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Published on: January 14, 2011
Collagen-Anchored Interleukin-2 and Interleukin-12 Safely Reprogram the Tumor Microenvironment in Canine Soft-Tissue
Jordan A Stinson1,2, Allison Sheen1,2, Noor Momin1,2
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Purpose:
Cytokine therapies such as IL2 and IL12 suffer from impractically small therapeutic windows driven by their on-target, off-tumor activity, limiting their clinical potential despite potent antitumor effects. We previously engineered cytokines that bind and anchor to tumor collagen following intratumoral injection, and sought to test their safety and biomarker activity in spontaneous canine soft-tissue sarcomas (STS).
Experimental Design:
Collagen-binding cytokines were canine-ized to minimize immunogenicity and were used in a rapid dose-escalation study in healthy beagles to identify a maximum tolerated dose. Ten client-owned pet dogs with STS were then enrolled into trial, receiving cytokines at different intervals prior to surgical tumor excision. Tumor tissue was analyzed through IHC and NanoString RNA profiling for dynamic changes within treated tumors. Archived, untreated STS samples were analyzed in parallel as controls.
Results:
Intratumorally administered collagen-binding IL2 and IL12 were well tolerated by STS-bearing dogs, with only Grade 1/2 adverse events observed (mild fever, thrombocytopenia, neutropenia). IHC revealed enhanced T-cell infiltrates, corroborated by an enhancement in gene expression associated with cytotoxic immune function. We found concordant increases in expression of counter-regulatory genes that we hypothesize would contribute to a transient antitumor effect, and confirmed in mouse models that combination therapy to inhibit this counter-regulation can improve responses to cytokine therapy.
Conclusions:
These results support the safety and activity of intratumorally delivered, collagen-anchoring cytokines for inflammatory polarization of the canine STS tumor microenvironment. We are further evaluating the efficacy of this approach in additional canine cancers, including oral malignant melanoma.
Insights
Engineered collagen-binding cytokines (interleukin-2 and -12) showed safety and immune-stimulating activity in dogs with soft-tissue sarcomas. This localized therapy warrants further investigation for canine cancers.
Area of Science:
- Oncology
- Immunotherapy
- Biotechnology
Background:
- Cytokine therapies like IL2 and IL12 have limited clinical use due to narrow therapeutic windows from off-tumor effects.
- Engineered cytokines that bind to tumor collagen offer a strategy to improve localized delivery and reduce systemic toxicity.
- Spontaneous canine soft-tissue sarcomas (STS) provide a relevant preclinical model for evaluating novel cancer therapies.
Purpose of the Study:
- To assess the safety and biomarker activity of intratumorally delivered, collagen-binding cytokines (IL2 and IL12) in dogs with STS.
- To determine the maximum tolerated dose (MTD) in healthy beagles.
- To evaluate the immunomodulatory effects within the tumor microenvironment.
Main Methods:
- Collagen-binding cytokines were adapted for canine use to minimize immunogenicity.
- A dose-escalation study in healthy beagles identified the MTD.
- Ten client-owned dogs with STS received cytokine therapy prior to surgical excision.
- Tumor tissues were analyzed using immunohistochemistry (IHC) and NanoString RNA profiling.
Main Results:
- Intratumoral collagen-binding IL2 and IL12 were well-tolerated, with only mild adverse events (Grade 1/2).
- IHC confirmed increased T-cell infiltration into tumors.
- Gene expression analysis revealed enhanced cytotoxic immune function and increased counter-regulatory gene expression.
- Mouse models indicated that inhibiting counter-regulation could improve cytokine therapy responses.
Conclusions:
- Intratumorally delivered, collagen-anchoring cytokines are safe and promote an inflammatory tumor microenvironment in canine STS.
- This localized cytokine delivery approach shows potential for treating canine cancers.
- Further evaluation in other canine cancers, such as oral malignant melanoma, is underway.
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