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Autologous therapeutic tumor-infiltrating lymphocyte (TIL) therapy is a promising strategy to enhance antitumor immunity. Optimization of ex vivo TIL expansion could expand current immunotherapy options. Previous attempts to generate TIL in renal cell carcinoma (RCC) have been technically challenging. We applied a second-generation manufacturing process, currently used to generate the melanoma TIL product lifileucel, in RCC. Resected primary and metastatic RCC samples were processed using the Gen 2 manufacturing process comprising of pre-Rapid Expansion Protocol (pre-REP) and REP steps. We assessed REP TILs for viability and performed phenotypic and functional characterization. We correlated the tumor immune microenvironment (TIME) with successful TIL expansion. Eight of 11 RCC samples underwent successful REP. Three failed cases demonstrated low CD8/FoxP3 ratio and high expression of PD-1 within FoxP3 cells. Expression of exhaustion markers differed between the TIME and expanded TILs; the latter had a TIM3-high/PD-1-low phenotype but retained functional capacity comparable to lifileucel. The Gen 2 manufacturing process used for lifileucel successfully expanded functional TILs from RCC samples, enabling further study in a clinical trial. TIME features such as low CD8/FoxP3 ratio and high PD-1 expression within FoxP3 cells warrant study as potential biomarkers of successful TIL expansion.
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Metastatic non-small-cell lung cancer (NSCLC) displays various molecular alterations in the RAS-MAPK pathway. In particular, NSCLCs show high rates of targetable gene fusion in ALK, RET, ROS1, NRG1 and NTRK, or MET exon 14 skipping. Rapid and accurate detection of gene fusion in EGFR/KRAS/BRAF mutations is important for treatment selection especially for first-line indications. RNA-based next-generation sequencing (NGS) panels appear to be the most appropriate as all targets are multiplexed in a single run. While comprehensive NGS panels remain costly for daily practice, optimal sequencing strategies using targeted DNA/RNA panel approaches need to be validated. Here, we describe our lung cancer screening strategy using DNA and RNA targeted approaches in a real-life cohort of 589 NSCLC patients assessed for molecular testing. Gene fusions were analysed in 174 patients negative for oncogene driver mutations or ALK immunohistochemistry in a two-step strategy. Targetable alterations were identified in 28% of contributive samples. Non-smokers had a 63.7% probability to have a targetable alteration as compared to 21.5% for smokers. Overall survival was significantly higher (p=0.03) for patients who received a molecularly matched therapy. Our study shows the feasibility in routine testing of NSCLC DNA/RNA molecular screening for all samples in a cost- and time-controlled manner. The significant high fusion detection rate in patients with wild-type RAS-MAPK tumours highlights the importance of amending testing strategies in NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares , Proteínas de Fusão Oncogênica , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnóstico , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , Proteínas de Fusão Oncogênica/genética , Adulto , Idoso de 80 Anos ou mais , Fusão Gênica , MutaçãoRESUMO
PURPOSE: Programmed cell death protein 1 (PD-1) expression on CD8+TIM-3-LAG-3- tumor-infiltrating cells predicts positive response to PD-1 blockade in metastatic clear-cell renal cell carcinoma (mccRCC). Because inhibition of PD-1 signaling in regulatory T cells (Treg) augments their immunosuppressive function, we hypothesized that PD-1 expression on tumor-infiltrating Tregs would predict resistance to PD-1 inhibitors. EXPERIMENTAL DESIGN: PD-1+ Tregs were phenotyped using multiparametric immunofluorescence in ccRCC tissues from the CheckMate-025 trial (nivolumab: n = 91; everolimus: n = 90). Expression of CD8, PD-1, TIM-3, and LAG-3 was previously determined (Ficial and colleagues, 2021). Clinical endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: In the nivolumab (but not everolimus) arm, high percentage of PD-1+ Tregs was associated with shorter PFS (3.19 vs. 5.78 months; P = 0.021), shorter OS (18.1 vs. 27.7 months; P = 0.013) and marginally lower ORR (12.5% vs. 31.3%; P = 0.059). An integrated biomarker (PD-1 Treg/CD8 ratio) was developed by calculating the ratio between percentage of PD-1+Tregs (marker of resistance) and percentage of CD8+PD-1+TIM-3-LAG-3- cells (marker of response). In the nivolumab (but not everolimus) arm, patients with high PD-1 Treg/CD8 ratio experienced shorter PFS (3.48 vs. 9.23 months; P < 0.001), shorter OS (18.14 vs. 38.21 months; P < 0.001), and lower ORR (15.69% vs. 40.00%; P = 0.009). Compared with the individual biomarkers, the PD-1 Treg/CD8 ratio showed improved ability to predict outcomes to nivolumab versus everolimus. CONCLUSIONS: PD-1 expression on Tregs is associated with resistance to PD-1 blockade in mccRCC, suggesting that targeting Tregs may synergize with PD-1 inhibition. A model that integrates PD-1 expression on Tregs and CD8+TIM-3-LAG-3- cells has higher predictive value.
