• CD276
• MEK/ERK
• Nimotuzumab
• Tumor-infiltrating lymphocytes (TILs)
• head and neck squamous cell carcinoma (HNSCC)

• Humans
• Animals
• Squamous Cell Carcinoma of Head and Neck/drug therapy
• Squamous Cell Carcinoma of Head and Neck/immunology
• Squamous Cell Carcinoma of Head and Neck/pathology
• Head and Neck Neoplasms/drug therapy
• Head and Neck Neoplasms/immunology
• Head and Neck Neoplasms/pathology
• Antibodies, Monoclonal, Humanized/pharmacology
• Antibodies, Monoclonal, Humanized/therapeutic use
• Cell Line, Tumor
• Mice
• Tumor Escape/drug effects
• Tumor Microenvironment/drug effects
• Xenograft Model Antitumor Assays
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/drug effects
• Antineoplastic Agents, Immunological/pharmacology
• Antineoplastic Agents, Immunological/therapeutic use
• ErbB Receptors/antagonists & inhibitors
• Female
• Transforming Growth Factor beta/metabolism
• Mice, Nude

• anti-tumor drugs
• chemotherapy drugs
• immunotherapy drugs
• intrathecal therapy
• leptomeningeal disease
• solid tumors
• targeted drugs

• Head and neck squamous cell carcinoma (HNSCC)
• IFN-γ
• MEK/ERK
• Nimotuzumab
• Programmed death ligand 1 (PD-L1)

• Humans
• B7-H1 Antigen/metabolism
• Antibodies, Monoclonal, Humanized/pharmacology
• Antibodies, Monoclonal, Humanized/therapeutic use
• Squamous Cell Carcinoma of Head and Neck/drug therapy
• Squamous Cell Carcinoma of Head and Neck/metabolism
• Squamous Cell Carcinoma of Head and Neck/pathology
• Squamous Cell Carcinoma of Head and Neck/genetics
• Cell Line, Tumor
• Animals
• Head and Neck Neoplasms/drug therapy
• Head and Neck Neoplasms/metabolism
• Head and Neck Neoplasms/pathology
• ErbB Receptors/metabolism
• Mice
• Male
• Gene Expression Regulation, Neoplastic/drug effects
• Female
• Mice, Nude
• Mice, Inbred BALB C
• MAP Kinase Signaling System/drug effects
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Xenograft Model Antitumor Assays
• Cisplatin/pharmacology
• Cisplatin/therapeutic use

• antibody-drug conjugates
• drug delivery
• esophageal cancer
• immunotherapy
• nanoparticles
• stents

• Humans
• Esophageal Neoplasms/therapy
• Drug Delivery Systems/methods
• Immunotherapy/methods
• Animals
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/therapeutic use
• Nanoparticles/chemistry

• R01 CA227433 NCI NIH HHS
• R01 CA232056 NCI NIH HHS
• T32 EB006359 NIBIB NIH HHS
• UL1 TR002541 NCATS NIH HHS

• immunotherapy
• nimotuzumab
• oral squamous cell carcinoma
• performance status score
• tislelizumab

• Humans
• Nasopharyngeal Carcinoma/drug therapy
• Retrospective Studies
• Nasopharyngeal Neoplasms/drug therapy
• Prospective Studies
• Chemoradiotherapy/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Induction Chemotherapy

To assess the clinical efficacy and toxicity of nimotuzumab in combination with chemoradiotherapy or chemoradiotherapy alone in the treatment of cervical cancer.

The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, China Biomedical Medicine, Wanfang, and VIP databases were systematically searched for relevant literature. Ultimately, six randomised controlled trials (n=393) were included in our meta-analysis.

