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Preprint WatchStrongOctober 25th, 2026

Novel retinoic acid receptor-related orphan receptor gamma inverse agonist enhances checkpoint blockade in hepatocellular carcinoma: a preclinical mouse study

Leo, S.; Dhoparee-Doomah, I.; Negi, S.; Fouda, A.; Bourdeau, F.; Evaristo, G.; Paraskevas, S.; Cools-Lartigue, J.; Tchervenkov, J.

RORgamma inverse agonism reduces intratumoural neutrophil recruitment and increases tumour-cell PD-L1 expression, and combining it with PD-L1 blockade improves tumour control over PD-L1 blockade alone in an orthotopic mouse model of hepatocellular carcinoma.

Strong contradiction

3 prior failures

Three or more documented clinical failures match this mechanism, or a Phase 3 efficacy failure is on record.

This preclinical mouse study reports that TF-S10, an inverse agonist of retinoic acid receptor-related orphan receptor gamma, reduced neutrophil migration and raised tumour-cell PD-L1 in vitro, and that combining it with anti-PD-L1 reduced endpoint liver tumour volume relative to anti-PD-L1 alone in orthotopic Hep-55.1c mice. The novel target is RORC, which carries no recorded failure in the Claidex graph, so the match here is on the checkpoint partner rather than on the new agent. CD274 carries three recorded failures. Avelumab with lenvatinib in paediatric high-grade CNS tumours is an efficacy failure (avelumab-lenvatinib-cd274-pediatric-cns-tumors-phase1-efficacy-failure). INCB099280 with axitinib in advanced solid tumours and INCB099280 in advanced cutaneous squamous cell carcinoma were both strategic discontinuations (incb099280-cd274-oral-pd-l1-solid-tumors-phase1-strategic-discontinuation and incb099280-cd274-cutaneous-squamous-cell-carcinoma-phase2-strategic-termination). A fourth checkpoint-combination failure was recorded in this same tumour today under a different target, where the only published efficacy signal for an anti-GARP antibody came from a single-arm escalation that could not separate the novel agent's contribution from the anti-PD-1 contribution (livmoniplimab-lrrc32-garp-tgfb1-hepatocellular-carcinoma-phase1b-program-discontinuation). The preprint's mouse experiment does include an anti-PD-L1 monotherapy arm, which is the comparison those clinical programmes skipped. The question for translation is whether that contribution-of-components structure survives into human trials rather than being dropped at the first dose escalation.

Abstract excerpt

Background and Aims: Neutrophil-associated inflammation is associated with poor outcomes in hepatocellular carcinoma (HCC), but tumour-intrinsic regulators of neutrophil recruitment and checkpoint response remain unclear. We evaluated whether inhibiting retinoic acid receptor-related orphan receptor gamma (RORgamma) alters neutrophil recruitment, programmed death-ligand 1 (PD-L1) expression, and response to PD-L1 blockade. Approach and Results: Survival associations were analysed in The Cancer Genome Atlas HCC cohort. Neutrophil migration toward HCC cells and PD-L1 expression were assessed after RORC silencing or TF-S10 treatment. Immunocompetent mice bearing orthotopic Hep-55.1c tumours received vehicle, TF-S10, anti-PD-L1, or combination treatment. Higher S100A9 and CXCL8 expression was associated with shorter survival (P = 0.000459 and P = 0.0004413, respectively), and tumour-bearing mice had higher neutrophil-to-lymphocyte ratios (P < 0.0001). RORgamma targeting reduced neutrophil migration and intratumoural Ly6G+; infiltration while increasing tumour-cell PD-L1 expression in vitro. Combination treatment reduced endpoint liver tumour volume versus anti-PD-L1 monotherapy (P < 0.01). Half of combination-treated mice had tumour volumes less than or equal to 0.10 cm^3 and none exceeded 1.00 cm^3, compared with 62% of controls exceeding 1.00 cm^3. Histologically, 85% of combination-treated mice had less than or equal to 10% liver tumour involvement, versus no controls. Combination treatment also reduced tumour-associated neutrophil populations and peripheral neutrophil-to-lymphocyte ratios. All active treatments reduced pulmonary metastatic burden versus controls, without significant differences among treatment groups; 53% of combination-treated mice had no detectable lung metastases. Conclusions: RORgamma inhibition reduces neutrophil recruitment and increases tumour-cell PD-L1 expression. Combined RORgamma inhibition and PD-L1 blockade improves hepatic tumour control in preclinical HCC and warrants further investigation.

Matching Claidex post-mortems

3 of 3 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.