Abstract 4171: Treatment of canine soft tissue sarcomas and melanomas with intratumoral collagen-anchored IL-2 and IL-12 is safe and effective
Authors: Stinson Jordan , Sheen Allison , Hampel Jordan , Momin Noor , Bernstein Rebecca , Kamerer Rebecca , Fan Timothy M. , Wittrup K. Dane 
Published: June 2022

Introduction: Successful translation of novel cancer immunotherapies could be accelerated by using tumor models that recapitulate human disease and receive relevant standard-of-care treatments. Some cancers that naturally arise in pet dogs share critical features with human disease including tumor heterogeneity (immune infiltration, mutational burden, metastatic progression) and patient characteristics (outbred population, immunocompetence, age, microbiome). Investigating novel immunotherapies alongside radiation, chemotherapy, or surgical treatment of spontaneous canine cancers meaningfully informs their clinical translation.

Methods: We have developed interleukin -2 and -12 cytokine fusion proteins that bind and anchor to collagen after intratumoral administration and have shown their superior activity and tolerability in murine tumor models (Momin 2019). Here in pet dogs, we test these cytokines for safety and efficacy in two cancer types. Soft tissue sarcomas (n=10) were treated with intratumoral IL-2 and -12 using different dose schedules prior to surgical resection with subsequent tumor tissues assessed by histology for immune infiltrates and by Nanostring for whole tumor transcriptomics. Oral malignant melanomas (n=10) were treated with 9 Gy radiation at day 0, and on day 1 treated with intratumoral injection of the cytokines Q2W for 6 total doses, with dose escalation performed in cohorts of 3. Plasma was collected for PK/PD analysis of drug and IFN-g post-injection, with serial CBC/chemistry profiles and CT scans for assessment of safety and radiologic response, respectively.

Results: Intratumoral dosing of collagen binding cytokines was well tolerated by 19/20 dogs, with transient body temperature elevation observed 24-72 hours post-injection and 1 episode of grade 3 transaminase elevation. Magnitude of fever did not correlate with peak serum IFN-g or cytokine dose level. At the lowest dose level (17 ug/kg IL-2, 40 ug/m2 IL-12), 1/3 pet dogs with oral melanomas achieved CR by RECIST criteria, and 3/3 pet dogs achieved near CR at the 2x dose level. Transcriptomic analysis of treated sarcomas revealed enrichment for antigen processing and T cell function two days after treatment. Moreover, IDO1 was upregulated in treated tumors, which suggests its systemic inhibitors combined with the locally-delivered cytokines may potentiate stronger responses.

Conclusions: This data supports the safety and efficacy of intratumorally delivered IL-2 and IL-12 collagen binding cytokines and the ability to combine with standard-of-care resection or radiation therapy. We are continuing to enroll dogs to evaluate safety and efficacy at higher dose levels, including response at metastatic sites. Canine cancers bridge the gap between murine and human disease, accelerating the build-test-learn design cycle for novel immunotherapies and treatment combinations.

Citation Format: Jordan Stinson, Allison Sheen, Jordan Hampel, Noor Momin, Rebecca Bernstein, Rebecca Kamerer, Timothy M. Fan, K. Dane Wittrup. Treatment of canine soft tissue sarcomas and melanomas with intratumoral collagen-anchored IL-2 and IL-12 is safe and effective [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4171.