Anti-EGF antibodies as surrogate biomarkers of clinical efficacy in stage IIIB/IV non-small-cell lung cancer patients treated with an optimized CIMAvax-EGF vaccination schedule

Abstract

We previously reported that CIMAvax-EGF vaccine is safe, immunogenic and efficacious to treat advanced non-small-cell lung cancer (NSCLC) patients. A phase III trial was designed using an optimized immunization schedule. It included higher antigen dose and injections at multiple sites. Immune response and circulating biomarkers were studied in a subset of patients. EGF-specific antibody titers, IgG subclasses, peptide immunodominance and circulating biomarkers were assessed by ELISA. In vitro EGF-neutralization capacity of immune sera and EGF-IgG binding kinetics was evaluated by Western Blot and Surface Plasmon Resonance (SPR) technology, respectively. We show that CIMAvax-EGF elicited mainly IgG3/IgG4 antibodies at titers exceeding 1:4000 in 80% of vaccinated patients after 3 months of treatment. The EGF-specific humoral response was directed against the central region of the EGF molecule. For the first time, the kinetic constants of EGF-specific antibodies were measured evidencing affinity maturation of antibody repertoire up to month 12 of vaccination. Notably, the capacity of post-immune sera to inhibit EGFR phosphorylation significantly increased during the course of the immunization scheme and was related to clinical outcome (P = .013, log-rank test). Basal concentrations of EGF and TGFα in the serum were affected by EGF-based immunization. In conclusion, the CIMAvax-EGF vaccine induces an EGF-specific protective humoral response in a high percent of NSCLC vaccinated patients, the quantity and quality of which were associated with clinical benefit (clinical trial registration number: RPCEC00000161, http://registroclinico.sld.cu/). Abbreviations: EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; Ab: antibody; AR: amphiregulin; NSCLC: non-small-cell lung cancer; rhEGF: recombinant human epidermal growth factor; BSC: best supportive care; TGFα: tumor growth factor alpha; IL-8: interleukin 8; MAb: monoclonal antibody; SPR: surface plasmon resonance.