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Carcinoma de Células Renais , Humanos , Carcinoma de Células Renais/patologia , Nivolumabe/uso terapêutico , Linfócitos T Reguladores/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Everolimo/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Background: Intravascular lymphoma is an uncommon cause of ischemic strokes. Because of its rarity and atypical pattern, most diagnoses are made post-mortem. Case study: We present a case of a 68-year-old male with multiple cardiovascular risk factors and recent SARS-CoV-2 infection who presented with recurrent strokes. Because of his stroke risk factors, he was initially managed with a sequentially escalating antithrombotic regimen. A malignant process was low on the differential at this point given his lack of systemic symptoms. When he continued to have new strokes despite these measures, including a spinal cord infarct, a broad workup was sent including for hypercoagulable states, vasculitis, and intravascular lymphoma. Eventually, a skin biopsy of a cherry angioma returned positive for lymphoma cells. He was treated with methotrexate followed by chemotherapy and rituximab. Unfortunately, he did not improve and was made comfort measures only by his family. Conclusion: This case illustrates the importance of considering intravascular lymphoma as a potential etiology of recurrent strokes, as early diagnosis and treatment are important for preventing irreversible neurological damage.
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Clear cell renal cell carcinoma (ccRCC) is molecularly heterogeneous, immune infiltrated, and selectively sensitive to immune checkpoint inhibition (ICI). However, the joint tumor-immune states that mediate ICI response remain elusive. We develop spatially aware deep-learning models of tumor and immune features to learn representations of ccRCC tumors using diagnostic whole-slide images (WSIs) in untreated and treated contexts (n = 1,102 patients). We identify patterns of grade heterogeneity in WSIs not achievable through human pathologist analysis, and these graph-based "microheterogeneity" structures associate with PBRM1 loss of function and with patient outcomes. Joint analysis of tumor phenotypes and immune infiltration identifies a subpopulation of highly infiltrated, microheterogeneous tumors responsive to ICI. In paired multiplex immunofluorescence images of ccRCC, microheterogeneity associates with greater PD1 activation in CD8+ lymphocytes and increased tumor-immune interactions. Our work reveals spatially interacting tumor-immune structures underlying ccRCC biology that may also inform selective response to ICI.
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Carcinoma de Células Renais , Carcinoma , Aprendizado Profundo , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , FenótipoRESUMO
Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Animais , Camundongos , Carcinoma de Pequenas Células do Pulmão/genética , Histona Desmetilases/genética , Cromatina , Epigenômica , Neoplasias Pulmonares/genéticaRESUMO
AIMS: Small cell lung carcinoma (SCLC) can be classified into transcription factor-based subtypes (ASCL1, NeuroD1, POU2F3). While in-vitro studies suggest intratumoral heterogeneity in the expression of these markers, how SCLC subtypes vary over time and among locations in patients remains unclear. METHODS AND RESULTS: We searched a consecutive series of patients at our institution in 2006-22 for those with greater than one available formalin-fixed paraffin-embedded SCLC sample in multiple sites and/or time-points. Immunohistochemistry for ASCL1, NeuroD1 and POU2F3 was performed and evaluated using H-scores, with subtype assigned based on the positive marker (H-score threshold >10) with the highest H-score. The 179 samples (75, lung; 51, lymph nodes; 53, non-nodal metastases) from 84 patients (74 with two, 10 with more than two samples) included 98 (54.7%) ASCL1-dominant, 47 (26.3%) NeuroD1-dominant, 15 (8.4%) POU2F3-dominant, 17 (9.5%) triple-negative and two (1.1%) ASCL1/NeuroD1 co-dominant samples. NeuroD1-dominant subtype was enriched in non-lung locations. Subtype concordance from pairwise comparison was 71.4% overall and 89.7% after accounting for ASCL1/NeuroD1-dual expressors and technical factors including <500 cells/slide, H-score thresholds and sample decalcification. No significant difference in subtype concordance was noted with a longer time lapse or with extrathoracic versus intrathoracic samples in this cohort. CONCLUSIONS: After accounting for technical factors, transcription factor-based subtyping was discordant among multiple SCLC samples in ~10% of patients, regardless of sample locations and time lapse. Our findings highlighted the spatiotemporal heterogeneity of SCLC in clinical samples and potential challenges, including technical and biological factors, that might limit concordance in SCLC transcription factor-based subtyping.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Transcrição/genética , Neoplasias Pulmonares/patologia , Pulmão/patologia , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Fatores de Transcrição de Octâmero/metabolismoRESUMO
Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49-0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39-0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Bevacizumab/uso terapêutico , Fator A de Crescimento do Endotélio Vascular , Antígeno B7-H1 , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologiaRESUMO
BACKGROUND: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy. METHODS: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies. RESULTS: 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of <5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death. CONCLUSIONS: Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity. TRIAL REGISTRATION NUMBER: NCT03117309.
