Immune responses in the thyroid cancer microenvironment: making immunotherapy a possible mission

The incidence of thyroid cancers has been steadily increasing worldwide over the past few decades. Although five-year survival rates for differentiated thyroid cancers are upwards of 90%, clinical outcomes for patients with undifferentiated, recurrent and/or metastatic disease are often dismal despite conventional interventions. As such, there is a demand for novel treatment options. Cancer immunotherapy represents the ultimate form of personalized medicine by leveraging the specificity and potency of a patient’s immune system to kill their tumor. The thyroid cancer microenvironment is rich in immunological cells, making it a reasonable candidate for immunotherapy. This review maps out the immunological features of thyroid cancers and how these can be modulated. There are surprising immunological consequences of conventional therapies that demand attention. Also, hormonal modulation of the immune system is highlighted as a unique and confounding feature of thyroid cancers. A variety of cutting-edge immune-based therapies are discussed, with an emphasis placed on how these can be integrated with the current standard of care. Several high priority areas in need of research are also highlighted.

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Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

Endocrine Related Cancer ◽

10.1530/erc-15-0555 ◽

2016 ◽

Vol 23 (4) ◽

pp. R185-R205 ◽

Cited By ~ 90

Author(s):

David Viola ◽

Laura Valerio ◽

Eleonora Molinaro ◽

Laura Agate ◽

Valeria Bottici ◽

...

Keyword(s):

Thyroid Cancer ◽

Targeted Therapies ◽

Kinase Inhibitors ◽

Survival Rates ◽

Current Status ◽

Thyroid Cancers ◽

Poorly Differentiated ◽

Advanced Thyroid Cancer ◽

Well Differentiated ◽

Differentiated Thyroid Cancers

AbstractThyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15–20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.

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Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities

International Journal of Molecular Sciences ◽

10.3390/ijms22063117 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3117

Author(s):

Loredana Lorusso ◽

Virginia Cappagli ◽

Laura Valerio ◽

Carlotta Giani ◽

David Viola ◽

...

Keyword(s):

Thyroid Cancer ◽

Kinase Inhibitors ◽

Therapeutic Option ◽

Progression Free Survival ◽

Thyroid Cancers ◽

Poorly Differentiated ◽

Differentiated Thyroid Cancers ◽

Approved Drugs ◽

New Generation ◽

Systemic Therapies

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

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Co-Clinical Trials: An Innovative Drug Development Platform for Cholangiocarcinoma

Pharmaceuticals ◽

10.3390/ph14010051 ◽

2021 ◽

Vol 14 (1) ◽

pp. 51

Author(s):

Brinda Balasubramanian ◽

Simran Venkatraman ◽

Kyaw Zwar Myint ◽

Tavan Janvilisri ◽

Kanokpan Wongprasert ◽

...

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Drug Development ◽

Surgical Resection ◽

Treatment Options ◽

Standard Of Care ◽

Time Data ◽

Current Standard ◽

Innovative Drug ◽

Curative Intent

Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.

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Reversal of Renal Insufficiency in an Aging Cat: A 5-year Multi-Crossover Case Study

The Journal of Science and Medicine ◽

10.37714/josam.v2i2.30 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

Robert Dennis ◽

John Dennis

Keyword(s):

