RESUMO
New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe "flu-like" symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor. Clinical trial registered with www.clinicaltrials.gov (NCT 01212367).
Assuntos
Terapia Genética , Fatores Imunológicos/administração & dosagem , Interferon-alfa/administração & dosagem , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Adenoviridae , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Técnicas de Transferência de Genes , Terapia Genética/efeitos adversos , Vetores Genéticos , Humanos , Fatores Imunológicos/genética , Interferon alfa-2 , Interferon-alfa/genética , Masculino , Mesotelioma/diagnóstico por imagem , Mesotelioma/imunologia , Pessoa de Meia-Idade , Imagem Multimodal , Projetos Piloto , Neoplasias Pleurais/diagnóstico por imagem , Neoplasias Pleurais/imunologia , Tomografia por Emissão de Pósitrons , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Tomografia Computadorizada por Raios XRESUMO
We evaluated a neutralizing anti-TGFß antibody (GC1008) in cancer patients with malignant pleura mesothelioma (MPM). The goal of this study was to assess immunoregulatory effects in relation to clinical safety and clinical response. Patients with progressive MPM and 1-2 prior systemic therapies received GC1008 at 3mg/kg IV over 90 min every 21 d as part of an open-label, two-center Phase II trial. Following TGFß blockade therapy, clinical safety and patient survival were monitored along with the effects of anti-TGFß antibodies on serum biomarkers and peripheral blood mononuclear cells (PBMC). Although designed as a larger trial, only 13 patients were enrolled when the manufacturer discontinued further development of the antibody for oncology indications. All participants tolerated therapy. Although partial or complete radiographic responses were not observed, three patients showed stable disease at 3 mo. GC1008 had no effect in the expression of NK, CD4+, or CD8+ T cell activating and inhibitory markers, other than a decrease in the expression of 2B4 and DNAM-1 on NK cells. However, serum from 5 patients showed new or enhanced levels of antibodies against MPM tumor lysates as measured by immunoblotting. Patients who produced anti-tumor antibodies had increased median overall survival (OS) (15 vs 7.5 mo, p < 0.03) compared with those who did not. To our knowledge, these data represent the first immune analysis of TGFß- blockade in human cancer patients.