ABSTRACT
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.
Subject(s)
B7-1 Antigen/genetics , Genetic Therapy , Immunotherapy , Melanoma/therapy , Vaccinia virus/genetics , Vaccinia virus/immunology , Adult , Aged , Antigens, Neoplasm , B7-1 Antigen/therapeutic use , CD8 Antigens/genetics , Female , Gene Expression , HLA-A Antigens , HLA-A2 Antigen , Humans , Injections, Intralesional , Interferon-gamma/genetics , Interleukin-10/genetics , MART-1 Antigen , Male , Melanoma/genetics , Melanoma/immunology , Melanoma/secondary , Middle Aged , Neoplasm Proteins/immunology , T-Lymphocytes/immunologySubject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/therapy , Interleukin-2/administration & dosage , Mastectomy, Segmental , Melanoma/therapy , Skin Neoplasms/pathology , Adult , Breast Neoplasms/drug therapy , Breast Neoplasms/secondary , Breast Neoplasms/surgery , Dose-Response Relationship, Drug , Female , Humans , Injections, Intravenous , Melanoma/drug therapy , Melanoma/secondary , Melanoma/surgery , Prognosis , Remission Induction , Time FactorsABSTRACT
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.
