WT1 as an immunotherapy target for thymic epithelial tumors: a novel method to activate anti-tumor immunity

Takahashi, Nobuyuki; Zhao, Chen; Rajan, Arun

doi:10.21037/med.2019.03.03

Cited by 4 publications

(5 citation statements)

References 29 publications

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“…Wilms’ tumor-1 (WT-1) has also been identified as a neoantigen in TETs and a WT1 peptide-based vaccine immunotherapy has undergone evaluation in patients with advanced TETs. Disease stabilization was seen in most vaccinated patients (75%) accompanied by induction of a WT1-specific immune response (43,44).…”

Section: Clinical Trials Evaluating Immunotherapy For Tetsmentioning

confidence: 99%

Immune checkpoint inhibitors for treatment of thymic epithelial tumors: how to maximize benefit and optimize risk?

Zhao

Rajan

2019

Mediastinum

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A greater understanding of anti-tumor immunity has resulted in rapid development of immunotherapy for a wide variety of cancers. Antibodies targeting the immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1), or its ligand (PD-L1) have demonstrated clinical activity and are approved for treatment of melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, bladder cancer, head and neck cancers, esophageal cancer, hepatocellular carcinoma, and Hodgkin lymphoma, among others. Treatment is generally well tolerated with relatively few adverse events compared with standard treatments such as chemotherapy. However, immune activation can potentially affect any organ system and a small fraction of patients are at risk for developing severe immunerelated adverse events. Immune checkpoint inhibitors (ICIs) and other immunotherapeutic modalities such as cancer vaccines are in nascent stages of development for treatment of thymic epithelial tumors (TETs). Since the thymus plays a key role in the development of immune tolerance, thymic tumors have a unique biology which can influence the risk-benefit balance of immunotherapy. Indeed, early results from clinical trials have demonstrated clinical activity, albeit at a cost of a higher incidence of immune-related adverse events, which seem to particularly affect skeletal and cardiac muscle and the neuromuscular junction. In this paper we describe the effects of thymic physiology on the immune system and review the results of clinical trials that have evaluated immunotherapy for treatment of relapsed thymoma and thymic carcinoma. We review ongoing efforts to mitigate the risk of immune-related complications in patients with TETs receiving immunotherapy and offer our thoughts for making immunotherapy a feasible alternative for treatment of thymic tumors.

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Section: Clinical Trials Evaluating Immunotherapy For Tetsmentioning

confidence: 99%

Immune checkpoint inhibitors for treatment of thymic epithelial tumors: how to maximize benefit and optimize risk?

Zhao

Rajan

2019

Mediastinum

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“…B7-H4 protein usually has low expression in normal tissues but higher expression several solid neoplasms [72][73][74]. High expression of B7-H4 protein by IHC staining (anti-B7-H4 monoclonal antibody, clone EP1165) is positively correlated with high regulatory T cells and forkhead box protein P3 (FOXP3) expression in the microenvironment, thus it can indicate the suppressive immune microenvironment and this relation could predict poor prognosis in patients with TETs [71,75]. The expression of tissue biomarkers such as TIM-3, CD137, GITR, ICOS and CTLA-4 on tumor infiltrating lymphocytes (TILs) of TETs has been recently evaluated.…”

Section: Emerging Biomarkers For Immunotherapy In Tetsmentioning

confidence: 99%

“…These data suggest a synergistic action of anti-TIM-3 or CD137 agonist with anti-PD-1/PD-L1 blockade, highlighting the potential need to evaluate the tissue expression of these biomarkers [ 48 ]. Moreover, recent results have been shown a Wilms’ tumour 1 (WT1) IHC expression on tumor cells, underlining the value of WT1 peptide as an immunotherapy target, particularly WT1 peptide vaccination as a new avenue for treatment of advanced or recurrent TETs [ 76 ]. The WT1 gene is a tumor suppressor and it’s overexpressed in several solid and non-solid neoplasms [ 77 – 83 ].…”

