Abstract 7296: PF-08046049 synergizes with checkpoint inhibitors to drive CD8+ T cell effector differentiation and tumor clearance in an IO-resistant model

Abstract The checkpoint inhibitors anti-PD-1 and anti-CTLA-4 have been clinically successful as therapeutics for melanoma due to their ability to reinvigorate the immune system. However, about half of patients do not benefit from these treatments, suggesting there are still barriers to CD8+ T cell activation or infiltration into the tumor microenvironment (TME). Additionally, while the combination therapy of anti-CTLA-4 and anti-PD-1 (Ipilimumab-Nivolumab) improves response rate and overall survival compared to monotherapies, it also leads to increased toxicity and immune-related adverse events. Recent studies have demonstrated that CD8+ T cell co-stimulation through the 41BB axis is critical for PD-1/PD-L1 blockade efficacy in melanoma, yet those signals may be limited or unavailable to tumor-associated antigen-specific T cells within the TME. However, nontargeted 4-1BB signaling poses a risk of widespread peripheral immune activation and liver toxicity, as was the case for the 4-1BB agonist Urelumab. PF-08046049 (BB228) is a bispecific molecule comprised of a CD228-specific antibody and 4-1BB-directed Anticalin proteins. CD228 is highly expressed in several cancer indications but is low on normal tissues, thus BB228 targets 4-1BB co-stimulation to T cells within the TME. We tested the efficacy of BB228 as a monotherapy and in combination with the current melanoma standard of care (SOC) treatments, anti-PD-1 and anti-PD-1/anti-CTLA-4. In an IO-resistant LL2 model, neither BB228 nor anti-PD-1 monotherapy led to tumor control. However, in combination, BB228 synergized with anti-PD-1 and anti-CTLA-4 to promote tumor clearance. We found that while anti-PD-1 and anti-CTLA-4 can target and expand stem-like CD8+ T cells in both the tumor-draining lymph node and TME, BB228 is able to drive the differentiation of those stem-like cells into effectors, resulting in tumor killing. These data illustrate that BB228 has a distinct and complementary mechanism of action from the current melanoma SOC treatments. Citation Format: Laila Shehata, Michelle Ulrich, Lupe Gutierrez, J. Hartsuyker, Raj Giraddi, Ryan A. Heiser, Brian P. O'Connor. PF-08046049 synergizes with checkpoint inhibitors to drive CD8+ T cell effector differentiation and tumor clearance in an IO-resistant model [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 7296.