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

Abstract

Effective antitumor immunity in mice requires activation of the type I interferon (IFN) response pathway. IFNα and IFNβ 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 IFNα and IFNβ 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.

Visualizing intratumoral injections in lung tumors by endobronchial ultrasound

“…Intervening in the tumor mechanical microenvironment with strategies such as vascular normalization or stress alleviation 9 might also enhance intratumoral retention and distribution of injected agents. Finally, drug retention may be further improved by modifying the physical or chemical properties of the injectate, such as anchoring the active drug to carrier molecules 23 , 24 or combining it with adjuvants that create synergistic local reactions in the tissue 25 .…”

Spatiotemporally programming cytokine immunotherapies through protein engineering

“…This effective increase in molecular weight, together with neonatal Fc receptor (FcRn)‐mediated salvage recycling, endows an extended half‐life in vivo, with up to an order of magnitude increase reported for a mouse serum albumin (MSA)‐IL‐2 fusion in mice 23 . MSA‐IFNɑ has also been reported to be present in serum 5 days after administration 27 . To maintain monovalent cytokine expression in an Fc‐fusion format, co‐transfection and orthogonal affinity tag purification or knob‐in‐hole mutations can be used 23,25,28 .…”

“…Despite initial accumulation following intratumoral delivery, much of the injected payload will rapidly leak out and lead to systemic exposure. We and others have shown this to be true for cytokines and antibodies in preclinical models 24,25,27,73,112 . Hence, simply changing the route of administration will not on its own ablate a cytokine's toxicity.…”

“…Lutz et al applied the alum‐binding platform to type I IFNs, another cytokine family known both for its potency and toxicity 27 . Unlike interleukins, type I IFNs can directly interact with tumor cells through the IFNAR receptor, opening up additional mechanisms for anti‐tumor immunity.…”

The role of interferons in ovarian cancer progression: Hinderer or promoter?

“…Attempting local administration and modification of IFNs to improve their bioavailability and targeting is a research trend. For example, coupling IFNs with polyethylene glycol, hyaluronic acid, or aluminum salts not only prolonged the duration of action but also improved drug targeting, allowing them to be trapped in the peritoneal cavity or in the tumor ( 138 – 141 ). In addition, bone marrow mononuclear cells (iPS-ML) have been genetically modified to produce IFN-β.…”