Meng Li

Background: Tumor angiogenesis is critical for tumor growth, infiltration and metastasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor and targeting it is important in reducing angiogenesis. Bevacizumab (Avastin), a monoclonal antibody that reacts directly against VEGF, has been demonstrated to be an effective treatment for various cancers such as rectal cancer, colon carcinoma, and non-small cell lung cancer, etc. Results: In the current study, we used the phage display technique to generate mimotopes that complemented the screening Avastin antibody (Ab). The candidate mimotopes of VEGF were isolated from a 12-mer peptide library. The phage displaying peptide DHTLYTPYHTHP (designated as 12P) exhibited high affinity to Avastin. The chemically synthesized 12P was conjugated to keyhole limpet hemocyanin (KLH) by glutaraldehyde (GA) to form vaccine KLH-12 peptide (KLH-12P). This epitope vaccine significantly induced humoral immunity in mice. The blood serum from KLH-12P-immunized mice associated with VEGF and blocked its binding to VEGFR, thus inhibiting vascular endothelial cell proliferation and migration. Conclusions: Our data indicate that the isolated mimotope 12P reported here could potentially elicit specific antibodies against VEGF and result in the induction of anti-angiogenesis responses.

We previously prepared a tumor necrosis factor (TNF)‐α mutant (rmhTNF‐α) that showed higher antitumor activity and lower systemic toxicity compared with native TNF‐α. The safety profile and the pharmacokinetic characteristics of rmhTNF‐α were suited for clinical use according to biological Investigational New Drug application, a standard guideline for new drug investigation in China. Here, we evaluate the activity and safety of rmhTNF‐α combined with chemotherapies in head/neck, lung, colorectal, stomach, and renal cancer patients. Ninety‐five eligible patients received i.m. rmhTNF‐α treatment combined with standard chemotherapies. Another 95 patients were treated with standard chemotherapies. After two treatment cycles, one patient achieved a complete response and 24 patients had partial response, yielding an overall response rate (complete response + partial response) of 27.47% in the rmhTNF‐α plus chemotherapy cohort. The chemotherapy alone group acquired only a 11.39% response rate (P < 0.05). When compared between different cancers, a 48.89% response rate was detected in the 45 lung cancer patients of the combination cohort. The most common grade 1–2 adverse events of rmhTNF‐α were drug‐related fever, allergy, flu‐like symptoms, and myalgia. No significant difference was found in grade 3–4 toxicities between the two cohorts. Based on the results of this research, rmhTNF‐α can significantly enhance the effectiveness of chemotherapy. An extended phase III trial of rmhTNF‐α combined with standard chemotherapy is warranted for evaluating its antitumor activity and toxicity in a larger cohort of tumor patients. The studies in this paper were registered with the State Food and Drug Administration of China (No. 2003S00692). (Cancer Sci 2012; 103: 288–295)