Palliative Care ◽

Renal Insufficiency ◽

Treatment Options ◽

Low Frequency ◽

Standard Of Care ◽

Omega 3 ◽

Current Standard ◽

Invasive Treatment ◽

Non Invasive ◽

Electro Magnetic

Renal failure is a leading cause of suffering and death in domestic cats, with approximately 1 in 3 cats affected. Current standard-of-care treatment usually involves palliative care, diets restricted in protein and phosphorus, plenty of fluids, and sometimes vitamin D and Omega-3. But even with early detection, which is difficult, treatment options are limited and often are not very effective. Dietary restrictions and palliative care are often the best that can be offered, but the creatinine levels tend to inexorably creep upward toward eventual kidney failure and death. We report the effectiveness of the use of a low-frequency, low-intensity, non-invasive treatment using Pulsed Electro-Magnetic Fields, specifically tuned to inductively generate micro-electric currents in deep tissues (ICES®-PEMF). This report chronicles the return to normal and then reversion to renal insufficiency in a single cat, when ICES®-PEMF was applied, then withheld, then applied again, over three cycles of application and non-application, over a 5-year period. A return to normal creatinine levels, with a subsequent return to renal insufficiency as indicated by loss of control of creatinine, correlated precisely with the application and non-application of ICES®-PEMF. The pattern observed during each cycle was as follows: when applied 2 to 3 times weekly for 20-60 minutes each treatment, creatinine levels declined to normal range within 2-3 months. During periods when treatment was discontinued, creatinine levels began to climb to high levels again. We suggest the further study and potential use of ICES®-PEMF as an effective, inexpensive, safe, non-invasive treatment for feline kidney disease.

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Towards Personalization in the Curative Treatment of Gastric Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.614907 ◽

2020 ◽

Vol 10 ◽

Author(s):

Astrid E. Slagter ◽

Marieke A. Vollebergh ◽

Edwin P. M. Jansen ◽

Johanna W. van Sandick ◽

Annemieke Cats ◽

...

Keyword(s):

Gastric Cancer ◽

Treatment Options ◽

Treatment Strategies ◽

Standard Of Care ◽

Molecular Characteristics ◽

Perioperative Chemotherapy ◽

Current Standard ◽

Common Cancer ◽

Resectable Gastric Cancer

Gastric cancer is the fifth most common cancer worldwide and has a high mortality rate. In the last decades, treatment strategy has shifted from an exclusive surgical approach to a multidisciplinary strategy. Treatment options for patients with resectable gastric cancer as recommended by different worldwide guidelines, include perioperative chemotherapy, pre- or postoperative chemoradiotherapy and postoperative chemotherapy. Although gastric cancer is a heterogeneous disease with respect to patient-, tumor-, and molecular characteristics, the current standard of care is still according to a one-size-fits-all approach. In this review, we discuss the background of the different treatment strategies in resectable gastric cancer including the current standard, the specific role of radiotherapy, and describe the current areas of research and potential strategies for personalization of therapy.

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A decision-analytic model of idelalisib in relapsed or refractory patients with follicular lymphoma in the United States.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.30_suppl.30 ◽

2014 ◽

Vol 32 (30_suppl) ◽

pp. 30-30 ◽

Cited By ~ 1

Author(s):

Nathaniel Smith ◽

Alexander Xenakis ◽

Rachel Beckerman ◽

Jagpreet Chhatwal ◽

Stephanie A. Gregory ◽

...

Keyword(s):

