Plasma exosome microRNAs in patients with advanced renal cell carcinoma treated with nivolumab and ipilimumab: Potential biomarkers of response to therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 338-338
Author(s):  
Maryam Soleimani ◽  
Marisa Thi ◽  
Neetu Saxena ◽  
Daniel Joseph Khalaf ◽  
Bernhard J. Eigl ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Healthy Volunteers ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Complete Response ◽  
Response To Therapy ◽  
Best Response ◽  
Number Of Patients

338 Background: There is a critical unmet need for predictive biomarkers in the management of metastatic renal cell carcinoma (mRCC). We sought to quantify plasma exosome microRNAs (miRNAs) and correlate with response to first line nivolumab and ipilimumab (N/I) to potentially serve as such a biomarker. Methods: We evaluated the expression of 11 miRNAs in 19 patients with mRCC (prior to initiation of N/I) and in 32 healthy volunteers. Exosomes were extracted from 500 uL of plasma (qEV original, Izon Science) and once confirmed, were used for miRNAs extraction. MiRNAs expression was evaluated by real time polymerase chain reaction using a TaqMan miRNA assay (Applied Biosystems). The relative quantity of each miRNA in patients was compared to healthy volunteers. The expression of each miRNA was correlated to the best response to N/I, categorizing patients as either responders or non-responders. Results: Clinical characteristics are summarized in the table below. Median age at the start of systemic therapy was 64.3 years. MiR200b demonstrated a significantly higher expression in mRCC patients than in healthy volunteers (unpaired t-test; p=0.04). We observed a variable pattern of miRNA expression based on response to N/I. Although not statistically significant, 4 miRNA (miR138, 155, 200b, 221) were upregulated in non-responders, while two (miR200a and 497) were upregulated in responders. Of note, the only patient to achieve a complete response had the lowest expression of miR138 and the highest expression of miR497. Conclusions: Although preliminary and limited by a small number of patients, these initial observational results are promising and suggest a potential role for miRNAs as predictive biomarkers in mRCC. MiR138 and 497 are known to regulate CTLA-4 and PD-L1, respectively. We speculate that these miRNA are potentially involved in response to immune checkpoint therapy. Ongoing work in evaluating expression of these and other miRNAs in blood and in tissue along with clinical correlation continues. [Table: see text]

scholarly journals Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study)

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2594
Author(s):  
Philip Zeuschner ◽  
Sebastian Hölters ◽  
Michael Stöckle ◽  
Barbara Seliger ◽  
Anja Mueller ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Unmet Need ◽  
Therapy Response ◽  
Predictive Biomarkers ◽  
Second Line ◽  
Cell Renal Cell Carcinoma ◽  
Therapy Initiation

There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.

scholarly journals Optimized Management of Nivolumab and Ipilimumab in Advanced Renal Cell Carcinoma: A Response-Based Phase II Study (OMNIVORE)

2020 ◽  
Vol 38 (36) ◽  
pp. 4240-4248
Author(s):  
Rana R. McKay ◽  
Bradley A. McGregor ◽  
Wanling Xie ◽  
David A. Braun ◽  
Xiao Wei ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Renal Cell ◽  
Adaptive Strategy ◽  
Complete Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Number Of Patients ◽  
Treatment Naïve

