Abstract 6077: A natural antibody response associated with improved survival of SCLC patients can be actively induced in a SCLC mouse model and leads to significantly improved survival

Abstract BACKGROUND: Small cell lung cancer (SCLC) has a 5-year survival of 8%, killing over 20,000 Americans annually. New therapies are urgently needed. ∼15% of SCLC patients exhibit a natural “anti-Hu” antibody response against ELAVL4 and show improved response to therapy with significantly better survival. Rare SCLC patients develop a severe and sometimes lethal autoimmune response to ELAVL4 and can show complete SCLC regression. We determined that the antigenic epitope consists of ELAVL4 that is isoaspartylated in its unstructured N-terminal region (aa 1-38). Isoaspartylation is an immunogenic type of protein damage that is normally repaired but appears to be abnormally present in ELAVL4 in SCLC. IsoAsp-ELAVL4 constitutes a cancer-specific neo-antigen. ELAVL4 has been shown to be expressed on the outside of SCLC cells. In rare cases the anti-ELAVL4 antibody response can lead to autoimmunity through epitope spreading. METHODS: Here we tested whether actively inducing an immune response against recombinant isoaspartylated Elavl4 (isoAsp-Elavl4) in a mouse SCLC model improves survival. We used a Trp53fl/fl; Rb1fl/fl inducible SCLC mouse model to examine: 1) Whether immunization with isoAsp-Elavl4 prior to SCLC induction is protective, and 2) Whether immunization with isoAsp-ELAVL4 following completion of cisplatin+etoposide therapyincreases survival. Mice were immunized with a recombinant N-terminal fragment of Elavl4 (isoAsp-Elavl4, aa 1-117) generated in Clear Coli and incubated under isoaspartyl-inducing conditions (7 days in PBS at 37°C), then emulsified in incomplete Freund’s adjuvant (IFA). The negative control was PBS in IFA; Elavl4 naturally undergoes isoaspartylation even after short periods under physiological conditions, preventing its use as a negative control. The trajectories of mice were closely monitored with a detailed body metric score, and serum was collected from blood draws every 2 weeks to monitor the anti-Elavl4 antibody response. The tumor immune microenvironment of ELAVL4 and control-immunized mice was examined using Visium HD spatial transcriptomics. RESULTS: ELISA data showed that all isoAsp-Elavl4-immunized animals became immune responsive against isoAsp-Elavl4, and just as in human SCLC patients, a small fraction of control-immunized animals spontaneously developed anti-Elavl4 reactivity. Immunization alone before SCLC induction in the absence of chemotherapy did not improve survival. In contrast, immunization following cisplatin+etoposide therapy significantly increased survival (p < 0.001). Visium HD analyses will be presented. CONCLUSIONS: An immune response against isoAsp-Elavl4 can be actively induced, and when given after chemotherapy can significantly improve SCLC survival in a mouse model. We are leveraging these observations for the development of a new SCLC therapy. Citation Format: Diego Alejandro Velarde, Joseph Valdes, Chunli Yan, Sarah Elmalh, Hannah Lee, Daniel James Mullen, Angie Moreno, Matthew A. Gladstone, JONATHAN CASTILLO, Crystal N. Marconett, Nicky Nie, Ming Li, W. Martin Kast, Ite A. Offringa. A natural antibody response associated with improved survival of SCLC patients can be actively induced in a SCLC mouse model and leads to significantly improved survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6077.