and resistance to tumor rechallenge.