Antisense oligonucleotides against TNFR1 prevent toxicity of TNF/IFNγ treatment in mouse tumor models

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Tumor Necrosis Factor (TNF) exhibits potent antitumor effects but is limited by severe systemic inflammatory toxicity.
• The receptor TNFR1 (P55) mediates both the therapeutic and toxic actions of TNF, as evidenced by the absence of these effects in P55-deficient mice.
• Partial deficiency in P55 (P55+/- mice) confers resistance to TNF toxicity while preserving the antitumor efficacy of TNF combined with Interferon gamma (IFNγ).

Purpose of the Study:

• To provide proof of principle for a therapeutic strategy involving the reduction of P55 levels to enhance TNF/IFNγ antitumor therapy.
• To evaluate the efficacy of antisense oligonucleotides (ASOs) in downregulating P55 protein and mitigating TNF-induced toxicity.
• To assess the safety and efficacy of P55 downregulation in combination with TNF/IFNγ treatment across various cancer models.

Main Methods:

• Mice were treated with antisense oligonucleotides (ASOs) specifically designed to target and reduce P55 protein levels.
• P55 protein expression was quantified in liver, small intestine, and blood mononuclear cells following ASO treatment.
• TNF toxicity was assessed by measuring hypothermia, systemic inflammation, and lethality. Antitumor efficacy was evaluated in B16Bl6, Lewis lung carcinoma, and lung colony cancer models.

Main Results:

• ASO treatment led to a significant reduction in P55 protein levels.
• Downregulation of P55 conferred substantial protection against acute TNF toxicity, including reduced hypothermia, inflammation, and lethality.
• The P55-targeted ASO treatment also protected mice against the toxicity associated with combined TNF/IFNγ therapy in multiple cancer models.

Conclusions:

• Reducing P55 expression via ASOs is a viable strategy to decouple the antitumor effects of TNF from its systemic toxicity.
• This approach demonstrates significant therapeutic potential for developing safer and more effective combination therapies using TNF and IFNγ for cancer treatment.
• The findings support the clinical translation of P55-targeted therapies to improve cancer treatment outcomes.