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Progress in oncolytic virotherapy for the treatment of thyroid malignant neoplasm.
Apr. 2015 | Guan, Mingxu; Romano, Gaetano; Coroniti, Roberta; Henderson, Earl E
Thyroid malignant neoplasm develops from follicular or parafollicular thyroid cells. A higher proportion of anaplastic thyroid cancer has an adverse prognosis. New drugs are being used in clinical treatment. However, for advanced thyroid malignant neoplasm such as anaplastic thyroid carcinoma, the major impediment to successful control of the disease is the absence of effective therapies. Oncolytic virotherapy has significantly progressed as therapeutics in recent years. The advance is that oncolytic viruses can be designed with biological specificity to infect, replicate and lyse tumor cells. Significant advances in virotherapy have being achieved to improve the accessibility, safety and efficacy of the treatment. Therefore, it is necessary to summarize and bring together the main areas covered by these investigations for the virotherapy of thyroid malignant neoplasm. We provide an overview of the progress in virotherapy research and clinical trials, which employ virotherapy for thyroid malignant neoplasm as well as the future prospect for virotherapy of thyroid malignant neoplasms. PMID 25366264

Antitumor Responses Stimulated by Dendritic Cells Are Improved by Triiodothyronine Binding to the Thyroid Hormone Receptor β.
Apr. 2015 | Alamino, Vanina A; Mascanfroni, Iván D; Montesinos, María M; Gigena, Nicolás; Donadio, Ana C; Blidner, Ada G; Milotich, Sonia I; Cheng, Sheue-Yann; Masini-Repiso, Ana M; Rabinovich, Gabriel A; Pellizas, Claudia G
Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) β mutant mouse (TRβPV) to establish the relevance of the T3-TRβ system in vivo. In this model, TRβ signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TRβ increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFNγ-producing CD8(+) T cells. Overall, our results establish an adjuvant effect of T3-TRβ signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy. PMID 25672979

Morphologic evidence of anti-tumor specificity of T cells activated by denritic cells derived from peripheral blood mononuclear cells of thyroid cancer patients.
Aug. 2012 | Lee, Dae-Heui
Recent studies suggest that immunization with autologous dendritic cells (DCs) results in protective immunity and rejection of established tumors in various human malignancies. The purpose of this study is to determine whether DCs are generated from peripheral blood mononuclear cells (PBMNs) by using cytokines such as F1t-3 ligand (FL), granulocyte macrophage-colony stimulating factor (GM-CSF), IL-4, and TNF-α, and whether cytotoxic T cells activated against the thyroid cancer tissues by the DCs. Peripheral blood was obtained from 2 patients with thyroid cancer. DCs were established from PBMNs by culturing in the presence of FL, GM-CSF, IL-4, and TNF-α for 14 days. At day 14, the differentiated DCs was analyzed morphologically. The immunophenotypic features of DCs such as CDla, CD83, and CD86 were analyzed by immunofluorelescence microscopy. At day 18, DCs and T cells were incubated with thyroid cancer tissues or normal thyroid tissues for additional 4 days, respectively. DCs generated from the PBMNs showed the typical morphology of DCs. Activated cytotoxic T lymphocytes (CTLs) were observed also. DCs and the CTLs were attached to the cancer tissues on scanning electron microscope. The DCs activated the CTLs, which able to specifically attack the thyroid cancer. This study provides morphologic evidence that the coculture of T cells/cancer tissues activated the T cells and differentiated CTLs. The CTLs tightly adhered to cancer tissues and lysed cancer tissues vigorously. Therefore DCs could be used as potential vaccines in the immunotherapy. PMID 22915989