Health Outcomes ◽

Follicular Lymphoma ◽

Survival Data ◽

Treatment Options ◽

Standard Of Care ◽

The United States ◽

Sensitivity Analyses ◽

Decision Analytic Model ◽

Current Standard ◽

Utilization Data

30 Background: There are currently few treatment options for relapsed/refractory (RR) indolent non-Hodgkin’s lymphoma (iNHL) patients. Idelalisib (IDELA) is a first-in class PI3Kδ inhibitor with substantial clinical efficacy in iNHL patients refractory to rituximab and an alkylating agent. A single-arm clinical trial (Study 101-09) showed RR iNHL patients treated with IDELA have a median of 11 and 20.3 months of progression-free and overall survival (PFS and OS), respectively. Efficacy was also demonstrated in patients with iNHL subtypes such as follicular lymphoma (FL). The objective of this study was to project the health outcomes of IDELA versus the current standard of care for US FL patients. Methods: A partitioned survival model simulated a cohort of RR FL patients over 10 year time horizon. Patients first received IDELA or an aggregate comparator of current RR iNHL chemotherapy regimens in a progression-free state before transitioning to a progressive-disease state where they received palliative care until death. Survival data was fit and extrapolated from Study 101-09 (IDELA) for FL patients. A real-world database claims analysis provided survival, disease- and treatment-related adverse event (AEs) profiles, and medical resource utilization data for RR iNHL patients for the comparator. All outcomes were discounted at 3%. Results: Claims data predicted a median of 6.16 and 13.04 months of PFS and OS, respectively, for the comparator. Our model suggests that IDELA treatment improved health outcomes over 10 years versus the comparator, increasing life-months (LMs) and progression-free life-months (PFLMs) by 9.94 and 4.63 mos, respectively. Over 1 year, IDELA reduced both AEs and hospitalisations in FL patients by 40.3% and 49.8%, respectively. Deterministic and probabilistic sensitivity analyses demonstrated the model results are robust across different methods of survival extrapolation. Conclusions: IDELA was projected to improve health outcomes in RR FL patients compared to current treatments, largely driven by improved PFS and OS; short-term reductions in AEs and hospitalisation were specifically related to a delayed disease progression.

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Thyroid Carcinoma in Hot Nodules: Review of the Literature

World Journal of Endocrine Surgery ◽

10.5005/jp-journals-10002-1126 ◽

2013 ◽

Vol 5 (2) ◽

pp. 50-54 ◽

Cited By ~ 2

Author(s):

Pouya Iranmanesh ◽

Marc Pusztaszeri ◽

John Robert ◽

Patrick Meyer ◽

Boris Schiltz ◽

...

Keyword(s):

Thyroid Cancer ◽

Thyroid Carcinoma ◽

Clinical Case ◽

Survival Rates ◽

Review Of The Literature ◽

Abnormal Finding ◽

Thyroid Cancers ◽

Thyroid Carcinomas ◽

Medical Databases ◽

The Past

ABSTRACT Thyroid hot nodules are virtually always considered benign. Rare cases of hot thyroid carcinoma exist. We briefly described a clinical case and performed a review of the literature. We performed an extensive research on medical databases, such as PubMed and compiled all published cases matching preset criteria defining true hot thyroid carcinomas as well as guidelines regarding their management. We analyzed 103 articles published over the past 50 years. We selected 16 articles, including 45 cases matching our criteria. The majority were follicular carcinomas. Papillary carcinomas were infrequently found in this setting. Recommended management and survival rates were similar to classical cold thyroid cancer. Although hot nodules should continue to be considered benign most of the time, rare cases of hot thyroid cancers exist and clinicians should not hesitate to ask for additional tests if they encounter any abnormal finding. This form of thyroid cancer can reasonably be managed the same way as the cold thyroid cancers. How to cite this article Iranmanesh P, Pusztaszeri M, Robert J, Meyer P, Schiltz B, Sadowski SM, Goumaz MO, Triponez F. Thyroid Carcinoma in Hot Nodules: Review of the Literature. World J Endoc Surg 2013;5(2):50-54.

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Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates?

Hematology ◽

10.1182/hematology.2021000253 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 219-225

Author(s):

Patrick Ellsworth ◽

Alice Ma

Keyword(s):

