一种与SCLC患者生存改善相关的天然抗体应答可在SCLC小鼠模型中被主动诱导并显著改善生存

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 Trp53 fl/fl ; Rb1 fl/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 therapy increases 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.