Advances in cellular therapy for the treatment of thyroid cancer.
Juli 2010 | Papewalis, Claudia; Ehlers, Margret; Schott, Matthias
Up to now, there are no curative therapies available for the subset of metastasized undifferentiated/anaplastic thyroid carcinomas. This review describes the possible use of immunocompetent cells which may help to restore the antitumor immune recognition for treating an existing tumor or preventing its recurrence. The most prominent experimental strategy is the use of dendritic cells (DCs) which are highly potent in presenting tumor antigens. Activated DCs subsequently migrate to draining lymph nodes where they present antigens to naïve lymphocytes and induce cytotoxic T cells (CTL). Alternatively to DC therapy, adoptive cell transfer may be performed by either using natural killer cells or ex vivo maturated CTLs. Within this review article we will focus on recent advances in the understanding of anti-tumor immune responses, for example, in thyroid carcinomas including the advances which have been made for the identification of potential tumor antigens in thyroid malignancies. PMID 20671939

Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma.
Juni 2009 | Santarpia, L; Ye, L; Gagel, R F
Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation. Activating mutations of RET are associated with the pathogenesis of MTC and have been demonstrated in nearly all hereditary and in 30-50% of sporadic MTC cases, making this receptor an excellent target for small-molecule inhibitors for this tumour. Clinical trials of small organic inhibitors of tyrosine kinase receptors (TKIs) targeting the RET receptor have shown efficacy for treatment of metastatic MTC with 30-50% of patients responding to these agents. Despite the importance of the RET receptor in MTC, it is clear that other signal transduction pathways, tyrosine kinase receptors, and tumour suppressor genes are involved in MTC tumourigenesis and progression. A better understanding of molecular cross-talk between these signal pathways and the RET receptor may lead to combinatorial therapy that will improve outcomes beyond what is currently possible with RET-directed TKIs. Finally, there is evidence that immunological-based therapy using dendritic cell vaccination strategies have been effective for reducing tumour mass in a small number of patients. The identification of additional MTC-specific tumour antigens and a better understanding of specific epitopes in these tumour antigens may lead to improvement of response rates. PMID 19522829

Pilot trial of autologous dendritic cells loaded with tumor lysate(s) from allogeneic tumor cell lines in patients with metastatic medullary thyroid carcinoma.
Mai 2009 | Bachleitner-Hofmann, Thomas; Friedl, Josef; Hassler, Michaela; Hayden, Hubert; Dubsky, Peter; Sachet, Monika; Rieder, Erwin; Pfragner, Roswitha; Brostjan, Christine; Riss, Stefan; Niederle, Bruno; Gnant, Michael; Stift, Anton
Immunotherapy with autologous dendritic cells (DCs) loaded with tumor lysate(s) from allogeneic tumor cell lines is a novel strategy to induce immune responses in cancer patients. We report on a pilot trial of autologous DCs pulsed with tumor cell lysate derived from allogeneic medullary thyroid carcinoma (MTC) cell lines in patients with metastatic MTC. The purpose of this study was to assess the safety, resulting immune responses and clinical activity of the DCs. DCs were injected into a groin lymph node at 3-week intervals. Monitoring included serial calcitonin tumor marker measurements, radiological imaging and immunological in vitro tests (T-cell interferon-gamma detection assay, T-cell cytotoxicity assay). Ten patients (median age 47 years, range 29-77) were enrolled. DC vaccinations were well-tolerated and safe. After a median follow-up of 11 months, (range 7-26), 3 (30%) of 10 patients had stable disease, while 7 (70%) of the patients progressed during treatment. In 2 patients with stable disease, calcitonin decreased below treatment levels, paralleled by a T-cell-mediated immune response. Notably, treatment with DCs pulsed with a combination of different tumor cell lysates was followed by a calcitonin decrease in 4 patients who had previously experienced a calcitonin increase during monotherapy with DCs pulsed with a single lysate. Allogeneic tumor cell lysate-based DC immunotherapy is well-tolerated and safe. Combined treatment with different tumor cell lysate-pulsed DCs increases the likelihood of a calcitonin tumor marker response and should therefore be preferred over monotherapy with DCs pulsed with a single lysate. PMID 19424640