A total of 393 patients were included, of which 197 were in the nimotuzumab combined with chemoradiotherapy group and 196 were in the chemoradiotherapy group. The results of our meta-analysis showed that the complete remission rate (risk ratio [RR] = 1.34, 95% confidence interval [CI]: 1.08-1.65, P = 0.007), objective response rate (RR = 1.30, 95% CI: 1.16-1.44, P < 0.05), and three-year survival rate (RR = 1.27, 95% CI: 1.06-1.51, P = 0.008) in the nimotuzumab combined with chemoradiotherapy group were significantly improved compared with the chemoradiotherapy group. This difference was not statistically significant when comparing the incidence of adverse reactions (such as leukocytopenia, gastrointestinal reaction, radiocystitis, and radioproctitis) between the two groups.

Nimotuzumab in combination with chemoradiotherapy has some advantages over chemoradiotherapy alone in the treatment of cervical cancer and does not increase toxicity. Therefore, nimotuzumab has the potential to be an effective treatment for cervical cancer; however, further evidence from large-scale randomised controlled trials is needed.

• National Natural Science Foundation of China

• epidermal growth factor receptor
• glioblastoma
• nimotuzumab
• radiotherapy
• survival
• temozolomide

To evaluate the safety and effectiveness of nimotuzumab in combination with chemoradiotherapy for locally advanced cervical esophageal squamous cell carcinoma.

Retrospective analysis was conducted from September 2012 to February 2017 among 50 locoregional-advanced cervical esophageal carcinoma (CEC) patients who received concurrent chemoradiotherapy (CRT) combined with or without nimotuzumab at Ningbo Medical Center Lihuili Hospital. Intensity-modulated radiotherapy (IMRT) was administrated on all patients. All patients were divided into two groups, of which 26 (Group A) received 200 mg (22 of 50) or 400 mg (4 of 50) of nimotuzumab per week with CRT and 24 (Group B) received definitive CRT.

The median follow-up time was 23 months. The median overall survival (OS) and progression-free survival (PFS) were 40.6 and 21.1 months for all, respectively. The 1-, 2-, and 3-year OS rates on the whole were 79.6%, 62.1%, and 47.8%. There was no statistical difference in overall response rate and disease control rate between the two groups. Patients treated with nimotuzumab (group A) had better PFS than the definitive CRT group (group B) (P < 0.05). However, the median OS was 41.4 months in group A and 32.4 months in group B, respectively (P = 0.517). Multivariate analysis showed that PFS among those with lower Eastern Cooperative Oncology Group (ECOG) score (HR = 5.11; P < 0.01), stage II (HR = 9.52; P < 0.01) and the application of nimotuzumab combined with CRT (HR = 0.16; P < 0.01) was much longer. Furthermore, ECOG, stage, C-reactive protein (CRP) baseline, and histological grade can also be used as independent predictors of OS. Grade >3 adverse reactions were not observed. The most common adverse event related to nimotuzumab was mild fever and the occurrence rate was 19% (5 of 26). The incidence of anemia was 65.4% in group A and 87.5% in group B (P < 0.05).

For locoregional-advanced CEC, nimotuzumab combined with IMRT and concomitant chemotherapy was tolerated and effective. In addition, patients with a normal pretherapeutic serum CRP level (CRP < 10 mg/L) can achieve better OS.

• C-reactive protein
• cervical esophageal carcinoma
• chemoradiotherapy
• intensity-modulated radiotherapy
• nimotuzumab

• COVID-19
• EGFR
• SARS-CoV-2
• brief research report nimotuzumab
• fibrosis
• inflammation
• monoclonal antibody

• Cohort Studies
• Humans
• Retrospective Studies
• SARS-CoV-2
• COVID-19 Drug Treatment

Background: Lung injury and STAT1 deficit induce EGFR overexpression in SARS-CoV-2 infection. Patients & methods: A phase I/II trial was done to evaluate the safety and preliminary effect of nimotuzumab, an anti-EGFR antibody, in COVID-19 patients. Patients received from one to three infusions together with other drugs included in the national guideline. Results: 41 patients (31 severe and 10 moderate) received nimotuzumab. The median age was 62 years and the main comorbidities were hypertension, diabetes and cardiovascular disease. The antibody was very safe and the 14-day recovery rate was 82.9%. Inflammatory markers decreased over time. Patients did not show signs of fibrosis. Conclusion: Nimotuzumab is a safe antibody that might reduce inflammation and prevent fibrosis in severe and moderate COVID-19 patients.

