Current status of antigen-specific T-cell immunotherapy for advanced renal-cell carcinoma

Xu, Yuexin; Miller, Chris P.; Warren, Edus H.; Tykodi, Scott S.

doi:10.1080/21645515.2020.1870846

Cited by 11 publications

(16 citation statements)

References 152 publications

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“…Since the 1970s, RCC has been recognized as an immune-responsive tumor with a well-documented sensitivity to T cell attack [ 97 , 98 , 99 ]. Yet, RCC patients do not benefit substantially more from the T cell activating immune checkpoint blockade therapy compared to patients with tumors previously considered to be non-immunogenic [ 23 , 25 , 26 , 100 , 101 ]. This suggests the existence of additional layers of tumor-mediated immunosuppression beyond targeted T cell checkpoints that hamper antitumor immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…Invigorating the T cell response through a blockade of the immune checkpoint molecules PD-1 or PD-L1, in combination with a blockade of the checkpoint CTLA-4 or with tyrosine kinase inhibition (TKI) has been approved as a first line treatment for advanced and metastatic RCC [ 23 , 24 ]. Despite some improvements in management of the disease through these T cell targeting therapies, only a fraction of patients has been shown to respond [ 23 , 24 , 25 , 26 ], suggesting that mechanisms beyond those directly targeting the T cells control the antitumor response. This underscores the critical need to better understand the tumor environment and to identify additional therapeutic targets beyond CTLA-4, PD-1 and PD-L1 to expand the range of patients that can be effectively treated.…”

Section: Introductionmentioning

confidence: 99%

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Dendritic Cells or Macrophages? The Microenvironment of Human Clear Cell Renal Cell Carcinoma Imprints a Mosaic Myeloid Subtype Associated with Patient Survival

Brech

Herbstritt

Diederich

et al. 2022

Cells

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Since their initial description by Elie Metchnikoff, phagocytes have sparked interest in a variety of biologic disciplines. These important cells perform central functions in tissue repair and immune activation as well as tolerance. Myeloid cells can be immunoinhibitory, particularly in the tumor microenvironment, where their presence is generally associated with poor patient prognosis. These cells are highly adaptable and plastic, and can be modulated to perform desired functions such as antitumor activity, if key programming molecules can be identified. Human clear cell renal cell carcinoma (ccRCC) is considered immunogenic; yet checkpoint blockades that target T cell dysfunction have shown limited clinical efficacy, suggesting additional layers of immunoinhibition. We previously described “enriched-in-renal cell carcinoma” (erc) DCs that were often found in tight contact with dysfunctional T cells. Using transcriptional profiling and flow cytometry, we describe here that ercDCs represent a mosaic cell type within the macrophage continuum co-expressing M1 and M2 markers. The polarization state reflects tissue-specific signals that are characteristic of RCC and renal tissue homeostasis. ErcDCs are tissue-resident with increasing prevalence related to tumor grade. Accordingly, a high ercDC score predicted poor patient survival. Within the profile, therapeutic targets (VSIG4, NRP1, GPNMB) were identified with promise to improve immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dendritic Cells or Macrophages? The Microenvironment of Human Clear Cell Renal Cell Carcinoma Imprints a Mosaic Myeloid Subtype Associated with Patient Survival

Brech

Herbstritt

Diederich

et al. 2022

Cells

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“…response rate and a worse prognosis. HLA class I expression correlates with tumor CTL infiltration and function (23).…”

Section: Discussionmentioning

confidence: 99%

Identifying tumor antigens and immune subtypes of renal cell carcinoma for immunotherapy development

