Immunizing small cell lung cancer mice with isoaspartylated Elavl4 after chemotherapy mimics improved survival of anti-ELAVL4 antibody-positive small cell lung cancer patients

Authors

Velarde, D. A., Valdes, J. A., Lee, H., Yan, C., Elmalh, S., Moreno, A. D., Mullen, D. J., Gladstone, M. A., Gulivani, S., Nie, Q., Li, M., Kast, W. M., Offringa, I. A.

Abstract

Introduction: Small cell lung cancer (SCLC) patients have an ~8% 5-year survival; new therapies are urgently needed. Approximately 15% of SCLC patients have naturally-occurring low-titer antibodies against neuronal ELAVL proteins, associated with improved response to therapy and significantly improved survival. We previously determined that the anti-ELAVL4 response is triggered by isoaspartylation in the unstructured ELAVL4 N-terminal region. Methods: We used a Tp53fl/fl;Rb1fl/fl inducible SCLC mouse model to test whether 1) immunization with isoaspartylated Elavl4 (isoAsp-Elavl4) prior to SCLC induction improves survival in the absence of any other treatment, and 2) immunization with isoAsp-Elavl4 following completion of 3 rounds of cisplatin+etoposide therapy improves survival. Immunizations contained incomplete Freund's adjuvant with either a recombinant N-terminal fragment of Elavl4 (amino acids 1-117), incubated under isoaspartyl-inducing conditions, or phosphate-buffered saline (used as the negative control, since Elavl4 spontaneously isoaspartylates). Mice were monitored by blinded assessors until euthanasia was indicated. Results: IsoAsp-Elavl4-immunized animals all became immune responsive, and spontaneous anti-isoAsp-Elavl4 antibodies were observed in 7% of the control animals. Kaplan-Meier analyses revealed that pre-SCLC immunization with isoAsp-ELAVL4 in the absence of other treatments did not affect survival. In contrast, immunization of SCLC mice following chemotherapy significantly improved survival. Conclusions: An anti-isoAsp-ELAVL4 response can be actively induced in mice and significantly increases SCLC survival when given following chemotherapy. This indicates that the anti-isoAsp-ELAVL4 immune response can be leveraged to develop new therapies for SCLC patients.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 02 Sep 2026.

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