Dendritic cell vaccination with xenogenic polypeptide hormone induces tumor rejection in neuroendocrine cancer.
Juli 2008 | Papewalis, Claudia; Wuttke, Margret; Seissler, Jochen; Meyer, Yvonne; Kessler, Caroline; Jacobs, Benedikt; Ullrich, Evelyn; Willenberg, Holger S; Schinner, Sven; Baehring, Thomas; Scherbaum, Werner A; Schott, Matthias
No relevant breakthrough has yet been achieved in the identification of tumor antigens in many neuroendocrine cancer types that exist, such as malignant gastrinoma, insulinoma, or medullary thyroid carcinoma. The aim of this study was to proof the concept of dendritic cell immunization with a tumor cell-specific polypeptide hormone as a target molecule in a transgenic mouse model for medullary thyroid carcinoma (Ret/Cal mice). PMID 18594013

Dendritic cell vaccination induces tumor epitope-specific Th1 immune response in medullary thyroid carcinoma.
Feb. 2008 | Papewalis, C; Wuttke, M; Jacobs, B; Domberg, J; Willenberg, H; Baehring, T; Cupisti, K; Raffel, A; Chao, L; Fenk, R; Seissler, J; Scherbaum, W A; Schott, M
The existence of inherited aggressive forms of medullary thyroid carcinoma (MTC) and their resistance to classical therapies make it a prime candidate for adoptive immunotherapy. Highly potent antigen-presenting cells, namely dendritic cells (DCs), may serve as an interesting tool for anticancer vaccination. Here we report on the IN VITRO findings of a vaccination trial in five MTC patients, who were treated with a new DC generation protocol consisting of granulocyte-macrophage colony-stimulating factor and interferon-alpha (IFN-DCs). These cells were pulsed with tumor-specific calcitonin and administered twice. In two patients who responded to therapy we found a large increase (in mean 2.9+/-1.9%) of antigen-specific IFN-gamma-secreting CD4+ cells as well as an increase of granzyme B positive CD8+ cells (mean 2.2+/-0.2%) in the peripheral blood. In parallel, a decrease of CD4+/CD25+/FoxP3+ regulatory T cells was seen. Importantly, IN VITRO stimulation of PBMC with 10 different 15mer calcitonin peptides resulted in the identification of two HLA class II epitope regions within the central part of full-length calcitonin. These data were in accordance with the results drawn from the computer-based algorithm epitope prediction software SYFPEITHI. Measurement of different pro- and anti-angiogenic factors did not allow for a distinct outcome of prediction of the treated patients. In summary, we have demonstrated that immunization with IFN-DCs leads to a tumor epitope-specific immune response in MTC patients and may, therefore, represent a promising tool for future vaccination trials. PMID 18283628

Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer.
Feb. 2007 | Kuwabara, Koichiro; Nishishita, Toshihide; Morishita, Mariko; Oyaizu, Naoki; Yamashita, Shunichi; Kanematsu, Takashi; Obara, Takao; Mimura, Yoshikazu; Inoue, Yusuke; Kaminishi, Michio; Kaga, Kimitaka; Amino, Nobuyuki; Kitaoka, Masafumi; Ito, Koichi; Miyauchi, Akira; Noguchi, Shiro; Uchimaru, Kaoru; Akagawa, Eiji; Watanabe, Nobukazu; Takahashi, Tsuneo A; Sato, Kaori; Inazawa, Takeshi; Nakaoka, Takashi; Yamashita, Naohide
We assessed the feasibility and efficacy of dendritic cell (DC) therapy for advanced thyroid papillary and follicular cancer. PMID 17274750

Heat shock treatment of tumor lysate-pulsed dendritic cells enhances their capacity to elicit antitumor T cell responses against medullary thyroid carcinoma.
Nov. 2006 | Bachleitner-Hofmann, Thomas; Strohschneider, Michaela; Krieger, Peter; Sachet, Monika; Dubsky, Peter; Hayden, Hubert; Schoppmann, Sebastian F; Pfragner, Roswitha; Gnant, Michael; Friedl, Josef; Stift, Anton
In vitro and in vivo studies have shown that dendritic cells (DCs) can stimulate antitumor T cell responses against medullary thyroid carcinoma (MTC). However, despite promising results in selected cases, the clinical efficacy of DC immunotherapy in patients with MTC has been limited. Recently, it has been demonstrated in mice that heat shock enhances the capacity of bone-marrow-derived DCs to stimulate antigen-specific T cells. The aim of our investigations was to evaluate whether heat shock also increases the capacity of human monocyte-derived DCs to stimulate antitumor T cell responses against MTC tumor cells. PMID 16954161

