Effective Inhibition of the Epidermal Growth Factor/Epidermal Growth Factor Receptor Binding by Anti–Epidermal Growth Factor Antibodies Is Related to Better Survival in Advanced Non–Small-Cell Lung Cancer Patients Treated with the Epidermal Growth Factor Cancer Vaccine

Abstract

Purpose: Epidermal growth factor (EGF) might be a suitable immunotherapeutic target in nonŝ mall-cell lung cancer (NSCLC). Our approach consists of active immunotherapy with EGF. The aim of the study is to characterize the humoral response and its effects on signal transduction in relation with the clinical outcome. Experimental Design: Eighty NSCLC patients treated with first-line chemotherapy were randomized to receive the EGF vaccine or supportive care. EGF concentration in sera, anti-EGF antibodies and their capacity to inhibit the binding between EGF/EGF receptor (EGFR), and the EGFR phosphorylation were measured. Results: Seventy-three percent of vaccinated patients developed a good antibody response, whereas none of the controls did. In good antibody-responder patients, self EGF in sera was significantly reduced. In 58% of vaccinated patients, the post-immune sera inhibited EGF/EGFR binding; in the control group, no inhibition occurred. Post-immune sera inhibited the EGFR phosphorylation whereas sera from control patients did not have this capacity. Good antibodyresponder patients younger than 60 years had a significantly better survival. A high correlation between anti-EGF antibody titers, EGFR phosphorylation inhibition, and EGF/EGFR binding inhibition was found. There was a significantly better survival for vaccinated patients that showed the higher capacity to inhibit EGF/EGFR binding and for those who showed an immunodominance by the central region of EGF molecule. Conclusions: Immunization with the EGF vaccine induced neutralizing anti-EGF antibodies capable of inhibiting EGFR phosphorylation. There was a significant positive correlation between antibody titers, EGF/EGFR binding inhibition, immunodominance of anti-EGF antibodies, and survival in advanced NSCLC patients.

A Phase III Clinical Trial of the Epidermal Growth Factor Vaccine CIMAvax-EGF as Switch Maintenance Therapy in Advanced Non–Small Cell Lung Cancer Patients

“…CIMAvax-EGF is built on the induction of a specific immune response, aiming to sequester EGF, a molecular driver of cancer cell proliferation (11)(12)(13)(14)(15). Its mechanism of action is based on the "hormone deprivation theory" that has proven to be effective for sexual hormones-dependent tumors (10).…”

“…Patients were classified in good antibody responders (GAR) if they developed anti-EGF antibody titers equal or higher than 1:4,000 and super-good antibody responders if they reached anti-EGF antibody titers equal or higher than 1:64,000. Those vaccinated patients that did not have titers above 1:4,000 were classified as poor antibodies responders (12)(13)(14)(15).…”

“…Patients younger than 60 years, those with good antibody response against EGF, and subjects in whom serum EGF concentration ([EGF]) decreased below a preestablished threshold, achieved a significant survival benefit with vaccination. Postimmune serum hampered the binding between EGF and EGFR in a radioreceptor assay and abrogated EGFR phosphorylation (14,15).…”

Strong humoral response elicited by a DNA vaccine targeting gastrin-releasing peptide with optimized adjuvants inhibits murine prostate carcinoma growth in vivo

“…This phenomenon suggests that GRP-specific Abs neutralize the self-peptide GRP and lower the concentration of GRP around the tumor, the activation of GRPR may therefore be interrupted and the successive signalling pathways can be blocked. Very recently, Garcia et al (2008) reported the humoral immune response of patients enrolled in a randomized phase II clinical trial using epidermal growth factor (EGF) vaccination blocked the binding of EGF to its receptor (EGFR), which slowed down tumor cell proliferation and correlated with survival in vaccinated non-small-cell lung cancer (NSCLC) patients. The strategy of exploiting anti-EGF autoantibodies to block the EGF/EGFR autocrine loop reduces the growth rate of EGF-dependent tumors, which can also support the function of anti-GRP autoantibodies in reducing the growth rate of GRP-dependent tumors.…”

Vaccines for the Treatment of Non-Small Cell Lung Cancer: A Renewed Anticancer Strategy

“…There was significant positive correlation among antibody titers, EGF-EGFR binding inhibition, immunodominance of anti-EGF antibodies, and survival in advanced NSCLC patients. The survival advantage for the vaccinated patients over the control group was statistically significant in the subgroup of patients aged Ͻ60 years (median OS time, 11.57 versus 5.33 months, respectively; p ϭ .0124) [40,41]. This suggests that, for certain vaccines, the best response may come only in younger patients.…”