Abstract 2230: Persistent elimination of tumors via balanced regulation of immune signals

Abstract Despite its success, there are still numerous unmet clinical needs in cancer immunotherapy. Many patients failed to respond due to the lack of effective and properly regulated T cell stimulation. Molecules capable of inhibiting multiple immune checkpoints, enhancing the co-stimulatory signals on T cells to “revive” the tumor antigen-specific T cell response, as well as sustaining the responses to prevent the recurrence of the tumor are highly desirable. Here we report a Fc-based, tripartite, multifunctional fusion protein JLM019 that has been rationally designed to integrate the multiple mechanisms of PD-1/PD-Ligands checkpoint inhibition and T cell co-stimulations through CD80-mediated signaling. Fused at the C-terminus of the Fc fragment, structure-guided mutations A132L and Loop15 were introduced into the human PD-1 ectodomain to improve affinity with its ligands. Fused at the N-terminus, the wild-type CD80 provided a canonical co-stimulatory signal compared to hyperreactive anti-CD28 agonistic antibodies. Combined effect of PD-1 signaling blockade and balanced T cell activation through CD80 binding with CTLA4/CD28 by JLM019 led to persistent elimination of wide spectrum of tumors, including tumors with no PD-L1 expression, or those resistant to conventional PD-1 checkpoint inhibitors in CDX models. JLM019 acts not only on the tumor but also through activating tumor-specific T cells that depend on other APCs and/or through PD-L2 signaling. Significantly, JLM019 treatment induced effective immune memory, which was confirmed by experiments using transferred splenocytes from cured mice that not only prevented tumor initiation but also eliminated tumors in the established tumor-bearing mice. The sophisticated mechanism of the action by JLM019 is explored and discussed. In summary, we developed an immune signal regulator JLM019 that can modulate immune signaling against advanced tumors in a potent yet well-balanced manner. Pre-clinical toxicity and PK/PD studies in cynomolgus monkey have shown a promising safety and toxicity profile, with a dose up to 100mg/kg being tolerated. These encouraging results prompted us to advance JLM019 for clinical studies in humans. Citation Format: Xiaodong Xiao, Lei Han, Yuan Yuan, Hua Jiang, Yueqing Xie, Jianwei Zhu. Persistent elimination of tumors via balanced regulation of immune signals [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 2230.