Immunesurveillance by dendritic cells: potential implication for immunotherapy of endocrine cancers.
Sep. 2006 | Schott, Matthias
Dendritic cells (DCs) are highly efficient antigen-presenting cells in the immune system with the potential to regulate the system and induce a cytotoxic T-cell response. As a proof of principle, a multitude of animal and human studies has demonstrated that immunization with antigen-loaded DCs may lead to anti-tumour immune responses with tumour regression and rejection of cancer. The identification of tumour antigens that can be recognized by T lymphocytes has facilitated the development of new protocols and enabled immunologists to monitor immune responses. However, to date, long-term clinical effects on larger numbers of cancer patients are missing, and there is no generally accepted DC generation or activation protocol. This review will focus on the most important findings on the role of DCs within the immune system and how to generate and activate these cells in order to induce cytotoxic immunity in non-endocrine and endocrine malignancies. Recently, we and other researchers reported on DC vaccinations in patients with endocrine malignancies mainly in metastasized medullary thyroid carcinoma resulting in tumour-specific immunity and partial clinical responses in some cases. Based on these and other in vitro data, new DC vaccination protocols for the treatment of patients with endocrine tumours have now been conducted. PMID 16954430

Medullary thyroid carcinoma: autologous tumor cell lines for dendritic cell vaccination.
Nov. 2005 | Pfragner, Roswitha; Skofitsch, Gerhard; Höger, Harald; Jech, Marion; Rinner, Beate; Siegl, Veronika; Niederle, Bruno; Gnant, Michael; Friedl, Josef; Stift, Anton
Medullary thyroid carcinoma (MTC) is a calcitonin-producing tumor of the parafollicular C-cells, accounting for 5-10% of all thyroid tumors. To date, the only effective treatment is the early and total surgical removal of all neoplastic tissue. As the prognosis of patients with advanced MTC, unresectable or distant metastases is poor, and chemotherapy or irradiation is of no significant value, alternative strategies have been sought. PMID 16309220

Dendritic cell-based immunotherapy in thyroid malignancies.
Sep. 2004 | Schott, Matthias; Scherbaum, Werner A; Seissler, Jochen
A new approach for anti-tumor immunotherapy is to use dendritic cells (DCs) as adjuvants in order to actively immunize cancer patients with antigens specifically expressed in tumor cells. DCs possess a unique capacity to effectively activate CD4+ T helper cells and CD8+ cytotoxic T cells. During the last years, several clinical trials in various malignancies demonstrated that immunizations with tumor antigen pulsed DCs could break the tolerance of the immune system against antigens expressed by the tumor cells resulting in partial or complete remission in some cases. This review describes the most important findings on the interaction between DCs and T cells as well as natural killer cells and summarizes recent data on DC vaccination of endocrine and non-endocrine malignancies. The results from current pilot studies suggest that DC vaccination may represent a promising strategy for the development of an anti-cancer vaccine to treat chemotherapy and radioresistant endocrine malignancies. PMID 15379726

Dendritic cell vaccination in medullary thyroid carcinoma.
Mai 2004 | Stift, Anton; Sachet, Monika; Yagubian, Rubina; Bittermann, Clemens; Dubsky, Peter; Brostjan, Christine; Pfragner, Roswitha; Niederle, Bruno; Jakesz, Raimund; Gnant, Michael; Friedl, Josef
Prognosis and treatment effectiveness for medullary thyroid carcinoma (MTC) are strictly related to tumor stage. Palliative treatment options show no significant benefit. A promising treatment approach for human cancer is based on the vaccination of autologous dendritic cells (DCs). PMID 15131029

