Biomarker Development for Metastatic Renal Cell Carcinoma: Omics, Antigens, T-cells, and Beyond

Miron, Benjamin; Xu, David; Zibelman, Matthew R.

doi:10.3390/jpm10040225

Cited by 8 publications

(9 citation statements)

References 76 publications

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“…Renal adenocarcinoma is frequently not diagnosed until after metastasis, a disease stage for which there are few effective prophylactic or curative treatment options; however, recent promising advances demonstrate that liquid biopsy of easily accessible blood-based biomarkers provide early detection of renal adenocarcinoma ( 38 ). Metastatic renal adenocarcinoma patients with the best prognosis have median overall survival of 43.2 months, and those with the worst prognosis have median overall survival of 7.8 months ( 39 ). In studies presented here, the suppression of lung metastasis in mice in response to combination treatment is hypothesized to have resulted from decreased orthotopic tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Alphataxin, a Small-Molecule Drug That Elevates Tumor-Infiltrating CD4+ T Cells, in Combination With Anti-PD-1 Therapy, Suppresses Murine Renal Cancer and Metastasis

2021

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By promoting the cytotoxic function of CD8+ T cells, immune checkpoint inhibitor therapy, e.g. programmed cell death protein-1 (PD-1), effectively inhibits tumor growth in renal cell carcinoma. Yet, as many as 87% of cancer patients do not respond to immune checkpoint therapy. Importantly, cytotoxic CD8+ T cell function crucially relies on CD4+ T helper cell cytokines, in particular, tumor necrosis factor beta (TNFβ) and its CD8+ T cell receptor (TNFR2) in the opposing manner as immune checkpoints and their receptors. Remarkably, despite advances in immunotherapy, there are no pharmaceutical treatments that increase circulating CD4+ T cell counts. Nor has there been much attention given to tumor-infiltrating CD4+ T cells. Using data from a clinical trial (NCT01731691), we discovered that the protein alpha-1 proteinase inhibitor (α1PI, alpha-1 antitrypsin) regulates the number of circulating CD4+ T cells. The orally available small-molecule drug Alphataxin acts as a surrogate for α1PI in this pathway. We aimed to examine how Alphataxin affected tumor growth in a murine model of renal cell carcinoma. Alphataxin, in combination with anti-PD-1 antibody, significantly elevated the ratio of circulating and tumor-infiltrating CD4+ T cells. In one study, following orthotopic implantation of syngeneic renal adenocarcinoma cells, combination treatment resulted in 100% regression of tumor growth. Moreover, in mice implanted orthotopically with one log more tumor cells, doubling Alphataxin dose in combination treatment led to 100% regression in one-third of mice and 81% suppression of tumor growth in the remaining two-thirds of mice. Lung metastasis was present in monotherapy, but significantly reduced in combination-treated mice. Orally available Alphataxin, the first and only drug developed to increase CD4+ T cells, in combination with anti-PD-1, is a powerful therapeutic method that provides long-term remission in renal cell carcinoma and potentially other T cell-responsive cancers by increasing the number of CD4+ tumor-infiltrating T cells.

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Section: Discussionmentioning

confidence: 99%

Alphataxin, a Small-Molecule Drug That Elevates Tumor-Infiltrating CD4+ T Cells, in Combination With Anti-PD-1 Therapy, Suppresses Murine Renal Cancer and Metastasis

2021

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“…Despite the above developments, a wide research gap still exists in understanding individual patient tumour biology and alignment of that with the choice of appropriate drug for treatment. Unlike most solid tumours, there are currently no biomarker driven drug approvals in RCC [230]. Immune and other targeted therapies are prescribed to RCC patients depending on specific risk scores [231].…”

Section: Future Direction and Conclusionmentioning

confidence: 99%

“…Furthermore, a more improved understanding of the biology of different subtypes of RCC based on the data collected by large public datasets such as TCGA, TRACERx Renal, etc. may provide identification of biomarker-oriented approaches necessary for the stratification of patients for specific treatment modalities [230]. This may guide clinicians to tailor best-personalized treatment to patients.…”

