Active immunotherapy with 1E10 anti-idiotype vaccine in patients with small cell lung cancer: report of a phase I trial.

1E10 is an anti-idiotype murine monoclonal antibody (Ab2 MAb) specific to an Ab1 MAb which reacts with NeuGc-containing gangliosides, sulfatides and with antigens expressed in some human tumors. Preparations containing this Ab2 were capable to induce a strong anti-metastatic effect in tumor-bearing mice. We conducted a Phase I clinical trial to evaluate the toxicity and humoral immune response elicited by 1E10 vaccine in patients with small cell lung cancer (SCLC). Eligible patients were those who after received chemotherapy and/or radiotherapy had partial or complete response to treatment. Patients received four biweekly injections with 2 mg of aluminum hydroxide-precipitated 1E10 MAb, then other six doses at 28-day intervals, and later the patients who maintained a good performance status were reimmunized. Six patients with limited-stage disease and three with extensive-stage disease were enrolled in the study. Most of the patients who received at least four doses of 1E10 vaccine developed strong specific antibody responses against 1E10 MAb and NeuGc-GM3 ganglioside. Antibodies able to react with lung carcinoma tissue sections were detected in sera from vaccinated patients. A prolonged survival was observed in several patients treated with the anti-idiotype vaccine. No evidence of serious adverse effects was found.

Prolonged use of nimotuzumab in children with central nervous system tumors: safety and feasibility.

Primary brain tumors constitute the most frequent solid tumor of childhood. High expression of the epidermal growth factor receptor (EGFR) protein has been associated with tumor progression and enhanced tumorigenicity in adult and children gliomas. Nimotuzumab is a humanized antibody that targets the EGFR and has proven efficacy in adult and children gliomas. To provide a new therapeutic option for patients with active, poor prognosis central nervous system (CNS) tumors and to evaluate the feasibility and safety of long-term nimotuzumab therapy in children with diverse CNS tumors, an expanded access program was launched at the Juan Manuel Marquez hospital. Patients were required to be 18 or younger and have one CNS tumor: low-grade glioma (LGG) or high-grade glioma (HGG), brainstem glioma (BSG), ependymoma or primitive neuroectodermal tumor (PNET), and a Lansky or Karnofsky performance status ≥40. Treatment consisted of weekly nimotuzumab administered at 150 mg/m(2) for 12 weeks, continuing every 14 days in the absence of severe condition worsening or unacceptable toxicity. Nimotuzumab was administered alone or in combination with radiotherapy, chemotherapy, or both, depending on the tumor type, stage, and previous treatment. Eighty-eight patients, 39 with BSG, 25 with HGG, 9 with progressive LGG, 9 with anaplastic ependymomas, and 6 with other tumor types, including PNET, neuroblastoma, meduloblastoma, and thalamic tumors, were treated with the antibody. The mean number of nimotuzumab doses was 36, from 1 to 108. The most frequent adverse events were mild to moderate skin rash, mucositis, vomiting, seizures, hypothermia, hyperthermia, and paleness. One patient had a grade 3 mucositis, while the other had a grade 3 bleeding on surgery. Sixteen children stopped treatment after at least 2 years with stable disease, partial or complete response. All children were able to maintain the best response achieved on treatment after a 3-year interruption. In summary, this study shows the feasibility of very prolonged administration of nimotuzumab together with the lack of rebound effect after treatment cessation.

Treatment of children with high grade glioma with nimotuzumab: a 5-year institutional experience.

Brain tumors are a major cause of cancer-related mortality in children. Overexpression of epidermal growth factor receptor (EGFR) is detected in pediatric brain tumors and receptor density appears to increase with tumor grading. Nimotuzumab is an IgG1 antibody that targets EGFR. Twenty-three children with high-grade glioma (HGG) were enrolled in an expanded access program in which nimotuzumab was administered alone or with radio-chemotherapy. The mean number of doses was 39. Nimotuzumab was well-tolerated and treatment with the antibody yielded a survival benefit: median survival time was 32.66 mo and the 2-y survival rate was 54.2%. This study demonstrated the feasibility of prolonged administration of nimotuzumab and showed preliminary evidence of clinical benefit in HGG patients with poor prognosis.

Effect of vaccination with N-glycolyl GM3/VSSP vaccine by subcutaneous injection in patients with advanced cutaneous melanoma.