Section: Immunotherapy In Tetsmentioning

confidence: 99%

“…Thus, although the data is still limited, WT1 overexpression in TETs provides an opportunity to develop specific cancer vaccines [ 93 ]; however, the impact of this therapeutic strategy on the development of autoimmune-related complications is not yet known. Therefore, future clinical studies are needed to demonstrate the real therapeutic value of WT1 peptide-based immunotherapy and to study the association of WT1 peptide vaccine with the development of autoimmune-related complications in TETs [ 76 , 94 ].…”

Section: Immunotherapy In Tetsmentioning

confidence: 99%

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Immunotherapy in thymic epithelial tumors: tissue predictive biomarkers for immune checkpoint inhibitors

Lucà,

Accardo,

Campione

et al. 2024

Exploration of Targeted Anti-Tumor Therapy

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Thymic epithelial tumors (TETs) are rare malignant neoplasms arising in the thymus gland. Nevertheless, TETs, including thymomas (TMs), thymic carcinomas (TCs), and thymic neuroendocrine neoplasms (TNENs), are the most common mediastinal malignancies overall. A multidisciplinary approach is required for the appropriate diagnostic and therapeutic management of TETs. To date, the main therapeutic strategies are largely depended on the stage of the tumor and they include surgery with or without neoadjuvant or adjuvant therapy, represented by platinum-based chemotherapy, radiotherapy or chemoradiotherapy. Immune checkpoint inhibitors (ICIs) are ongoing under evaluation in the advanced or metastatic diseases despite the challenges related to the very low tumor mutation burden (TMB) and the high incidence of immune-related adverse events in TETs. In this regard, predictive impact of tissue biomarkers expression such as programmed cell death ligand-1 (PD-L1), and other emerging biomarkers, as well as their optimal and shared interpretation are currently under evaluation in order to predict response rates to ICIs in TETs.

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“…So far, only anecdotal achievements were reported. Clinical response was seen in patients treated with personalized dendritic cell vaccine that targets mutation of CDC73 gene (31) and Wilms' tumor-1 (WT-1) peptidebased vaccine (32,33).…”

Section: Immunotherapies For Tetsmentioning

confidence: 99%

Immunotherapy for thymoma

Jakopović¹,

Bitar²,

Seiwerth³

et al. 2020

J Thorac Dis

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Thymic epithelial tumors (TETs) are rare thymic neoplasms. There are approximately 1.5 cases per million TETs per year. They are the most common anterior mediastinal tumors in adults. Due to limited activity of available treatment options novel strategies and treatment options are needed and treatment with immune checkpoint inhibitors is an attractive option. Thymic epithelial tumors have one of the lowest tumor mutational burden among all cancer in adults, but high expression of PD-L1 on tumor cells and abundant CD8+ lymphocytes provide a strong rational for implementing immune checkpoint inhibitors (ICIs) which target PD-1/PD-L1 pathway in the treatment of TETs. Few small early stage clinical trials were published so far evaluating efficacy of pembrolizumab and avelumab in thymoma and thymic carcinoma patients. Al trials showed reasonable response rates and progression-free survival. Higher PD-L1 expression was predictor of response in all trials. However, increased incidence of immune-related adverse events was seen in TET patients treated with immune checkpoint inhibitors compared to patients with other cancers. At the moment, ICIs are not standard of care for patients with TET and larger trials are needed to establish the right role of ICIs regarding efficacy and safety of these agents.

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WT1 as an immunotherapy target for thymic epithelial tumors: a novel method to activate anti-tumor immunity

Cited by 4 publications

References 29 publications

Immune checkpoint inhibitors for treatment of thymic epithelial tumors: how to maximize benefit and optimize risk?

Immune checkpoint inhibitors for treatment of thymic epithelial tumors: how to maximize benefit and optimize risk?

Immunotherapy in thymic epithelial tumors: tissue predictive biomarkers for immune checkpoint inhibitors

Immunotherapy for thymoma

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