PURPOSE In this phase II response-adaptive trial, we investigated the rational application of immune checkpoint blockade in renal cell carcinoma (RCC; ClinicalTrials.gov identifier: NCT03203473 ). METHODS We enrolled patients with metastatic RCC with no prior checkpoint inhibitor exposure. All patients received nivolumab alone with subsequent arm allocation based on response. Patients with a confirmed partial response (PR) or complete response (CR) within 6 months discontinued nivolumab and were observed (arm A). Patients with stable disease or progressive disease (PD) after no more than 6 months of nivolumab received two doses of ipilimumab (arm B). The primary endpoints were the proportion of patients with PR/CR at 1 year after nivolumab discontinuation (arm A) and proportion of nivolumab nonresponders who converted to PR/CR after ipilimumab (arm B). RESULTS Overall, 83 patients initiated treatment, of whom 96% had clear-cell histology, 51% were treatment naïve, and 67% had intermediate/poor-risk disease. Median follow-up was 19.5 months. Within 6 months, induction nivolumab resulted in a confirmed PR in 12% of patients (n = 10). Fourteen patients were not allocated to a study arm (seven because of toxicity, seven because of PD). Twelve patients (14%) were allocated to arm A and discontinued nivolumab, of whom five (42%; 90% CI, 18% to 68%) remained off nivolumab at ≥ 1 year. Of 57 patients (69%) allocated to arm B, two patients converted to a confirmed PR (4%; 90% CI, 1% to 11%), and no CRs were observed. CONCLUSION In this study, nivolumab followed by two doses of ipilimumab resulted in no CRs and a low PR/CR conversion. The number of patients evaluated for nivolumab discontinuation was too small to assess the value of this approach. Currently, our data do not support a response-adaptive strategy for checkpoint blockade in advanced RCC.

MicroRNAs as predictive biomarkers of response to tyrosine kinase inhibitor therapy in metastatic renal cell carcinoma

2018 ◽  
Vol 56 (9) ◽  
pp. 1426-1431 ◽  
Author(s):  
Julia Kovacova ◽  
Alexandr Poprach ◽  
Tomas Buchler ◽  
William C. Cho ◽  
Ondrej Slaby
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Current Knowledge ◽  
Predictive Biomarkers ◽  
Response To Therapy ◽  
Secondary Resistance ◽  
First Choice

Abstract Renal cell carcinoma (RCC) accounts for 2%–3% of all malignant tumours. The first-choice treatment in metastatic RCC (mRCC) patients is tyrosine kinase inhibitors (TKIs). Although TKIs may prolong survival of the treated patients who are not primary resistant, almost all of them will eventually develop secondary resistance to the treatment after a progression-free period. To predict treatment response, thus, we need efficient biomarkers for rational indication of TKIs in mRCC. MicroRNAs (miRNAs) not only play important roles in the pathogenesis of many cancers, including RCC but also have been shown to serve as promising diagnostic, prognostic and predictive biomarkers in various cancers. However, the potential of miRNAs to predict response to therapy with TKIs in mRCC has not yet gained sufficient attention. Because personalisation of the TKIs indication in mRCC presents an important unmet medical need, we summarise research on this topic and give an overall insight on the current knowledge in this field.

Clinical, pathologic, and genomic profiles of exceptional responders to anti−PD1 therapy in renal cell carcinoma.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 625-625 ◽  
Author(s):  
Mark Wayne Ball ◽  
Michael Hiroshi Johnson ◽  
Michael A. Gorin ◽  
Maria Rodriguez ◽  
Luis A. Diaz ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Somatic Mutations ◽  
Complete Response ◽  
Response To Therapy ◽  
Rna Expression ◽  
Refractory Disease ◽  
Durable Response ◽  
Durable Complete Response

625 Background: Previous studies have correlated response to PD−1 blockade with PD−L1 over−expression, as well as cell−mediated immune transcripts). However, factors associated with long−term, durable response to nivolumab in patients with RCC have not yet been elucidated. To better understand these factors, we conducted a study to characterize the two extremes of response to therapy – exceptional responders who had durable, complete response and patients who had primary refractory disease. Methods: Patients with durable, complete response (“exceptional responders”) (n=4) and primary refractory disease (n=3) were analyzed. Immunohistochemical staining for PD−L1, CD8 and FOXP3, whole−exome sequencing and quantitative RNA expression profiling was performed and correlated with clinical outcomes. Results: Exceptional responders had trends toward greater CD8+ lymphocyte infiltrate (126.7 vs 28.8 lymphocytes/hpf), higher number of somatic mutations (67 vs 35 somatic mutations/genome), and higher number of predicted mutation associated neoantigens than primary refractory patients (44 vs 8). Expression analysis demonstrated acute phase and immune tolerance signatures in primary refractory patients, while exceptional responders had higher expression of T cell and innate immune signatures. Conclusions: Exceptional responders and primary refectory patients have distinct pathologic, genomic and RNA expression profiles. Larger studies are needed to fully elucidate the basis of response to PD−1 blockade in patients with renal cell carcinoma.