et al. 2022

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Renal cell carcinoma (RCC) is one of the leading causes of death in men. Messenger ribonucleic acid (mRNA) vaccines may be an attractive means to achieve satisfactory results. Cancer immunotherapy is a promising cancer treatment strategy. However, immunotherapy is not widely used in renal cell carcinoma, as only a few patients show a positive response. The present study aimed to identify potential antigens associated with renal cell carcinoma to develop an anti-renal cell carcinoma mRNA vaccine. Moreover, the immune subtypes of renal cell carcinoma cells were determined. The Cancer Genome Atlas (TCGA) analysis revealed gene expression profiles and clinical information. Antigen-presenting cells infiltrated the immune system using Tumor Immune Estimation Resource (TIMER) tool (http://timer.cistrome.org/). GDSC (Genomics of Drug Sensitivity in Cancer) database were used to estimate drug sensitivity. The 13 immune-related genes discovery could be targets for immunotherapy in renal cell carcinoma patients, as they were associated with a better prognosis and a higher level of antigen-presenting cells. These immune subtypes have significant relationships with immunological checkpoints, immunogenic cell death regulators, and RCC prognostic variables. Furthermore, DBH-AS1 was identified as a potential antigen for developing an mRNA vaccine. The CCK8 assay demonstrated that the proliferative capacity of 786-O and Caki-1 cells overexpressing DBH-AS1 was higher than in the control group. In addition, transwell assay revealed that 786-O and Caki-1 cells overexpressing DBH-AS1 showed higher invasion capacity compared with control. This study provides a theoretical basis for the development of mRNA vaccines. Our findings suggest that DBH-AS1 could be potential antigens for developing RCC mRNA vaccines.

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“…A phase I/II, single-arm, open-label trial ( NCT03638206 ) is testing T cells with engineered CAR vectors targeting the tyrosine-protein kinase MET (c-MET) [ 88 ]. Participants will be treated with cyclophosphamide or fludarabine and receive CAR-T cells that have modified CAR vectors that specifically target c-MET expressed in RCC.…”

Section: Ongoing Trials In Renal Cell Carcinomamentioning

confidence: 99%

“…Participants will be treated with cyclophosphamide or fludarabine and receive CAR-T cells that have modified CAR vectors that specifically target c-MET expressed in RCC. The primary outcome is the number of adverse events [ 88 ].…”

Section: Ongoing Trials In Renal Cell Carcinomamentioning

confidence: 99%

Current and future perspectives on CAR-T cell therapy for renal cell carcinoma: A comprehensive review

2022

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In the clinical setting of renal cell carcinoma (RCC), immune reactions such as tumor-specific T cell responses can be spontaneous events or can be elicited by checkpoint inhibitors, cytokines, and other immunotherapy modalities. The results from immunotherapy have led to significant advances in treatment methods and patient outcomes. The approval of nivolumab primarily as a second-line monotherapy and the latest approval of novel combination therapies as first-line treatment have established the significance of immunotherapy in the treatment of RCC. In this perspective, chimeric antigen receptor (CAR)-T cell therapy represents a major advance in the developing field of immunotherapy. This treatment modality facilitates T cells to express specific CARs on the cell surface which are reinfused to the patient to treat the analogous tumor cells. After showing treatment potential in hematological malignancies, this new therapeutic approach has become a strong candidate as a therapeutic modality for solid neoplasms. Although CAR-T cell therapy has shown promise and clinical benefit compared to previous T-cell modulated immunotherapies, further studies are warranted to overcome unfavorable physiological settings and hindrances such as the lack of specific molecular targets, depletion of CAR-T cells, a hostile tumor microenvironment, and on/off-tumor toxicities. Several approaches are being considered and research is ongoing to overcome these problems. In this comprehensive review, we provide the rationale and preliminary results of CAR-T cell therapy in RCC and discuss emerging novel strategies and future directions.

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Current status of antigen-specific T-cell immunotherapy for advanced renal-cell carcinoma

Cited by 11 publications

References 152 publications

Dendritic Cells or Macrophages? The Microenvironment of Human Clear Cell Renal Cell Carcinoma Imprints a Mosaic Myeloid Subtype Associated with Patient Survival

Dendritic Cells or Macrophages? The Microenvironment of Human Clear Cell Renal Cell Carcinoma Imprints a Mosaic Myeloid Subtype Associated with Patient Survival

Identifying tumor antigens and immune subtypes of renal cell carcinoma for immunotherapy development

Current and future perspectives on CAR-T cell therapy for renal cell carcinoma: A comprehensive review

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