NeuGc-containing gangliosides have been described in melanoma cells and are an attractive target for cancer immunotherapy because they are minimally or not expressed in normal human tissues. Melanoma patients treated with a vaccine based on N-glycolyl gangliosides have shown benefit in progression free survival and overall survival. We conducted a multicenter Phase I/II clinical trial in patients with metastatic cutaneous melanoma treated with the N-gycolyl GM3/very-small-size proteoliposomes vaccine by the subcutaneous route. Selecting the optimal biological dose of the vaccine was the principal objective based on immunogenicity, efficacy, and safety results. Six dose levels were studied and the treatment schedule consisted of five doses administered every 2 weeks and then monthly until 15 doses had been given. Dose levels evaluated were 150, 300, 600, 900, 1200, and 1500 µg with five patients included in each dose level except the 900 µg dose (n = 10). Immunogenicity was determined by antibody titers generated in patients after vaccination. Antitumor effect was measured by response criteria of evaluation in solid tumors and safety was evaluated by common toxicity criteria of adverse events. The vaccine was safe and immunogenic at all doses levels. The most frequent adverse events related to vaccination were mild to moderate injection site reactions and flu-like symptoms. Vaccination induced specific anti-NeuGcGM3 immunoglobulin M and immunoglobulin G antibody responses in all patients. Disease control (objective response or stable disease) was obtained in 38.46% of patients. Global median overall survival was 20.20 months. Two patients achieved overall survival duration of about 4 and 5 years, respectively. The 900 µg dose resulted in overall survival duration of 19.40 months and was selected as the biological optimal dose.

Efficacy and safety of iorEPOCIM for chemotherapy- or radiotherapy-induced anemia in pediatric cancer patients.

INTRODUCTION: Recombinant human erythropoietin (RHuEPO) is an erythropoiesis stimulating agent (ESA) used to treat anemia in patients with total or relative erythropoietin deficit. In cancer patients, it is administered to optimize hemoglobin (Hb) levels, correct anemia and reduce the need for transfusions. Cuba produces a RHuEPO, registered in 1998 as iorEPOCIM, that is widely used in the national public health system, mainly to treat patients with anemia due to chronic kidney disease (CKD). OBJECTIVE: Evaluate the efficacy and safety of iorEPOCIM in pediatric cancer patients with anemia following chemotherapy or radiotherapy. The working hypothesis posed an Hb increase>or=15 g/l in 70% of patients receiving iorEPOCIM for 8 weeks. METHODS: A Phase IV, multicenter, open clinical trial was conducted. Participants were 157 patients aged 1-19 years with anemia and cyto-histological diagnosis of cancer in any location. Patients received either 600 U/kg iorEPOCIM intravenously, once weekly, or 150 U/kg iorEPOCIM subcutaneously, 3 times a week, for 8 weeks. All patients had blood tests every week to determine hemoglobin and hematocrit, and reticulocyte and platelet counts. Mean number of transfusions required by patients during the treatment period was compared to the mean number of transfusions received in the preceding 8 weeks. Adverse events (AE) were recorded at the 4th and 8th weeks and classified by intensity and causality. RESULTS: Hb levels rose>or=15 g/l in 68.8% of patients, and transfusion requirements decreased 17%. The most frequent adverse events were fever (19.3%), vomiting (10.2%) and flu-like syndrome (9.6%). Intensity of AE was predominantly mild. Only 7 AE were classified as very probably related to the product and none of those was severe. CONCLUSIONS: iorEPOCIM proved to be safe and effective at the doses and frequencies used in this patient population. As a result, this medication was recommended for use in all pediatric oncology and hematology services in the country.

Immunogenicity and safety of a NeuGcGM3 based cancer vaccine: Results from a controlled study in metastatic breast cancer patients.

Increased levels of NeuGc-containing gangliosides have been described in human breast cancer. A controlled Phase II clinical trial was conducted in patients with metastatic breast cancer to evaluate immunogenicity, safety and to identify evidences of biological activity of a cancer vaccine composed by NeuGcGM3 in a proteoliposome of Neisseria meningitidis together with Montanide ISA 51 as adjuvant. After first line chemotherapy, 79 women were randomized 1:1 to receive the vaccine candidate or best supportive care. All patients achieved at least stable disease to the first line therapy for the metastatic condition. Treatment consisted on 5 vaccine doses every 2 weeks and then, monthly re-immunization to complete 15 doses. Vaccination with the NeuGcGM3 based vaccine was safe and the most frequent adverse events consisted on injection site reactions, fever, arthralgia and chills. The vaccine was immunogenic and a sustained increase of both IgG and IgM antibody titters against NGcGM3 was observed after the second vaccination month. Antibodies were able to recognize the NeuGcGM3(+) murine tumor cell line L1210 and the myeloma cell line P3X63. Humoral response was specific since vaccination did not result in Neu-Acetyl GM3 or GM2-antibody response. Hyperimmune sera from vaccinated patients were able to prevent the NeuGcGM3 mediated CD4 down-modulation on T lymphocytes. In the intent to treat analysis, there was a trend toward a survival advantage for the vaccine group and this effect was significant for women bearing non-visceral metastasis. Two phase III clinical studies with this vaccine candidate are ongoing.

Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin.

Nimotuzumab is a humanized therapeutic monoclonal antibody against epidermal growth factor receptor (EGFR). Clinical trials are ongoing globally to evaluate nimotuzumab in different indications. Nimotuzumab has been granted approval for use in squamous cell carcinoma of head and neck (SCCHN), glioma and nasopharyngeal cancer in different countries. This review focuses on the unique functional characteristics of nimotuzumab. Also, it discusses the safety and efficacy data obtained from the Phase IIb clinical trial conducted in India in SCCHN. Post marketing surveillance data from Cuba for the use of nimotuzumab in pediatric and adult glioma is also discussed. Overall, nimotuzumab has immense therapeutic potential in cancers of epithelial origin.

