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
PURPOSE: Delineation of the long-term follow-up data on a series of patients with malignant mesothelioma, who received a single intrapleural dose of a nonreplicative adenoviral (Ad) vector encoding the herpes simplex virus thymidine kinase "suicide gene" (Ad.HSVtk) in combination with systemic ganciclovir. EXPERIMENTAL DESIGN: This report focuses on the 21 patients receiving "high-dose" therapy, defined by an intrapleural dose of vector (> or =1.6 x 10(13) viral particles), where transgene-encoded tk protein was reliably identified on immunohistochemical staining. In 13 patients, the vector was deleted in the E1 and E3 regions of the Ad; in the other eight patients, the vector had deletions in the Ad genes E1 and E4. Safety, immunologic responses, transgene expression, and clinical responses were evaluated. RESULTS: Both the E1/E3-deleted vector and the E1/E4-deleted vector were well tolerated and safe, although production of the E1/E4 vector was more difficult. Posttreatment antibody responses against the tumors were consistently seen. Interestingly, we observed a number of clinical responses in our patients, including two long-term (>6.5 year) survivors, both of whom were treated with the E1/E4-deleted vector. CONCLUSIONS: Intrapleural Ad.HSVtk/ganciclovir is safe and well tolerated in mesothelioma patients and resulted in long-term durable responses in two patients. Given the limited amount of gene transfer observed, we postulate that Ad.HSVtk may have been effective due to induction of antitumor immune responses. We hypothesize that approaches aiming to augment the immune effects of Ad gene transfer (i.e., with the use of cytokines) may lead to increased numbers of therapeutic responses in otherwise untreatable pleural malignancies.
Assuntos
Ganciclovir/uso terapêutico , Terapia Genética/métodos , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Timidina Quinase/genética , Adenoviridae/genética , Adenoviridae/imunologia , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Seguimentos , Terapia Genética/efeitos adversos , Humanos , Mesotelioma/genética , Mesotelioma/patologia , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Tomografia por Emissão de Pósitrons , Simplexvirus/enzimologia , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: To identify treatment modalities and corresponding nursing implications for the high-risk and metastatic melanoma patient. DATA SOURCES: Texbooks, research articles, and professional experience. CONCLUSIONS: Recent advances in the field of melanoma include identification of prognostic factors, refinement of surgical techniques, and identification of effective adjuvant therapy. Novel therapies are currently under investigation. IMPLICATIONS FOR NURSING PRACTICE: Nurses play a vital role in the treatment of melanoma patients through education regarding their disease and treatment options, patient identification for clinical trials, and intensive monitoring and management for treatment-related side effects.