Clinical Trial Registration: RPCEC00000369 (rpcec.sld.cu).

Background: After SARS-CoV-2 infection, many cells in the lung express a new receptor called EGFR. Overexpression of EGFR can worsen the pulmonary disease and provoke fibrosis. Patients & methods: The initial impact of using a drug that blocks EGFR, nimotuzumab, was evaluated in COVID-19 patients. Results: 41 patients received nimotuzumab by the intravenous route together with other medications. The median age was 62 years, and patients had many chronic conditions including hypertension, diabetes and cardiac problems. Treatment was well tolerated and 82.9% of the patients were discharged by day 14. Serial laboratory tests, x-rays and CT scan evaluations showed the improvement of the patients. Conclusion: Nimotuzumab is a safe drug that can be useful to treat COVID-19 patients.

• COVID-19
• EGFR
• SARS-CoV-2
• fibrosis
• inflammation
• monoclonal antibody
• nimotuzumab

Lung cancer is one of the leading causes of cancer-related deaths in the world among both men and women. Several studies in the literature report that overexpression and mutation of the epidermal growth factor receptor (EGFR) are implicated in the pathogenesis of some lung cancers. Nimotuzumab is a humanized monoclonal antibody (mAb) that inhibits EGF binding because it binds to the extracellular domain of the EGFR. Nimotuzumab requires bivalent binding for stable attachment to cellular surface, which leads to nimotuzumab selectively binding to cells that express mAbs of moderate to high EGFR levels, and this could explain its low toxicity. This property has an advantage for development of nimotuzumab as a therapeutic and diagnostic agent. Monoclonal antibodies are large in size (150 kDa), thus penetrating slowly and residing in the blood for extended periods of time (from days to weeks); their use in imaging studies can result in low signal-to-background ratios and poor image quality. A reduction in the size of the immunoglobulin molecule has also been proposed as a means for increasing tumor penetration by mAbs. Nevertheless, it is known that the penetration of mAb into tumor cell is slow, due to its high molecular weight. Therefore, mAb is not very attractive to be used for imaging diagnostic purpose because of its kinetics and potential to elicit antibody response. The objective of this research was to study the homology modeling of a simpler functional molecule based on nimotuzumab, which consists of 2 antigen-binding fragments (Fab), namely, F(ab′)₂, using MODELER. The crystal structure of Fab of nimotuzumab from protein data bank was used as a template to construct the model of F(ab′)₂. Molecular dynamic simulation was performed to evaluate the stability of F(ab′)₂ and conformational changes of F(ab′)₂ in simulation. The result showed the dynamic behavior of antigen-binding site region of F(ab′)₂ throughout simulation. This result is expected to be useful in the further development of F(ab′)₂ fragment nimotuzumab as a lung cancer diagnostic.

• F(ab′)2
• Nimotuzumab
• diagnostics
• lung cancer
• molecular dynamics

• A single B cell monoclonal antibody generation technology
• immunotherapy
• monoclonal antibody
• phage display technology
• tumour

• COVID-19
• EGFR
• SARS-CoV-2
• cytokine release syndrome
• monoclonal antibody
• nimotuzumab

• glypican-1
• personalized dosimetry
• radioimmunotherapy
• solid tumors
• theranostic

• GlyTherix

Hepatocellular carcinoma (HCC) continues to be a cancer with rising incidence, high mortality, and recurrence rate. The therapeutic effects on HCC are not satisfactory currently. Epidermal growth factor receptor (EGFR) is an important factor, while anti-EGFR agencies have not shown ideal results in HCC.

