Abstract 7246: 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 just 8%, killing over 20, 000 Americans annually, thus new therapies are urgently needed. ∼15% of SCLC patients naturally develop anti-Hu (an antibody response against ELAVL4) and show improved response to therapy with significantly extended survival. Rare SCLC patients develop a severe and sometimes lethal autoimmune response against ELAVL4 and can show complete SCLC regression. We determined that the antibody-initiating antigenic epitope consists of ELAVL4 isoaspartylated (isoAsp-ELAVL4) in its unstructured N-terminal region (aa 1-38). Isoaspartylation is an immunogenic type of protein damage that is normally repaired but appears abnormally persist 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-isoAsp-ELAVL4 antibody response can lead to autoimmunity through epitope spreading to unmodified ELAVL4. Methods: Here we tested whether actively inducing an immune response against recombinant isoaspartylated Elavl4 in a mouse SCLC model improves survival. We used a Trp53fl/fl; Rb1fl/fl inducible SCLC mouse model to examine both: whether immunization with isoAsp-Elavl4 prior to SCLC induction is protective, and whether immunization with isoAsp-ELAVL4 extends survival following completion of cisplatin+etoposide therapy. Mice were immunized with a recombinant N-terminal fragment of Elavl4 (aa 1-117) generated in Clear Coli and incubated under isoaspartyl-inducing conditions (phosphate-buffered saline at 37°C for 7 days), then emulsified in incomplete Freund’s adjuvant (IFA). The negative control was phosphate-buffered saline in IFA; recombinant Elavl4 naturally undergoes isoaspartylation even after short periods at 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. 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 extends overall survival (p = 0.00088). Conclusions: An immune response against isoAsp-Elavl4 can be actively induced, and when given after chemotherapy can significantly improve SCLC overall survival in a mouse model. Citation Format: Diego Alejandro Velarde, Joseph Valdes, Chunli Yan, Sarah Elmalh, Hannah Lee, Daniel J. Mullen, Angie Moreno, Matthew A. Gladstone, Nicky Nie, Ming Li, 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 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7246.