RESUMO
This study aimed to investigate the immunogenicity of a cancer vaccine consisting of the NeuGcGM3 ganglioside combined with the outer membrane protein complex of Neisseria meningitides to form very small size particles. The vaccine is administered together with Montanide ISA51, as adjuvant treatment for breast cancer patients. After surgical resection and standard first-line chemo/radiotherapy, breast cancer patients in stage II-III were enrolled in a phase III clinical trial and allocated into 2 strata, according to the number of positive lymph nodes [stratum I (0-3); stratum II (≥4)]. Subsequently, patients were randomly assigned to receive the vaccine or placebo. The treatment consisted of 5 vaccine doses (200 µg) every 2 weeks and thereafter monthly reimmunizations to complete 15 doses. The vaccine was well-tolerated and high titers of immunoglobulin M and immunoglobulin G anti-NeuGcGM3 antibodies were similarly detected in each stratum. Hyperimmune sera were able to specifically recognize and kill the NeuGcGM3-expressing L1210 tumor cell line, and these functional capacities were significantly associated with a better clinical outcome in patients of stratum II. Besides, postimmune sera had the capacity to revert in vitro the immunosuppression induced by NeuGcGM3, as measured by the prevention of CD4 downmodulation on human T lymphocytes. Vaccination had no impact on the frequency of regulatory T cells or circulating NK cells. This study demonstrated, for the first time, the immunogenicity of the NeuGcGM3/VSSP/Montanide ISA 51 vaccine in the adjuvant setting and describes the functionality of induced anti-NeuGcGM3 antibodies as potential surrogate biomarkers of clinical benefit.
Assuntos
Proteínas da Membrana Bacteriana Externa/genética , Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Gangliosídeo G(M3)/análogos & derivados , Neisseria meningitidis/genética , Adjuvantes Imunológicos/administração & dosagem , Anticorpos/sangue , Apoptose , Biomarcadores Farmacológicos/sangue , Neoplasias da Mama/imunologia , Vacinas Anticâncer/genética , Linhagem Celular Tumoral , Feminino , Gangliosídeo G(M3)/genética , Humanos , Imunidade Humoral , Manitol/administração & dosagem , Manitol/análogos & derivados , Pessoa de Meia-Idade , Neisseria meningitidis/metabolismo , Estadiamento de Neoplasias , Ácidos Oleicos/administração & dosagem , Resultado do TratamentoRESUMO
NGcGM3 ganglioside is a tumor-specific antigen expressed in human breast tumors. The NGcGM3/VSSP vaccine, consisting in very small-sized proteoliposomes (VSSP) obtained by the incorporation of NGcGM3 into the outer membrane protein complex of Neisseria meningitidis, has been previously tested in a Phase II trial in patients with metastatic breast cancer (MBC) but emulsified with Montanide ISA 51. An Expanded Access study was carried out in MBC patients aiming to find if a nonemulsive formulation of NGcGM3/VSSP, without Montanide ISA 51, could be more safe and effective. A total of 104 patients were vaccinated with the nonemulsive formulation (900 µg), subcutaneously (SC), or with the emulsive formulation (200 µg), intramuscularly (IM). An intent-to-treat analysis of efficacy was performed with all patients, and 93 patients were split off according to the site of metastases (visceral/nonvisceral). Of note, SC-treated patients exhibited a superior median overall survival (OS) than IM-treated patients (23.6 vs. 8.2 months; log rank P = 0.001). Even though in the subset of patients with nonvisceral metastases SC vaccination duplicated the median OS compared to the alternative option (31.6 vs. 16.5 months), this difference did not reach statistical significance (log rank P = 0.118). Curiously, in patients with visceral metastases, the advantage of the nonemulsive formulation was more apparent (median OS 21.0 vs. 6.2 months; log rank P = 0.005). The vaccine was safe for both formulations.
RESUMO
Gangliosides are glycosphingolipids that are present in the plasma membranes of vertebrates and are involved in multiple cellular processes. In the Center of Molecular Immunology an NGcGM3 ganglioside based vaccine has been developed and is conceptualized as a targeted therapy in cancer. NGcGM3/VSSP vaccine had been used as treatment of metastatic melanoma patients and had showed to be safe and immunogenic. The treatment improved antitumoral response or maintain the response obtained with previous onco-specific treatment as chemotherapy. The results indicate that the vaccine improved overall survival of metastatic melanoma patients after first line-chemotherapy. The clinical trial ongoing currently will allow corroborating these results.
Assuntos
Vacinas Anticâncer/administração & dosagem , Gangliosídeo G(M3)/administração & dosagem , Imunoterapia/métodos , Melanoma/terapia , Proteolipídeos/administração & dosagem , Ensaios Clínicos como Assunto , Humanos , Resultado do TratamentoRESUMO
The prognosis of patients with advanced head and neck cancer remain dismal. For this tumor type, elevated levels of EGFR are associated with a shorter disease free survival and time to treatment failure, reflecting a more aggressive phenotype. Nimotuzumab is a humanized monoclonal antibody that recognizes domain III of the extracellular region of the EGFR, within an area that overlaps with both the surface patch recognized by cetuximab and the binding site for EGF. In order to assess the efficacy of nimotuzumab in combination with radiotherapy, a controlled, double blind, randomized clinical trial was conducted in 106 advanced squamous cell carcinoma of the head and neck patients, mostly, unfit for chemoradiotherapy. Control patients received a placebo and radiotherapy. Treatment was safe and the most frequent adverse events consisted on grade I or II asthenia, fever, headache and chills. No skin rash was detected. A significant complete response rate improvement was found in the group of patients treated with nimotuzumab as compared to the placebo. In the intent to treat analysis, a trend towards survival benefit for nimotuzumab treated subjects was found. The survival benefit became significant when applying the Harrington-Fleming test, a weighted log-rank that underscores the detection of differences deferred on time. In addition, a preliminary biomarker investigation showed a significant survival improvement for nimotuzumab treated patients as compared to controls for subjects with EGFR positive tumors. All patients showed a quality of life improvement and a reduction of the general and specific symptoms of the disease.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas/mortalidade , Estudos de Casos e Controles , Cetuximab , Intervalo Livre de Doença , Método Duplo-Cego , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Feminino , Neoplasias de Cabeça e Pescoço/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/induzido quimicamente , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , PrognósticoRESUMO
Conventional treatment of non-small cell lung cancer (NSCLC) has apparently reached a plateau of effectiveness in improving the survival of the patients. For that reason the search for new therapeutic strategies in this type of tumor is justified. 1E10 is an anti-idiotype murine monoclonal antibody (Ab2 MAb) specific to P3 Ab1 MAb, which reacts with NeuGc-containing gangliosides, sulfatides and with antigens expressed in some tumors, including those from the lung. We report the treatment with aluminum hydroxide-precipitated 1E10 MAb of 34 stage IIIb and 37 stage IV NSCLC patients. These patients were treated with the anti-idiotype vaccine, after received standard chemotherapy and radiotherapy, in a compassionate-use basis study. Patients received five bi-weekly injections of 1 mg of 1E10/Alum, other 10 doses at 28-day intervals and later the patients who maintained a good performance status continued to be immunized at this same time interval. No evidence of unexpected or serious adverse effects was reported. The median survival time of the 56 patients who entered the study with partial response or disease stabilization and with a PS 1 after the first line of chemo/radiotherapy, was 11.50 months from starting vaccination. In contrast, the median survival time calculated for patients who started vaccination with progressive disease and/or a PS2 was 6.50 months.