We tested efficacy of nimotuzumab and EGFR expression on cell surface in six HCC cell lines (Hep 3B2.1–7, Li-7, PLC/PRF/5, SK-HEP-1, SNU-182, and SNU-387). Then, we analyzed RNA sequences of every cell line and performed a bioinformatic analysis. Differentially expressed genes (DEGs) were analyzed. The data, TCGA-LIHC from The Cancer Genome Atlas (TCGA) and GSE102079 from Gene Expression Omnibus (GEO), were used to analyse DEGs of Hoshida subclass.

Hep 3B2.1–7 and PLC/PRF/5 were sensitive to nimotuzumab whereas Li-7, SK-HEP-1, SNU-182, and SNU-387 cell lines were resistant. Then, we compared the DEGs between sensitive and resistant group cell lines. We enriched DEGs in GO and KEGG and performed GSEA in each group. Genes in two groups did not show obvious different expressions in EGFR pathways, while Hoshida subclass of HCC seemed to associate with the efficacy of nimotuzumab in that S2 and S3 showed better therapeutic effect than S1. Therefore, we analyzed genes in human tumor samples which were from TCGA-LIHC and GSE102079. We found that COL1A1, COL1A2, COL3A1, and MMP9 were the focus DEGs of S1 and S2 & S3 related to EGFR.

The efficacy of nimotuzumab in HCC did not show direct relevance with EGFR protein expression and EGFR-related pathway. However, efficacy could associate with Hoshida subclass of HCC. Three ECM genes (COL1A1, COL1A2, COL3A1) and MMP9 were paid attention, as they might play important roles in the curative effect of nimotuzumab in HCC.

• GEO
• Hoshida subclass
• TCGA
• bioinformatic analysis
• cell line
• hepatocellular carcinoma
• nimotuzumab

Induction docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy followed by definitive concurrent chemoradiation remains the standard of care in locally advanced squamous cell carcinoma of head and neck cancers despite which the survival remains low. So, we analyzed the efficacy and adverse effect profile of the addition of nimotuzumab to standard TPF induction chemotherapy. Methods. We included 20 patients with locally advanced squamous cell carcinoma of the head and neck. Patients were administered with induction chemotherapy with nimotuzumab plus docetaxel, cisplatin, and 5-fluorouracil (TPF + N) followed by definitive concurrent chemoradiation with carboplatin. Treatment responses were assessed by PET-CT following induction chemotherapy and concurrent chemoradiation. Response rates, survival, and adverse effects data were tabulated and analyzed using the Kaplan Meier method.

At a minimum follow-up of two years, the median progression-free survival (PFS) and median overall survival (OS) were 16 months and 38 months, respectively. PFS and OS were not reached (NR) in patients who showed a complete radiological response (CR). Median PFS and OS in patients who had partial response were 17.6 and 34.5 months, respectively. All subsites of primary including oral cavity, hypopharynx, and oropharynx showed similar response rates and survival. Overall the treatment was well tolerated with predominantly grade 1/2 toxicities.

Patients with locally advanced head and neck cancer could possibly have a better response and survival with nimotuzumab added to the standard TPF regimen. A complete response may serve as a good surrogate for survival irrespective of the primary site of head and neck cancer.

• oesophageal disease
• oncology
• therapeutics

• Antineoplastic Agents/adverse effects
• Carcinoma, Non-Small-Cell Lung/drug therapy
• China
• ErbB Receptors
• Esophageal Neoplasms/drug therapy
• Humans
• Lung Neoplasms/drug therapy

• Liaoning Social Science Planning Fund Project

• Cisplatin
• EGFR
• Squamous cell carcinoma
• Therapeutic antibody
• Vinorelbine

