Radiosensitisation of U87MG brain tumours by anti-epidermal growth factor receptor monoclonal antibodies

As epidermal growth factor receptor (EGFR) has been reported to be a radiation response modulator, HER inhibitors are regarded to act as potential radiosensitisers. Our study examined the role of nimotuzumab and cetuximab both, the two monoclonal antibodies (mAbs) to EGFR, as radiosensitisers in a murine glioma model in vivo. Co-administration of both the antibodies with radiation increased the radiosensitivity of U87MG, resulting in a significant delay of subcutaneous (s.c.) tumour growth. Furthermore, the addition of antibodies to the radiation decreased brain tumour sizes and is inhibited by 40–80% the increased tumour cell invasion provoked by radiotherapy, although promoted tumour cell apoptosis. Whereas nimotuzumab led to a reduction in the size of tumour blood vessels and proliferating cells in s.c. tumours, cetuximab had no significant antiangiogenic nor antiproliferative activity. In contrast, cetuximab induced a more marked inhibition of EGFR downstream signalling compared with nimotuzumab. Moreover, both antibodies reduced the total number of radioresistant CD133+ cancer stem cells (CSCs). These results were encouraging, and showed the superiority of combined treatment of mAbs to EGFR and radiation over each single therapy against glioblastoma multiforme (GBM), confirming the role of these drugs as radiosensitisers in human GBM. In addition, we first showed the ability of mAb specifics against EGFR to target radioresistant glioma CSC, supporting the potential use in patients

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

The expression and activity of the epidermal growth factor receptor (EGFR) are determinants of radiosensitivity in several tumour types, including non-small cell lung cancer (NSCLC). However, little is known of whether genetic alterations of EGFR in NSCLC cells affect the therapeutic response to monoclonal antibodies (mAbs) to EGFR in combination with radiation. We examined the effects of nimotuzumab, a humanised mAb to EGFR, in combination with ionising radiation on human NSCLC cell lines of differing EGFR status. Flow cytometry revealed that H292 and Ma-1 cells expressed high and moderate levels of EGFR on the cell surface, respectively, whereas H460, H1299, and H1975 cells showed a low level of surface EGFR expression. Immunoblot analysis revealed that EGFR phosphorylation was inhibited by nimotuzumab in H292 and Ma-1 cells but not in H460, H1299, or H1975 cells. Nimotuzumab augmented the cytotoxic effect of radiation in H292 and Ma-1 cells in a clonogenic assay in vitro, with a dose enhancement factor of 1.5 and 1.3, respectively. It also enhanced the antitumor effect of radiation on H292 and Ma-1 cell xenografts in nude mice, with an enhancement factor of 1.3 and 4.0, respectively. Nimotuzumab did not affect the radioresponse of H460 cells in vitro or in vivo. Nimotuzumab enhanced the antitumor efficacy of radiation in certain human NSCLC cell lines in vitro and in vivo. This effect may be related to the level of EGFR expression on the cell surface rather than to EGFR mutation

Control of Advanced Cancer: The Road to Chronicity

Despite the recent trend toward a slight decrease in age-adjusted cancer mortality in some countries, crude mortality rates will continue to increase, driven by the demographic shift towards an aged population. Small molecules (small molecules and biologics) are not only a new therapeutic acquisition, but the tools of a more fundamental transition: the transformation of cancer from a rapidly fatal disease into a chronic condition. Antibodies and cancer vaccines can be used for a long time, even beyond progressive disease, and in aged patients, usually unfit for more aggressive conventional treatments. However, this transition to chronicity will require novel developmental guidelines adequate to this kind of drugs, for which optimal dose is not usually the maximal tolerated dose, pharmacokinetics does not define treatment schedule, and tumor shrinkage is not a good correlate of survival. The ongoing cancer immunotherapy program (including several monoclonal antibodies and therapeutic vaccines) at the Centre of Molecular Immunology can illustrate the issues to be addressed, both biological and social, along the path to transform advanced cancer into a chronic non-communicable disease compatible with years of quality life

Efficacy of nimotuzumab according to inflammatory indices in patients with advanced non-small cell lung cancer

Introduction: The response to therapies in advanced lung cancer could be related to certain prognostic factors such as inflammatory indices. Objective: To evaluate the efficacy of the humanized monoclonal antibody nimotuzumab in patients with advanced non-small cell lung cancer according to inflammatory indices. Method: A retrospective longitudinal evaluation study was carried out in a universe of 498 patients older than 18 years, with a cytohistological diagnosis of non-small cell lung cancer, in advanced stages, after the first line of oncological therapy, including in multicenter clinical trials promoted by the Center for Molecular Immunology from 2002 to 2018. Descriptive statistics were applied, the x-tile 3.6.1 software was used for the Kaplan Meier test, significant differences were considered when p< 0,05. Results: In the patients analyzed, nimotuzumab showed therapeutic benefit in the group of patients who did not progress to the first line of treatment with chemotherapy or chemoradiotherapy, when they had a lower neutrophil-lymphocyte index (p= 0,017 and p= 0,027) and a lower platelet-lymphocyte index (p= 0,030 and p= 0,009). Conclusion: Selecting a patient with a lower inflammatory index benefits the efficacy of treatment with the humanized mAb nimotuzumab in advanced non-small cell lung cancer, which becomes a predictive tool for response to treatment

Safety and effectiveness of CIMAvax-EGF administered in community polyclinics

In spite of the advances in immunotherapy and targeted therapies, lung cancer continues to be the leading cause of cancer-related death. The epidermal growth factor receptor is an established target for non-small cell lung cancer (NSCLC), and its overactivation by the ligands can induce accelerated proliferation, angiogenesis, and metastasis as well as proinflammatory or immunosuppressive signals. CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy that is approved for the treatment of NSCLC patients in Cuba. The study was designed as a phase IV trial to characterize the safety and effectiveness of CIMAvax-EGF in advanced NSCLC patients treated in 119 community polyclinics and 24 hospitals. CIMAvax-EGF treatment consisted of four bi-weekly doses followed by monthly boosters. Overall, 741 NSCLC patients ineligible for further cancer-specific treatment were enrolled. CIMAvax-EGF was safe, and the most common adverse events consisted of mild-to-moderate injection site reactions, fever, chills, tremors, and headache. For patients completing the loading doses, the median survival was 9.9 months. For individuals achieving at least stable disease to the frontline and completing vaccination induction, the median survival was 12 months. Most of the functional activities and symptoms evaluated through the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire improved over time. In conclusion, this real-world trial demonstrated that CIMAvax-EGF was safe and effective in patients who were vaccinated in the maintenance scenario. A larger effect was seen in subjects with poor prognosis like those with squamous tumors and high EGF levels. Remarkably, this community-based intervention was very important because it demonstrated the feasibility of treating advanced lung cancer patients with active immunotherapy in primary care institutions. In addition to CIMAvax-EGF, patients received supportive care at the community clinic. Vaccine administration by the family doctors at the polyclinics reduced the patients’ burden on the medical oncology services that continued providing chemotherapy and other complex therapies. We conclude that community polyclinics constitute the optimal scenario for administering those cancer vaccines that are safe and require prolonged maintenance in patients with advanced cancer, despite the continuous deterioration of their general condition.Clinical trial registrationhttps://rpcec.sld.cu/trials/RPCEC00000205-En, identifier RPCEC00000205