Thyroglobulin-pulsed human monocyte-derived dendritic cells induce CD4+ T cell activation.
Dez. 2003 | Morishita, Mariko; Uchimaru, Kaoru; Sato, Katsuaki; Ohtsuru, Akira; Yamashita, Shunichi; Kanematsu, Takashi; Yamashita, Naohide
Although thyroglobulin (Tg) would be expected to act as a tumor-associated antigen that might be exploitable by immunotherapy against thyroid cancers, it remains unclear how to effectively enhance the immune response to Tg in human since it is a self-component glycoprotein. We therefore tested whether and how human peripheral blood (PB) monocyte-derived dendritic cells (DCs) pulsed with human (h)Tg would induce activation of hTg-specific T cells. We found that immature DCs (iDCs) exhibited a higher endocytic capacity for fluorescein isothiocyanate-conjugated hTg than did mature DCs (mDCs). Although freshly isolated T cells responded poorly to mDCs, hTg-primed T cells responded much more strongly to hTg pulsed mDCs, which selectively induced IFN-gamma-secreting T cells. These results suggest that hTg-pulsed mDCs enhance the responses of Tg-specific T cells, raising the possibility that vaccination with hTg-pulsed mDCs may be an effective approach as immunotherapy to potentiate thyroid cancer specific therapy. PMID 14654967

Dendritic cell vaccination: new hope for the treatment of metastasized endocrine malignancies.
Apr. 2003 | Schott, Matthias; Seissler, Jochen
Dendritic cells (DCs) are antigen-presenting cells that are involved in the induction of primary immune responses. The unique ability of DCs to activate naive and memory CD4+ and CD8+ T cells suggests that they could be used for the induction of a specific antitumour immunity. In the past few years, several in vitro and in vivo studies in rodents and humans have demonstrated that immunizations with DCs pulsed with tumour antigens result in protective immunity and rejection of established tumours in various malignancies. Here, we focus on recent results of how DCs regulate immune responses that are important for generating antitumour cytotoxic T cells, and summarize clinical vaccination trials for the treatment of endocrine and nonendocrine carcinomas. Preliminary results suggest that DC vaccines might be novel tools for antitumour immunotherapies to treat chemotherapy-resistant and radioresistant endocrine cancers, such as metastasized medullary thyroid carcinomas and other neuroendocrine carcinomas. PMID 12714275

Calcitonin-specific antitumor immunity in medullary thyroid carcinoma following dendritic cell vaccination.
Nov. 2002 | Schott, Matthias; Feldkamp, Joachim; Klucken, Melanie; Kobbe, Guido; Scherbaum, Werner A; Seissler, Jochen
In this study, we investigated the immune response following immunotherapy with calcitonin-pulsed dendritic cells (DC) in 7 patients with metastasized medullary thyroid carcinoma. After immunization with 1-5 x 10(6) autologous DC, significant calcitonin-specific T cell proliferation was detectable in 3 patients. Measurement of cytokine release from T lymphocytes demonstrated high post-treatment interferon-gamma (IFN-gamma) secretion after stimulation with calcitonin in 5 patients, one of whom experienced significant tumor regression. In contrast, antigen-specific interleukin-4 (IL-4) production was only slightly increased in 4 patients. All 7 patients developed a strong delayed-type hypersensitivity (DTH) skin reaction, which was confirmed to be mediated by infiltrating CD4+ T-helper cells and CD8+ cytotoxic T cells in all 3 patients who underwent skin biopsy. This is the first study to show that a polypeptide hormone can be used to develop a DC vaccination strategy for the immunotherapy of highly malignant endocrine cancers. PMID 12439612