• 177Lu-Nimotuzumab
• DNA damage
• DRR genes
• apoptosis
• cytotoxicity

EGFR activation induces cell proliferation, neoformation of blood vessels, survival, and metastasis of the cancer cells. Nimotuzumab is an engineered, intermediate affinity anti-EGFR antibody, that apart from other drugs in its class, is very safe and does not cause hypomagnesemia or grade 3–4 cutaneous rash. The antibody inhibits cell proliferation and angiogenesis, activates natural killer cells, stimulates dendritic cell maturation, and induces cytotoxic T cells. Nimotuzumab restores MHC-I expression on tumor cells, hindering one of the EGFR immune-escape ways. The antibody has been extensively studied in 7 clinical trials, concurrently with irradiation or irradiation plus chemotherapy in subjects with inoperable head and neck tumors. Nimotuzumab was safe and efficacious in unfit patients receiving irradiation alone and in subjects treated with cisplatin and radiotherapy. In patients with locally advanced squamous cell carcinomas of the head and neck, nimotuzumab in combination with low dose cisplatin and radiotherapy was superior to cisplatin and radiotherapy in progression free survival, disease free survival, and locoregional tumor control.

• EGFR
• head and neck
• monoclonal antibody
• nimotuzumab
• radiotherapy

To compare the clinical efficacy and safety of nimotuzumab combined with chemotherapy versus chemotherapy alone as first-line treatment for advanced colorectal cancer (ACRC).

We retrospectively enrolled patients with ACRC treated with nimotuzumab plus chemotherapy (n = 40) or chemotherapy alone (n = 44). Responses were evaluated according to the Response Evaluation Criteria in Solid Tumors and adverse events according to the Common Terminology Criteria for Adverse Events 3.0.

The objective overall response rate and disease control rate were higher in the combined-treatment group (55.0% vs 36.4% and 85.0% vs 75.0%, respectively), but the differences were not significant. There was no significant difference in median progression-free survival or median survival time between the combined-treatment and chemotherapy-alone groups (9.89 vs 7.86 months and 22.32 vs 18.10 months, respectively). There was no significant difference in adverse events between the two groups.

Nimotuzumab combined with chemotherapy had similar efficacy and safety to chemotherapy alone in patients with ACRC. The efficacy and safety of the combined treatment should be further studied in a randomized multicenter trial with a larger number of patients with ACRC.

• Advanced colorectal cancer
• adverse events
• chemotherapy
• combined treatment
• nimotuzumab
• survival

To assess the efficacy of Nimotuzumab in combination with first-line chemoradiotherapy treatment in Chinese patients with primary III-IVb stage nasopharyngeal carcinoma.

Patients with primary locoregionally advanced nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy (IMRT) and concurrent cisplatin-based chemotherapy between January 2008 and December 2013 at a single institution were retrospectively reviewed. Group A received at least 6 doses of Nimotuzumab, while Group B did not receive Nimotuzumab. A propensity score matching method was used to match patients from each group in a 1:3 ratio.

In total, 730 eligible patients were propensity matched, with 184 patients in Group A and 546 patients in Group B. Significant differences were not observed in the patient and tumor characteristics between Group A and Group B. At a median follow-up of 74.78 months (range 3.53–117.83 months), locoregional recurrence, distant failure and death were observed in 10.68, 11.10 and 16.03% of all patients, respectively. The estimated 5-year locoregional relapse–free survival, distant metastasis–free survival, progression-free survival and overall survival in the Group A versus Group B were 85.34% versus 89.79% (P = 0.156), 93.09% versus 85.61% (P = 0.012), 79.96% versus 77.99% (P = 0.117) and 88.91% versus 78.30% (P = 0.006), respectively.

This nimotuzumab-containing regimen resulted in improved long-term survival of III-IVb stage NPC patients and warrants further prospective evaluation.

• Chemotherapy
• IMRT
• Nasopharyngeal carcinoma
• Nimotuzumab
• Prognosis

Background: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) antibody that has shown preclinical and clinical anticancer activity in cerebral glioblastoma multiforme (GBM). We conducted a phase II, single-arm, multicenter clinical trial to evaluate the benefit of adding nimotuzumab to current standard chemo-radiotherapy for patients with GBM with positive EGFR expression.