scholarly journals Anti-angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

2020 ◽  
Vol 9 (5) ◽  
pp. 1594 ◽  
Author(s):  
Antonella Argentiero ◽  
Antonio Giovanni Solimando ◽  
Markus Krebs ◽  
Patrizia Leone ◽  
Nicola Susca ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Molecular Taxonomy ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Individual Sensitivity ◽  
Molecular Alterations ◽  
Tailored Treatment ◽  
Improve Patient

Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintains and reinforces their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.

scholarly journals Cytoreductive Nephrectomy Following Immunotherapy-Base Treatment in Metastatic Renal Cell Carcinoma: A Case Series and Review of Current Literature

2021 ◽  
Vol 28 (3) ◽  
pp. 1921-1926
Author(s):  
Scott J. Dawsey ◽  
Steven C. Campbell ◽  
Moshe C. Ornstein
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Case Series ◽  
Complete Response ◽  
Response To Therapy ◽  
Cytoreductive Nephrectomy ◽  
Cell Renal Cell Carcinoma ◽  
Treatment Paradigm

The role and timing of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma receiving immunotherapy-based regimens is unclear. However, the ability to achieve a complete response for metastatic renal cell carcinoma likely requires a nephrectomy at some point during treatment. Here we present a case series of three patients with metastatic clear-cell renal-cell carcinoma who received front-line immunotherapy-based treatment and subsequently underwent a cytoreductive nephrectomy. All three patients had a complete response to therapy and have subsequently remained off systemic therapy for a median of 531 days (range, 476–602). We also review the limited literature in this setting and highlight ongoing clinical trials. Although the role of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma receiving immunotherapy-based treatment is uncertain, a subset of patients will benefit from either an immediate or deferred cytoreductive nephrectomy. Ongoing trials are underway to further determine how to incorporate cytoreductive nephrectomy into the treatment paradigm for patients with metastatic renal cell carcinoma.

Plasma exosome microRNA-155 expression in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors: A potential biomarker of response to systemic therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4570-4570
Author(s):  
Maryam Soleimani ◽  
Marisa Thi ◽  
Neetu Saxena ◽  
Bernhard J. Eigl ◽  
Daniel Joseph Khalaf ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Healthy Volunteers ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Unmet Need ◽  
First Line ◽  
Fuhrman Grade ◽  
Potential Biomarker

4570 Background: The search for a reliable predictive biomarker of response to immune checkpoint-based therapy (ICBT) remains a critically unmet need in the management of metastatic renal cell carcinoma (mRCC). We sought to evaluate the biomarker potential of plasma exosome microRNAs (miRNAs) implicated in RCC and in augmentation of the tumour microenvironment (TME) for such a role. Methods: Eleven miRNAs that are over-expressed in RCC and/or immune-associated were evaluated in 40 patients with mRCC (prior to initiating ICBT) and in 30 healthy volunteers. Exosomes were extracted from 500 uL of plasma and were used for miRNAs extraction. MiRNAs expression was evaluated by RT-PCR. Cycle threshold values were normalized to miR-30-3b, and the relative quantity of the expression (RQ) was compared to those of healthy volunteers and calculated using the 2ΔΔCt method. Mann-Whitney U test was used to evaluate the expression of miRNAs between mRCC pts and healthy volunteers according to best response to first line ICBT between responders (n = 27) v non-responders (n = 13). The cut-off value of significant expression was established by Youden’s index. Responders were defined as those patients experiencing complete response, partial response or stable disease and non-responders were those who experienced progressive disease. Results: The most common first line ICBT was nivolumab + ipilimumab (n = 32), followed by pembrolizumab + axitinib (n = 5), and avelumab + axitinib (n = 3). A significantly higher expression of miRNA-1233 (median 1.85 v 0.81 p = 0.008) and miRNA-155 [miR-155] (3.69 v 0.21 p = 0.006) were found in patients compared to healthy volunteers. Higher miR-155 expression was associated with higher Fuhrman grade (p = 0.002). There was no association with other clinical prognostic factors. MiR-155 was expressed at a significantly lower level in responders than in non-responders (median 0.61 v 35.29, p = 0.042). Response rate amongst patients with low and high expression of miR-155 (RQ ≤ 2.5) was statistically different (p = 0.042) and 84.2% of the pts with low miR-155 expression responded to the treatment. Conclusions: Lower expression of miR-155 was associated with response to ICBT in patients with mRCC. Functionally, miR-155 is involved in regulation and modulation of the TME. These results underscore the need for further work in this area to elucidate the role of this and other miRNAs as biomarkers of response in mRCC.

