Abstract 5138: Systemic agonist anti-CD40 treatment delivers precise melanoma immunotherapy within established autoimmune landscapes

Abstract The overlapping signatures of type 1 interferons (IFN) and IFN-gamma (IFNg) has proven challenging in human autoimmunity and cancer immunotherapy, particularly for resistance to anti-programmed death 1 (anti-PD1) monotherapy. By contrast, agonist abs targeting of CD40 (anti-CD40) antibodies (abs) has clinically elicit anti-tumor immunity with limited autoimmune complications. Here, we explore the relationships between anti-PD1 or agonist CD40 responses in melanoma tumors from type 1 IFN alpha receptor (IFNAR)-sufficient and type 1 IFNAR-deficient lupus-prone mice that overexpress IFNg. To address this, RNA-sequencing (RNA-seq) data on tumors treated with either anti-PD1 or agonist anti-CD40 was evaluated for tumor objective responses compared to untreated controls. Cellular and canonical pathway identification from RNA-seq data were interrogated from the IPA library for significantly differential expressed genes (DEG). Variance patterns of the anti-PD1 and anti-CD40 monotherapies identified known resistance and response pathways highly concordant with IFN co-expression patterns in the RNA-sequencing data, respectively. IPA biomarker analysis for uniquely regulated genes showed that anti-PD1 induced only 59 DEG; while anti-CD40 induced 494 DEG including Il-27, and PR/SET Domain 1 (PRDM1), a transcription factor regulated by IL-27. Specifically, signatures of MDSC development (irf8, il10); and adaptive resistance (pdcd1, pdcd1lg2, and TNFRSF5/CD40)) were negatively associated with response to anti-P1 monotherapy. By contrast, signatures of IFN activation (stat1, Ifng, and Ifngr1), chemotaxis (Cxcl10, Il12b and Il-27), attractants (Sema3g and Sema4a), and antigen presentation MHC II (h2-Aa, h2-Ab1, and ciita) were associated positively with response to agonist anti-CD40 monotherapy. Importantly, anti-CD40 alone delivered anti-tumor immune responses in type 1 IFN receptor-deficient lupus-prone mice that overexpress IFNg (Ifnar-/-ARE-/-) mice suggesting synergy with therapies blocking type 1 IFN signaling. Thus, these findings indicate that the rational use of CD40 agonists abs provide a better therapeutic platform to deliver precise anti-melanoma responses in complex autoimmune landscapes. Citation Format: Julio C. Valencia, Michael Sanford, Howard A. Young. Systemic agonist anti-CD40 treatment delivers precise melanoma immunotherapy within established autoimmune landscapes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5138.