Methods: Newly diagnosed patients with histologically proven single supratentorial GBM and epidermal growth factor receptor (EGFR) positive expressions were recruited. All patients were treated with nimotuzumab, administered once a week intravenously for 6 weeks in addition to radiotherapy with concomitant and adjuvant temozolomide after surgery. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary objectives included objective response rate (ORR) and toxicity.

Results: A total of 39 patients were enrolled and 36 patients were evaluated for efficacy. The ORR at the end of RT was 72.2%. Median OS and PFS were 24.5 and 11.9 months. The 1-year OS and PFS rates were 83.3% and 49.3%. The 2-year OS and PFS rates were 51.1% and 29.0%. O (6)-methylquanine DNA methyl-tranferase (MGMT) expression is known to affect the efficacy of chemotherapy and status of its expression is examined. No significant correlation between treatment outcomes and MGMT status was found. Most frequent treatment-related toxicities were mild to moderate and included constipation, anorexia, fatigue, nausea, vomiting, and leucopenia.

Conclusions: Our study show that nimotuzumab in addition to standard treatment is well tolerable and has increased survival in newly diagnosed GBM patients with EGFR positive expression.

• O (6)-methylquanine DNA methyl-tranferase (MGMT)
• epidermal growth factor receptor
• glioblastoma
• nimotuzumab
• radiotherapy
• temozolomide

• Children
• DIPG
• Diffuse midline glioma
• EGFR
• Nimotuzumab
• Radiotherapy

• Adolescent
• Antibodies, Monoclonal, Humanized/adverse effects
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antineoplastic Agents, Immunological/adverse effects
• Antineoplastic Agents, Immunological/therapeutic use
• Brain Stem Neoplasms/diagnostic imaging
• Brain Stem Neoplasms/therapy
• Chemoradiotherapy/adverse effects
• Child
• Child, Preschool
• Disease Progression
• Female
• Glioma/diagnostic imaging
• Glioma/therapy
• Humans
• Male
• Pons
• Survival Analysis
• Treatment Outcome
• Young Adult

• EGFR
• HPV
• PD-1
• PD-L1
• biomarkers
• head and neck cancer
• immunotherapy
• tumour microenvironment

This study was conducted to evaluate the efficacy and safety of nimotuzumab combined with chemotherapy as first‐line therapy in advanced lung squamous cell carcinoma (LSCC), and to explore predictive biomarkers of the efficacy of nimotuzumab.

A retrospective study was conducted of patients with advanced LSCC administered nimotuzumab combined with chemotherapy as first‐line therapy from June 2012 to December 2016 at the Department of Respiratory Medicine, Peking Union Medical College Hospital. The associations between EGFR expression, EGFR gene copy numbers, and clinical efficacy were detected by immunohistochemistry and fluorescence in situ hybridization (FISH).

Twenty‐six patients were enrolled, including 22 men and 4 women. The objective response rate was 50% and the disease control rate was 100%. The median progression‐free survival (PFS) and overall survival were 6.7 and 16.3 months, respectively. Patients whose samples were tested via FISH and showed positive EGFR expression had a trend of longer median PFS (10.0 months; P = 0.10). Adverse effects included 15 cases (57.7%) of bone marrow suppression, 15 (57.7%) of sensory neuropathy, 14 (53.8%) of alopecia, nine (34.6%) of nausea/vomiting and one case (3.8%) of elevated creatinine level. All adverse effects were attributed to chemotherapy.

Nimotuzumab combined with chemotherapy might be a possible option as first‐line therapy in patients with advanced LSCC. EGFR gene copy number examined by FISH might be a possible predictive biomarker.

