Regression of Metastatic Merkel Cell Carcinoma Following Transfer of Polyomavirus-Specific T Cells and Therapies Capable of Reinducing HLA Class-I
Cancer immunology research
04/2014; 2(1):27-36. DOI: 10.1158/2326-6066.CIR-13-0087
Merkel cell carcinoma (MCC) is an aggressive skin cancer that typically requires the persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins that can serve as ideal immunotherapeutic targets. Several immune evasion mechanisms are active in MCC including down-regulation of HLA class-I expression on tumor cells and dysfunctional endogenous MCPyV-specific CD8 T cell responses. To overcome these obstacles, we combined local and systemic immune therapies in a 67-year-old man, who developed metastatic MCPyV-expressing MCC. Intralesional IFNβ-1b or targeted single-dose radiation was administered as a pre-conditioning strategy to reverse the down-regulation of HLA-I expression noted in his tumors and to facilitate the subsequent recognition of tumor cells by T cells. This was followed by the adoptive transfer of ex vivo expanded polyclonal, polyomavirus-specific T cells as a source of reactive antitumor immunity. The combined regimen was well-tolerated and led to persistent up-regulation of HLA-I expression in the tumor and a durable complete response in two of three metastatic lesions. Relative to historical controls, the patient experienced a prolonged period without development of additional distant metastases (535 days compared to historic median of 200 days, 95% confidence interval = 154-260 days). The transferred CD8(+) T cells preferentially accumulated in the tumor tissue, remained detectable and functional for >200 days, persisted with an effector phenotype, and exhibited evidence of recent in vivo activation and proliferation. The combination of local and systemic immune stimulatory therapies was well-tolerated and may be a promising approach to overcome immune evasion in virus-driven cancers.
Available from: sciencedirect.com
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ABSTRACT: Endoscopic ultrasound (EUS)-guided interventions for treatment of periluminal tumors allows for a minimally invasive alternative to other more invasive methods of tumor therapies such as surgery or percutaneous ablation. For many tumors, especially pancreatic and peripancreatic tumors, EUS allows the most direct access for providing therapy. However, our experience with EUS-guided tumor ablation therapy remains limited. Several promising methods for EUS-guided ablation are in development or undergoing clinical evaluation. There have been case reports and several limited studies evaluating various injection therapies such as alcohol or biologic agents. In addition, laser, photodynamic therapy, radiofrequency ablation, and high-intensity focused ultrasound are currently being investigated as possible modalities for EUS-guided ablation. These methods for performing EUS-guided ablation are reviewed.
Available from: Robin L Jones
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ABSTRACT: Adoptive T cell therapy represents an attractive modality for the treatment of patients with cancer. Peripheral blood mononuclear cells have been used as a source of antigen specific T cells but the very low frequency of T cells recognizing commonly expressed antigens such as NY-ESO-1 limit the applicability of this approach to other solid tumors. To overcome this, we tested a strategy combining IL-21 modulation during in vitro stimulation with first-in-class use of tetramer-guided cell sorting to generate NY-ESO-1 specific cytotoxic T lymphocytes (CTL).
CTL generation was evaluated in 6 patients with NY-ESO-1 positive sarcomas, under clinical manufacturing conditions and characterized for phenotypic and functional properties.
Following in vitro stimulation, T cells stained with NY-ESO-1 tetramer were enriched from frequencies as low as 0.4% to >90% after single pass through a clinical grade sorter. NY-ESO-1 specific T cells were generated from all 6 patients. The final products expanded on average 1200-fold to a total of 36 billion cells, were oligoclonal and contained 67-97% CD8+, tetramer+ T cells with a memory phenotype that recognized endogenous NY-ESO-1.
This study represents the first series using tetramer-guided cell sorting to generate T cells for adoptive therapy. This approach, when used to target more broadly expressed tumor antigens such as WT-1 and additional Cancer-Testis antigens will enhance the scope and feasibility of adoptive T cell therapy.
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This study aimed to document three new cases of primary small cell carcinoma (SmCC) of the parotid and examine immunohistochemical and quantitative real-time PCR (qPCR) data of the recently developed Merkel cell polyomavirus (MCPyV) within these tumors.
Immunohistochemistry for neuroendocrine markers (Chromogranin A, CD56, CD57, [NSE], [TTF-1]), epithelial markers (CK20, CK7, CAM 5.2), and MCPyV large T antigen (LTAG) were examined. qPCR and Sanger sequencing were performed to confirm the presence of MCPyV LTAg gene.
Two males and one female, average age 76, presented with left parotid masses. Clinical examinations, histories, and imaging studies were negative for cutaneous Merkel cell carcinoma, pulmonary and extrapulmonary SmCC, or any other malignancy. Immunohistochemical analysis demonstrated positive immunoreactivity for CK20 in a perinuclear dot-like pattern (3/3), CAM 5.2 (3/3), (2/3), NSE (3/3), CD56 (2/3), and CD57 (3/3). Two cases stained positive for MCPyV, showing moderate to strong, diffuse positivity, confirmed with qPCR. PCR-Sanger sequencing of LTAg exon 2 showed >97% similarity to the MCPyV reference genome in both cases.
Our findings expand the number of reported cases classified as primary parotid SmCC which harbor MCPyV, and underscore the similarity between cutaneous MCC and parotid SmCC. Further investigation is needed to determine whether immune-based therapeutic strategies targeting MCPyV in MCC are also effective in the setting of parotid SmCC harboring MCPyV.
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