Related Experiment Video
Updated: Oct 29, 2025
09:15
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
3.7K
Thymic Lymphomas in a 6-Month rasH2-Tg Mouse Carcinogenicity Study With the RORγt Inverse Agonist, BMS-986251.
Helen G Haggerty1, Jean G Sathish1, Carol R Gleason2
1Nonclinical Research and Development, Bristol Myers Squibb, New Brunswick, New Jersey 08903, USA.
Summary
BMS-986251, a drug targeting retinoid-related orphan receptor gamma t (RORγt) for autoimmune diseases, caused thymic lymphomas in mice. This led to the drug's discontinuation due to safety concerns.
Area of Science:
- Pharmacology and Toxicology
- Immunology
- Oncology
Background:
- Retinoid-related orphan receptor gamma t (RORγt) is a key transcription factor in T helper 17 cell differentiation, implicated in autoimmune diseases.
- RORγt inhibition is a therapeutic strategy for autoimmune conditions, but potential safety risks, including carcinogenicity, require thorough investigation.
- Previous studies indicate RORγt deficiency can lead to thymic lymphomas in mice, highlighting the importance of evaluating RORγt-targeting agents for oncogenic potential.
Purpose of the Study:
- To assess the potential carcinogenicity of BMS-986251, a novel RORγt inverse agonist, in a relevant animal model.
- To determine if BMS-986251 administration leads to an increased incidence of tumors, particularly thymic lymphomas.
- To identify a no-effect dose for potential tumor induction by BMS-986251.
Main Methods:
- A 6-month carcinogenicity study was conducted in rasH2-Tg hemizygous mice.
- BMS-986251 was administered orally at doses of 0, 5, 25, or 75 mg/kg/day; N-methyl-N-nitrosourea served as a positive control.
- Tumor incidence, specifically thymic lymphomas, and lymphoid cellularity were evaluated.
Main Results:
- BMS-986251 treatment resulted in an increased incidence of thymic lymphomas, particularly in female mice at mid and high doses.
- Lymphoid hyperplasia in the thymus was observed in BMS-986251-treated groups, suggesting a preneoplastic change.
- The incidence of thymic lymphomas exceeded historical control data, and a no-effect dose for tumor induction was not identified.
Conclusions:
- BMS-986251 demonstrated potential carcinogenicity, specifically inducing thymic lymphomas and lymphoid hyperplasia in a rasH2-Tg mouse model.
- The observed safety concerns led to the discontinuation of BMS-986251 development for autoimmune diseases.
- Targeting RORγt for therapeutic purposes presents significant challenges due to potential oncogenic risks, necessitating careful risk-benefit assessments.