• Chemotherapy
• lung squamous cell carcinoma
• nimotuzumab

• EGFR inhibitor
• KRAS wildtype
• gemcitabine
• nimotuzumab
• pancreatic cancer

Nimotuzumab is a humanized anti‐epidermal growth factor receptor IgG1 monoclonal antibody. This phase I study assessed the tolerability, safety, efficacy, and pharmacokinetics of nimotuzumab in combination with chemoradiotherapy in Japanese patients with esophageal cancer. Patients with stage II, III, and IV esophageal cancer were enrolled. Patients were planned to receive nimotuzumab (level 1: 200 mg/wk for 25 weeks; or level 2: 400 mg/wk in the chemoradiation period, 400 mg biweekly in an additional chemotherapy period [8 weeks after the chemoradiation period] and a maintenance therapy period [after chemotherapy to 25 weeks]) combined with cisplatin (75 mg/m² on day 1) and fluorouracil (1000 mg/m² on days 1‐4) in the chemoradiation and additional chemotherapy periods. Radiotherapy was given concurrently at 50.4 Gy. A total of 10 patients were enrolled in level 1. Dose‐limiting toxicities were observed in 2 patients (grade 3 infection and renal disorder). Maximum‐tolerated dose was estimated to be at least 200 mg/wk and the dose was not escalated to level 2. The most common grade ≥3 toxicities were lymphopenia (90%), leukopenia (60%), neutropenia (50%), and febrile neutropenia, decreased appetite, hyponatremia, and radiation esophagitis (30% each). Neither treatment‐related death nor grade ≥3 skin toxicity was observed in any patient. Complete response rate was 50%. Progression‐free survival was 13.9 months. One‐ and 3‐year survival rates were 75% and 37.5%, respectively. Immunogenicity was not reported in any patient. Nimotuzumab in combination with concurrent chemoradiotherapy was tolerable and effective for Japanese patients with esophageal cancer.

• Japanese
• chemoradiotherapy
• epidermal growth factor receptor
• esophageal cancer
• nimotuzumab

Defining how epidermal growth factor receptor (EGFR)-targeting therapies influence the immune response is essential to increase their clinical efficacy. A growing emphasis is being placed on immune regulator genes that govern tumor – T cell interactions. Previous studies showed an increase in HLA class I cell surface expression in tumor cell lines treated with anti-EGFR agents. In particular, earlier studies of the anti-EGFR blocking antibody cetuximab, have suggested that increased tumor expression of HLA class I is associated with positive clinical response. We investigated the effect of another commercially available anti-EGFR antibody nimotuzumab on HLA class I expression in tumor cell lines. We observed, for the first time, that nimotuzumab increases HLA class I expression and its effect is associated with a coordinated increase in mRNA levels of the principal antigen processing and presentation components. Moreover, using 7A7 (a specific surrogate antibody against murine EGFR), we obtained results suggesting the importance of the increased MHC-I expression induced by EGFR-targeted therapies display higher in antitumor immune response. 7A7 therapy induced upregulation of tumor MHC-I expression in vivo and tumors treated with this antibody display higher susceptibility to CD8⁺ T cells-mediated lysis. Our results represent the first evidence suggesting the importance of the adaptive immunity in nimotuzumab-mediated antitumor activity. More experiments should be conducted in order to elucidate the relevance of this mechanism in cancer patients. This novel immune-related antitumor mechanism mediated by nimotuzumab opens new perspectives for its combination with various immunotherapeutic agents and cancer vaccines.