Clinical experience with nimotuzumab in cuban pediatric patients with brain tumors, 2005 to 2007.

Introduction Nimotuzumab, developed in Cuba, is a humanized monoclonal antibody that targets the epidermal growth factor receptor (EGFR). It has been evaluated in malignant brain tumors in adults and children, and shown to be therapeutically safe and effective in terms of increased survival and improved quality of life. Objective Describe nimotuzumab's safety profile and clinical benefits in terms of disease control and survival in pediatric patients with progressive or recurrent primary brain tumors who were included in an expanded access program. Methods An open, prospective clinical study was designed. Between December 2005 and December 2007, 22 patients were included, all of whom had an histological and/or radiological diagnosis of progressive or recurrent primary brain tumor, classified as high-grade malignant glioblastoma (n=6), diffuse brain stem glioma (n=6), ependymoblastoma (n=5), low-grade glioma (n=4), or thalamic tumor (n=1); life expectancy of at least 4 weeks; and a Karnofsky or Lansky Performance Status score of ≥50. Nimotuzumab was administered on a 100 mg weekly intravenous infusion schedule for 6 to 8 weeks, followed by a bi-weekly maintenance phase, as long as there was no deterioration in the patient's functional capacity. Therapeutic protocols were followed for administration as monotherapy or in combination with chemotherapy and/or radiotherapy. All patients received clinical and imaging follow-up. Results Nimotuzumab was well tolerated in all therapeutic modalities, even with prolonged exposure. A minority of patients reported slight or moderate adverse events, such as vomiting, mucositis and chills, as classified by the Common Terminology Criteria for Adverse Events (CTCAE). The disease was controlled in 64% (14/22) of patients; 6-month and 1-year survival rates were 82% and 64%, respectively; average survival was 20.3 months and median survival, 19 months. Recovery of neurological functions and improvement in general status were notable in patients who attained control of the disease. Conclusions As used in this study, nimotuzumab demonstrated a broad safety profile, making it acceptable for chronic use, and implied clinical benefits in terms of increased survival and improved functional status in these patients, compared to findings described in the literature. These results indicate further studies of this product are warranted.

Heterophilic NeuGcGM3 ganglioside cancer vaccine in advanced melanoma patients: results of a Phase Ib/IIa study.

NeuGcGM3 ganglioside is especially attractive because it is expressed on melanoma cells but it is minimally or not expressed at all on most normal human tissues. A Phase Ib/IIa clinical trial was carried out in patients with advanced cutaneous and ocular malignant melanomas, to evaluate immunogenicity and toxicity of an intramuscularly administered cancer vaccine and composed by NeuGcGM3 in a proteoliposome of Neisseria meningitides with Montanide ISA 51 as adjuvant. Twenty two patients were included, twelve at dose level of 200 microg and 10 at 400 microg. The first five doses were administered every other week and then monthly until 9 doses. 12 patients received additional immunizations. Vaccination induced specific anti-NeuGcGM3 IgM, IgG and IgA antibodies responses. Titers of IgM were greater for the highest vaccine doses. Vaccination also elicited DTH response in 45.5% of patients in the lower doses and 77.8% in the higher doses. Toxicities were mostly grade 1 or 2, according CTC-NCI criteria. Interestingly, 3 patients developed vitiligo at the lower dose (none in the highest dose) although the nominal antigen NeuGcGM3 is not present in melanocytes. Survival analysis was not the goal of this Phase I trial; nevertheless, the fact that seven patients are alive for more than 2 years after inclusion is noteworthy. Safety and immunogenicity with NeuGcGM3 vaccine treatment in advanced melanoma patients were established. The prognostic value of autoimmunity and the possibilities of dissociating anti-tumor immunity from autoimmunity deserve further research.

Immune responses in breast cancer patients immunized with an anti-idiotype antibody mimicking NeuGc-containing gangliosides.

A phase I clinical trial was conducted in patients with stage III/IV breast cancer who were treated with the anti-idiotype mAb 1E10 specific to an Ab1 mAb able to react specifically with N-glycolyl-containing gangliosides and with antigens expressed on human melanoma and breast carcinoma cells. Patients were treated with 1 or 2 mg of aluminum hydroxide-precipitated 1E10 mAb every other week for six injections. Two patients at each dose were reimmunized 7-9 months after completing the induction phase. In hyperimmune sera from eight of the nine patients who received at least four doses of anti-Id vaccine preparations, strong specific responses were observed both against 1E10 mAb and NeuGc-GM3 ganglioside (Ab3 Id+Ag+). Nonclassical Ab1' antibodies (Id-Ag+) were also elicited by 1E10 mAb vaccine treatment. There were no differences between the two levels of dose tested in relation to toxicity and immunogenicity. No evidence of serious or unexpected effects was observed.