Introduction

The field of immune-oncology (IO) has exploded over the past decade with scores of innovative immunotherapeutic strategies. Historically, cytokines have held promise for amplifying adaptive immune responses against immunogenic cancers; yet despite their documented activity, the systemic administration of pro-inflammatory cytokines, i.e., IL2/IL12, has been hampered by severe adverse or even fatal on-tumor, off-target toxicities. To reap benefits of cytokine strategies, yet minimize toxicities, protein engineering efforts have focused on intratumoral cytokine retention innovations capable of promoting intense and sustained localized immune activation sufficient for local tumor control and exertion of potent abscopal effects against metastases. In this study, we have generated caninized collagen-anchored IL2/IL12 (CaCol-IL2/12) as an innovative intratumoral delivery strategy, and evaluated tolerability, pharmacodynamics, immune-activation, and therapeutic effects in healthy beagle and dogs with measurable malignant melanoma (MMM).

Methods

Beagle dogs were included for MTD assessment of intradermal CaCol-IL2/12. Dogs with MMM were recruited (3+3 design) to be treated with a single fraction of radiation (9 Gy), followed with bimonthly CaCol-IL2/IL12 intratumoral injections with hematologic, biochemical, immunologic, and radiologic reevaluations.

Results

Conservative MTD of CaCol-IL2/IL12 in beagles was 0.2 mg/kg IL2/0.022 mg/kg IL12. Six dogs with MMM were treated at 1x and 2x MTD. Treatments were well tolerated with dogs developing transient fever and self-limiting localized facial edema. Strong local cytoreduction was achieved in 4 of 6 patients, and evidence for abscopal activities on regional metastases was observed too.

Conclusion

CaCol-IL2/IL12 is a tolerable and active immunotherapeutic strategy that holds promise for reaping the benefits of cytokine manipulation yet minimizing systemic toxicities.

Funding Information

None.