• EGFR
• HLA class I molecules
• antibodies
• nimotuzumab
• tumor cells

We aimed to evaluate the efficacy of dual inhibition of epidermal growth factor receptor (EGFR) with nimotuzumab (EGFR monoclonal antibody) plus gefitinib (EGFR-tyrosine kinase inhibitor) in advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy. An open label, randomized, phase II trial was conducted at 6 centers; 160 patients were randomized (1:1) to either gefitinib alone or nimotuzumab (200 mg, i.v. weekly) plus gefitinib (250 mg p.o. daily) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 3 months. Of the total 160 enrolled patients, 155 (77: gefitinib, 78: nimotuzumab plus gefitinib) received at least one dose and could be evaluated for efficacy and toxicity. The majority had adenocarcinoma (65.2%) and ECOG performance status of 0 to 1 (83.5%). The median follow-up was 22.1 months, and the PFS rate at 3 months was 48.1% in gefitinib and 37.2% in nimotuzumab plus gefitinib (P = not significant, NS). The median PFS and OS were 2.8 and 13.2 months in gefitinib and 2.0 and 14.0 months in nimotuzumab plus gefitinib. Combined treatment was not associated with superior PFS to gefitinib alone in patients with EGFR mutation (13.5 vs. 10.2 months in gefitinib alone, P=NS) or those with wild-type EGFR (0.9 vs. 2.0 months in gefitinib alone, P=NS). Combined treatment did not increase EGFR inhibition-related adverse events with manageable toxicities. The dual inhibition of EGFR with nimotuzumab plus gefitinib was not associated with better outcomes than gefitinib alone as a second-line treatment of advanced NSCLC (NCT01498562).

• epidermal growth factor receptor
• gefitinib
• nimotuzumab
• non-small cell lung cancer

• T cells
• head and neck cancer
• human epidermal growth factor receptor
• monoclonal antibodies
• natural killer cells

• Cancer therapy
• ErbB3
• HER3
• heregulin
• internalization
• phage display
• receptor tyrosine kinase
• therapeutic antibody

• EdU
• cell-based assays
• high-content screening
• proliferation
• therapeutic antibodies

• Chemotherapy
• Clinical trials
• Gastric cancer
• Helicobacter pylori infection
• New treatment advances
• Targeted therapy

• Antibodies, Monoclonal/therapeutic use
• Apoptosis
• Cell Cycle/drug effects
• ErbB Receptors/antagonists & inhibitors
• Humans
• Immunotherapy
• Insulin-Like Growth Factor I/antagonists & inhibitors
• Molecular Targeted Therapy
• Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
• Proto-Oncogene Proteins c-met/antagonists & inhibitors
• Receptor, ErbB-2/antagonists & inhibitors
• Receptors, Fibroblast Growth Factor/antagonists & inhibitors
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/pathology
• Vascular Endothelial Growth Factor A/antagonists & inhibitors

Interaction between epidermal growth factor receptor (EGFR) signaling with GM3 ganglioside expression has been previously described. However, little is known about EGFR and NeuGcGM3 co-expression in cancer patients and their therapeutic implications. In this paper, we evaluate the co-expression of EGFR and NeuGcGM3 ganglioside in tumors from 92 patients and in two spontaneous lung metastasis models of mice (Lewis lung carcinoma (3LL-D122) in C57BL/6 and mammary carcinoma (4T1) in BALB/c). As results, co-expression of EGFR and NeuGcGM3 ganglioside was frequently observed in 63 of 92 patients (68 %), independently of histological subtype. Moreover, EGFR is co-expressed with NeuGcGM3 ganglioside in the metastasis of 3LL-D122 and 4T1 murine models. Such dual expression appears to be therapeutically relevant, since combined therapy with mAbs against these two molecules synergistically increase the survival of mice treated. Overall, our results suggest that NeuGcGM3 and EGFR may coordinately contribute to the tumor cell biology and that therapeutic combinations against these two targets might be a valid strategy to explore.

• Co-expression
• Combination therapy
• EGFR, NeuGcGM3
• Pulmonary metastasis

• advanced cancer
• chemotherapy
• monoclonal antibody
• nimotuzumab

• Antibodies, Monoclonal, Humanized/administration & dosage
• Antibodies, Monoclonal, Humanized/adverse effects
• Antineoplastic Agents, Immunological/administration & dosage
• Antineoplastic Agents, Immunological/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• China
• Disease Progression
• Disease-Free Survival
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neoplasms/mortality
• Neoplasms/pathology
• Proportional Hazards Models
• Protein Kinase Inhibitors/administration & dosage
• Protein Kinase Inhibitors/adverse effects
• Retrospective Studies
• Risk Factors
• Time Factors
• Treatment Outcome