RESUMO
Immunotherapy for the treatment of metastatic melanoma remains a major clinical challenge. The melanoma microenvironment may lead to local T cell tolerance in part through downregulation of costimulatory molecules, such as B7.1 (CD80). We report the results from the first clinical trial, to our knowledge, using a recombinant vaccinia virus expressing B7.1 (rV-B7.1) for monthly intralesional vaccination of accessible melanoma lesions. A standard 2-dose-escalation phase I clinical trial was conducted with 12 patients. The approach was well tolerated with only low-grade fever, myalgias, and fatigue reported and 2 patients experiencing vitiligo. An objective partial response was observed in 1 patient and disease stabilization in 2 patients, 1 of whom is alive without disease 59 months following vaccination. All patients demonstrated an increase in postvaccination antibody and T cell responses against vaccinia virus. Systemic immunity was tested in HLA-A*0201 patients who demonstrated an increased frequency of gp100 and T cells specific to melanoma antigen recognized by T cells 1 (MART-1), also known as Melan-A, by ELISPOT assay following local rV-B7.1 vaccination. Local immunity was evaluated by quantitative real-time RT-PCR, which suggested that tumor regression was associated with increased expression of CD8 and IFN-gamma. The local delivery of vaccinia virus expressing B7.1 was well tolerated and represents an innovative strategy for altering the local tumor microenvironment in patients with melanoma.
Assuntos
Antígeno B7-1/genética , Terapia Genética , Imunoterapia , Melanoma/terapia , Vaccinia virus/genética , Vaccinia virus/imunologia , Adulto , Idoso , Antígenos de Neoplasias , Antígeno B7-1/uso terapêutico , Antígenos CD8/genética , Feminino , Expressão Gênica , Antígenos HLA-A , Antígeno HLA-A2 , Humanos , Injeções Intralesionais , Interferon gama/genética , Interleucina-10/genética , Antígeno MART-1 , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Linfócitos T/imunologiaRESUMO
Recombinant interleukin-2 (IL-2) has demonstrated antitumor activity and durable clinical responses in patients with metastatic melanoma. Careful screening and selection of appropriate patients has improved the safety profile of IL-2 administration. Gross hematuria would ordinarily preclude the safe delivery of IL-2. We report a case of metastatic melanoma to the bladder presenting with hematuria. A complete resection was performed and subsequently allowed the administration of high-dose, bolus IL-2. The combination of resection and IL-2 therapy resulted in a partial response maintained for more than 18 months. Symptomatic bladder melanoma should be aggressively treated to allow for systemic immunotherapy, which can provide durable responses.