Abstract 3414: PD-1 targeting increases the tolerance of IL-12 while maintaining potent anti-tumor immunity

Preclinical studies have shown that IL-12 is a potent immunostimulatory cytokine that is capable of directly boosting CD8 T cell and IFNγ-dependent anti-tumor immunity. However, fully potent IL-12 therapies have limited clinical safety profiles. We have designed PF-07921585 to overcome this challenge by targeting IL-12 pharmacology on PD-1+ immune cells, a subset of CD8 T cells often enriched in the tumor microenvironment. PF-07921585 is a fusion protein consisting of an effector null bivalent anti-human PD-1 full length IgG1 and a single, potency reduced, human IL-12 mutein. PF-07921585 was specifically designed to permit simultaneous binding of PD-1 antagonists and enable combination with PD-1/L1 agents (PDx). Combination potential was confirmed in a mixed-lymphocyte reaction assay where we observed that PF-07921585 promoted robust IFNγ-responses as a single agent and boosted PDx-dependent IFNγ responses when given in combination. These data also suggested that targeted IL-12 receptor agonism and PDx checkpoint blockade have potential to non-redundantly amplify anti-tumor immune responses. In further support of this hypothesis, we found that combining a PF-07921585 mouse surrogate with PDx therapy can elicit greater efficacy in both PDx-sensitive and resistant mouse syngeneic tumor models than when either the surrogate or PDx therapy were administered as single agents. Administration of mouse surrogate as a single-agent also elicited potent anti-tumor CD8/IFNγ-dependent efficacy in PD-sensitive/resistant models and less peripheral toxicity compared to an untargeted, fully potent IL-12. Mechanistically, single-agent surrogate treatment enhanced the effector states (including increased IFNγ production) of several PD-1+ exhausted CD8 T cell subsets including the most dysfunctional subset, terminally exhausted cells. This latter effect was most striking as many published studies suggest PDx therapies only elicit efficacy by affecting the least dysfunctional exhausted T cell subsets, stem-like/progenitor cells. In summary, these data suggest that PF-07921585 may be better tolerated than other IL-12 therapies and has potential to deliver efficacy in PDx-refractory patients by heightening the effector function of CD8 T cell subsets not previously achieved by existing PDx therapies. Citation Format: Stephen Searles, Kritika Mohan, Wenjing Yang, Elena Galitovskaya, Lynn Wang, Haikuo Zhang, Lidia Mosyak, Changhua Ji, Javier Chaparro-Riggers, Tzu-Hsuan Huang, Gabriel Starbeck-Miller. PD-1 targeting increases the tolerance of IL-12 while maintaining potent anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3414.