scholarly journals Anti-Angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

2020 ◽  
Author(s):  
Antonella Argentiero ◽  
Antonio Giovanni Solimando ◽  
Markus Krebs ◽  
Patrizia Leone ◽  
Nicola Susca ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Molecular Taxonomy ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Individual Sensitivity ◽  
Molecular Alterations ◽  
Tailored Treatment ◽  
Improve Patient

Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintained and reinforced their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.

scholarly journals A multi-layered systems approach for renal cell carcinoma

2020 ◽  
Author(s):  
Lindsay S. Cooley ◽  
Justine Rudewicz ◽  
Wilfried Souleyreau ◽  
Kim Clarke ◽  
Francesco Falciani ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Primary Tumor ◽  
Renal Cell ◽  
Clonal Selection ◽  
Predictive Biomarkers ◽  
Response To Therapy ◽  
Primary Tumor Growth

AbstractRenal cell carcinoma (RCC) still lacks prognostic and predictive biomarkers to monitor the disease and the response to therapy. The usual strategy in translational research is to start from human samples, to identify molecular markers and gene networks and then to functionally validate them in vitro and in animal models. We devised herein a completely opposite strategy from “mouse to man” by performing an aggressiveness screen and used functional genomics, imaging, clinical data and computational approaches in order to discover molecular pathways and players in renal cancer development and metastasis. Multiple cell lines for primary tumor growth, survival in the blood circulation and lung metastasis or metastatic spread from the primary tumor were generated and analyzed using a multi-layered approach which includes large-scale transcriptome, genome and methylome analyses. Transcriptome and methylome analyses demonstrated distinct clustering in three different groups. Remarkably, DNA sequencing did not show significant genomic variations in the different groups which indicates absence of clonal selection during the in vivo amplification process. Transcriptome analysis revealed distinct signatures of tumor aggressiveness which were validated in patient cohorts. Methylome analysis of full-length DNA allowed clustering of the same groups and revealed clinically relevant signatures. Furthermore, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. We also uncovered IL34 as another soluble prognostic biomarker and key regulator of renal cell carcinoma (RCC) progression. This was also functionally validated in vivo, and a mathematical model of IL34-dependent primary tumor growth and metastasis development was provided. These results indicate that such multilayered analysis in a RCC animal model leads to meaningful results that are of translational significance.One Sentence SummaryAn aggressiveness screen with multilayer systems analysis to identify signatures and biomarkers for renal cell carcinoma aggressiveness.

scholarly journals Brain Complete Response to Cabozantinib prior to Radiation Therapy in Metastatic Renal Cell Carcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-4 ◽  
Author(s):  
An Uche ◽  
Chad Sila ◽  
Tad Tanoura ◽  
James Yeh ◽  
Neil Bhowmick ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Radiation Therapy ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Complete Response ◽  
Heavily Pretreated ◽  
Treatment Paradigm ◽  
Endothelial Growth Factor

Cabozantinib represents an established vascular endothelial growth factor- (VEGF-) tyrosine kinase inhibitor (TKI) in the treatment paradigm of metastatic renal cell carcinoma (mRCC). Its activity in mRCC patients with brain metastases (BMs) has been largely underreported in prospective clinical trials. We present the unique case of a heavily pretreated mRCC patient with BMs who achieved a brain complete response to cabozantinib prior to receiving radiation therapy. We end with a literature review and discussion of the biologic rationale and growing evidence supporting the intracranial activity of cabozantinib.

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