Section: Future Direction and Conclusionmentioning

confidence: 99%

Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma

Sharma

Kadife²,

Myers

et al. 2021

J Exp Clin Cancer Res

102

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Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) have been the mainstay of treatment for patients with advanced renal cell carcinoma (RCC). Despite its early promising results in decreasing or delaying the progression of RCC in patients, VEGF-TKIs have provided modest benefits in terms of disease-free progression, as 70% of the patients who initially respond to the treatment later develop drug resistance, with 30% of the patients innately resistant to VEGF-TKIs. In the past decade, several molecular and genetic mechanisms of VEGF-TKI resistance have been reported. One of the mechanisms of VEGF-TKIs is inhibition of the classical angiogenesis pathway. However, recent studies have shown the restoration of an alternative angiogenesis pathway in modulating resistance. Further, in the last 5 years, immune checkpoint inhibitors (ICIs) have revolutionized RCC treatment. Although some patients exhibit potent responses, a non-negligible number of patients are innately resistant or develop resistance within a few months to ICI therapy. Hence, an understanding of the mechanisms of VEGF-TKI and ICI resistance will help in formulating useful knowledge about developing effective treatment strategies for patients with advanced RCC. In this article, we review recent findings on the emerging understanding of RCC pathology, VEGF-TKI and ICI resistance mechanisms, and potential avenues to overcome these resistance mechanisms through rationally designed combination therapies.

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“…PRBM1 mutations are associ-ated with an improved response to anti-angiogenesis therapy and ICI therapy in ccRCC [50]. PBRM1 is encoded on a gene locus near VHL on chromosome 3 p and is thought undergo mutation early in RCC pathogenesis [51]. Chromosome 3 loss is associated with tRCC, naturally leading to an investigation of PBRM1 as a biomarker in the metastatic MiT family, tRCC.…”

Section: Future Potential Immunotherapeutic Avenuesmentioning

confidence: 99%

Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

Zarrabi

Walzer

Zibelman

2021

Cancers

Self Cite

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Renal cell carcinoma (RCC) is a histologically heterogeneous disease with multiple subtypes. Clear cell RCC (ccRCC) represents the most common histology and has thus been easiest to study in clinical trials. Non-clear cell RCC (nccRCC) represents about 25% of RCC tumors, with fewer treatment options available, compared to ccRCC, and with poorer outcomes. Non-clear cell RCC tumors are histologically diverse, with each subtype having distinct molecular and clinical characteristics. Our understanding of nccRCC is evolving, with a gradual shift from treating nccRCC as a single entity to approaching each subtype as its own disease with unique features. Due to the scarcity of patients for study development, trials have predominantly combined all nccRCC subtypes and re-purposed drugs already approved for ccRCC, despite the decreased efficacy. We are now in the early stages of a potential paradigm shift in the treatment of nccRCC, with a rapid development of clinical studies with a focus on this subset of tumors. Investigators have launched trials focused on the molecular drivers of tumorigenesis using targeted therapies. Harboring the immunogenicity of some nccRCC subtypes, and based on promising retrospective studies, clinicians have also devised multiple trials using immune checkpoint inhibitors (ICIs), both alone or in combination with targeted therapies, for nccRCC subtypes. We highlight the promising completed and ongoing studies employing ICIs that will likely continue to improve outcomes in patients with nccRCC and propose future potential immunotherapeutic avenues.

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Biomarker Development for Metastatic Renal Cell Carcinoma: Omics, Antigens, T-cells, and Beyond

Cited by 8 publications

References 76 publications

Alphataxin, a Small-Molecule Drug That Elevates Tumor-Infiltrating CD4+ T Cells, in Combination With Anti-PD-1 Therapy, Suppresses Murine Renal Cancer and Metastasis

Alphataxin, a Small-Molecule Drug That Elevates Tumor-Infiltrating CD4+ T Cells, in Combination With Anti-PD-1 Therapy, Suppresses Murine Renal Cancer and Metastasis

Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma

Immune Checkpoint Inhibition in Advanced Non-Clear Cell Renal Cell Carcinoma: Leveraging Success from Clear Cell Histology into New Opportunities

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