Stimulation of autologous antitumor T-cell responses against medullary thyroid carcinoma using tumor lysate-pulsed dendritic cells.
März 2002 | Bachleitner-Hofmann, T; Stift, A; Friedl, J; Pfragner, R; Radelbauer, K; Dubsky, P; Schüller, G; Benkö, T; Niederle, B; Brostjan, C; Jakesz, R; Gnant, M
Dendritic cells (DCs) have attracted wide interest because of their unique capacity to elicit primary and secondary antitumor responses. We have generated autologous tumor lysate-pulsed DCs from three patients with medullary thyroid carcinoma (MTC) and tested them for their ability to stimulate cytotoxic T-cell responses against autologous MTC tumor cells in vitro. The aim of our investigations was to evaluate the potential efficacy of DC-based immunotherapy in patients with MTC. DCs were generated from peripheral blood monocytes using GM-CSF and IL-4 (immature DCs) or GM-CSF, IL-4, and TNFalpha (mature DCs). Our results indicate that mature tumor lysate-pulsed DCs are able to elicit a human leukocyte antigen class I-restricted cytotoxic T-cell response against autologous MTC tumor cells, whereas immature tumor lysate-pulsed DCs do not stimulate significant antitumor activity. We feel that our data may be relevant for future clinical trials of active immunotherapy using tumor lysate-pulsed DCs in patients with MTC who have residual or distant disease after surgical treatment. The fact that mature DCs displayed a substantially higher capacity to stimulate autologous antitumor T-cell responses than immature DCs underlines the importance of a maturation step in immunotherapy protocols based on DCs. PMID 11889172

Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination.
Okt. 2001 | Schott, M; Seissler, J; Lettmann, M; Fouxon, V; Scherbaum, W A; Feldkamp, J
Recent studies suggest that immunization with autologeous dendritic cells (DCs) pulsed with tumor antigen result in protective immunity and rejection of established tumors in various human malignancies. The objective of this study was to develop a DC vaccination therapy in patients with metastasized medullary thyroid carcinoma (MTC). Mature DCs were generated from peripheral blood monocytes in the presence of granulocyte macrophage colony-stimulating factor, IL-4, and TNFalpha. After loading with calcitonin and carcinoembryonic antigen (CEA) peptide, 2-5 x 10(6) DCs were repeatedly delivered by sc injections. During follow-up (mean, 13.1 months) all patients developed a strong delayed-type hypersensitivity skin reaction caused by perivascular and epidermal infiltration with CD4+ memory T cells and CD8+ cytotoxic T cells. Clinical responses with a decrease of serum calcitonin and CEA were initially documented in three of seven patients. One of these patients had a complete regression of detectable liver metastases and a significant reduction of pulmonary lesions. T-cell response in this patient revealed a calcitonin- and CEA-specific immunreactivity. Our data indicate that vaccination with calcitonin and/or CEA peptide-pulsed DC results in the induction of a cellular, antigen-specific immune response in patients with MTC, leading to clinical response in some patients. Our approach may represent the basis for the development of new therapeutic strategies not only in MTC but also in other endocrine malignancies. PMID 11600571

Hyperthermia inhibits proliferation and stimulates the expression of differentiation markers in cultured thyroid carcinoma cells.
Dez. 1994 | Trieb, K; Sztankay, A; Amberger, A; Lechner, H; Grubeck-Loebenstein, B
In the last two decades hyperthermia has increasingly been used as adjuvant therapy for the treatment of malignant tumours. The effects of heat were therefore analysed on cultured thyroid epithelial cells from patients with thyroid cancer and from non-malignant control thyroids. Purified thyroid cells were subjected to heat treatment (42.5 degrees C; 90 min). After 24 h [3H]thymidine incorporation was assessed and the expression of heat shock protein 72 (hsp72), thyroglobulin, CD54 (ICAM-I) and MHC class-Il were analysed by immunofluorescence staining. Additionally mRNA analysis was performed by Northern blotting. Whereas hyperthermia inhibited the proliferation of thyroid cells, it significantly increased the expression of hsp72, thyroglobulin, CD54 and HLA-DR (P < 0.05). Our results suggest that hyperthermia may suppress growth while supporting differentiation and immune recognition in thyroid cancer. It may therefore be beneficial as a treatment for patients with thyroid carcinoma. PMID 7954371

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