Hemophilia A ◽

Treatment Options ◽

Standard Of Care ◽

Factor Ix ◽

Coagulation Cascade ◽

Coagulation System ◽

Current Standard ◽

Factor Viiia ◽

Hemorrhagic Tendency ◽

The Many

Abstract Hemophilia A (HA) and B are inherited bleeding disorders caused by a deficiency of factor VIII or factor IX, respectively. The current standard of care is the administration of recombinant or purified factor. However, this treatment strategy still results in a high economic and personal burden to patients, which is further exacerbated by the development of inhibitors—alloantibodies to factor. The treatment landscape is changing, with nonfactor therapeutics playing an increasing role in what we consider to be the standard of care. Emicizumab, a bispecific antibody that mimics the function of factor VIIIa, is the first such nonfactor therapy to gain US Food and Drug Administration approval and is rapidly changing the paradigm for HA treatment. Other therapies on the horizon seek to target anticoagulant proteins in the coagulation cascade, thus “rebalancing” a hemorrhagic tendency by introducing a thrombotic tendency. This intricate hemostatic balancing act promises great things for patients in need of more treatment options, but are these other therapies going to replace factor therapy? In light of the many challenges facing these therapies, should they be viewed as a replacement of our current standard of care? This review discusses the background, rationale, and potential of nonfactor therapies as well as the anticipated pitfalls and limitations. This is done in the context of a review of our current understanding of the many aspects of the coagulation system.

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What's New in Molecular Targeted Therapies for Thyroid Cancer?

Korean Society for Head and Neck Oncology ◽

10.21593/kjhno/2021.37.2.1 ◽

2021 ◽

Vol 37 (2) ◽

pp. 1-9

Author(s):

Seonyoung Min ◽

Hyunseok Kang

Keyword(s):

Thyroid Cancer ◽

Targeted Therapies ◽

Radioactive Iodine ◽

Checkpoint Inhibitors ◽

Braf V600e Mutation ◽

Braf V600e ◽

Thyroid Cancers ◽

Ret Mutation ◽

Poorly Differentiated ◽

Differentiated Thyroid Cancers

Thyroid cancer refers to various cancers arising from thyroid gland. Differentiated thyroid cancers (DTCs) include papillary, follicular, and Hurthle cell carcinomas and represent cancers retain normal thyroid functions such as iodine uptake. Radioactive iodine (RAI) is generally used for upfront treatment of metastatic DTCs, but RAI refractory DTCs remain to be clinical challenges. Sorafenib and lenvatinib were approved for the treatment of RAI refractory DTCs and more recently, genomics-based targeted therapies have been developed for NTRK and RET gene fusion-positive DTCs. Poorly differentiated and anaplastic thyroid cancers (ATCs) are extremely challenging diseases with aggressive courses. BRAF/MEK inhibition has been proven to be highly effective in BRAF V600E mutation-positive ATCs and immune checkpoint inhibitors have shown promising activities. Medullary thyroid cancers, which arise from parafollicular cells of thyroid, represent a unique subset of thyroid cancer and mainly driven by RET mutation. In addition to vandetanib and cabozantinib, highly specific RET inhibitors such as selpercatinib and pralsetinib have demonstrated impressive activity and are in clinical use.

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The Tumor Microenvironment and Immunotherapy of Oropharyngeal Squamous Cell Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2020.545385 ◽

2020 ◽

Vol 10 ◽

Author(s):

Marij J. P. Welters ◽

Saskia J. Santegoets ◽

Sjoerd H. van der Burg

Keyword(s):

Squamous Cell Carcinoma ◽

Immune System ◽

Cell Carcinoma ◽

Squamous Cell ◽

Standard Of Care ◽

Oropharyngeal Squamous Cell Carcinoma ◽

Current Standard ◽

Preclinical Phase ◽

New Findings ◽

New Treatment

Oropharyngeal squamous cell carcinoma (OPSCC) develops as a consequence of several mutations in the tumor suppressor pathways or after a progressive infection with high risk human papillomavirus (HPV). The dismal side effects of the current standard of care and the clear involvement of the immune system has led to a surge in clinical trials that aim to reinforce the tumor-specific immune response as a new treatment option. In this review, we have focused on the most recent literature to discuss the new findings and insights on the role of different immune cells in the context of OPSCC and its etiology. We then applied this knowledge to describe potential biomarkers and analyzed the rationale and outcomes of earlier and ongoing immunotherapy trials. Finally, we describe new developments that are still at the preclinical phase and provide an outlook on what the near future may bring, now that several new and exciting techniques to study the immune system at the single cell level are being exploited.

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