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Carcinoma de Células Renais , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Ipilimumab/efeitos adversos , Terapia de SalvaçãoRESUMO
While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Epigenômica , Fatores de Transcrição/genética , Oncogenes , Fatores de Transcrição Forkhead/genéticaRESUMO
Clear cell renal cell carcinoma (ccRCC) is molecularly heterogeneous, immune infiltrated, and selectively sensitive to immune checkpoint inhibition (ICI). Established histopathology paradigms like nuclear grade have baseline prognostic relevance for ccRCC, although whether existing or novel histologic features encode additional heterogeneous biological and clinical states in ccRCC is uncertain. Here, we developed spatially aware deep learning models of tumor- and immune-related features to learn representations of ccRCC tumors using diagnostic whole-slide images (WSI) in untreated and treated contexts (n = 1102 patients). We discovered patterns of nuclear grade heterogeneity in WSI not achievable through human pathologist analysis, and these graph-based "microheterogeneity" structures associated with PBRM1 loss of function, adverse clinical factors, and selective patient response to ICI. Joint computer vision analysis of tumor phenotypes with inferred tumor infiltrating lymphocyte density identified a further subpopulation of highly infiltrated, microheterogeneous tumors responsive to ICI. In paired multiplex immunofluorescence images of ccRCC, microheterogeneity associated with greater PD1 activation in CD8+ lymphocytes and increased tumor-immune interactions. Thus, our work reveals novel spatially interacting tumor-immune structures underlying ccRCC biology that can also inform selective response to ICI.
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Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine "inflammatory" phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.
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Fator 1 de Resposta a Butirato/metabolismo , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Transcrição/metabolismoRESUMO
PURPOSE: PD-L1 expression on tumor cells (TC) is associated with response to anti-PD-1-based therapies in some tumor types, but its significance in clear cell renal cell carcinoma (ccRCC) is uncertain. We leveraged tumor heterogeneity to identify molecular correlates of TC PD-L1 expression in ccRCC and assessed their role in predicting response to anti-PD-1 monotherapy. EXPERIMENTAL DESIGN: RNA sequencing was performed on paired TC PD-L1 positive and negative areas isolated from eight ccRCC tumors and transcriptomic features associated with PD-L1 status were identified. A cohort of 232 patients with metastatic ccRCC from the randomized CheckMate-025 (CM-025) trial was used to confirm the findings and correlate transcriptomic profiles with clinical outcomes. RESULTS: In both the paired samples and the CM-025 cohort, TC PD-L1 expression was associated with combined overexpression of immune- and cell proliferation-related pathways, upregulation of T-cell activation signatures, and increased tumor-infiltrating immune cells. In the CM-025 cohort, TC PD-L1 expression was not associated with clinical outcomes. A molecular RCC subtype characterized by combined overexpression of immune- and cell proliferation-related pathways (previously defined by unsupervised clustering of transcriptomic data) was enriched in TC PD-L1 positive tumors and displayed longer progression-free survival (HR, 0.32; 95% confidence interval, 0.13-0.83) and higher objective response rate (30% vs. 0%, P = 0.04) on nivolumab compared with everolimus. CONCLUSIONS: Both TC-extrinsic (immune-related) and TC-intrinsic (cell proliferation-related) mechanisms are likely intertwined in the regulation of TC PD-L1 expression in ccRCC. The quantitation of these transcriptional programs may better predict benefit from anti-PD-1-based therapy compared with TC PD-L1 expression alone in ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Nivolumabe/uso terapêutico , TranscriptomaRESUMO
PURPOSE: To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy. METHODS: Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%. RESULTS: One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively (P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade ≥ 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab. CONCLUSION: Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit.
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Carcinoma de Células Renais , Nivolumabe , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Ipilimumab , Nivolumabe/efeitos adversosRESUMO
AIMS: Renal cell carcinomas (RCCs) represent 2-5% of kidney malignancies in children and adolescents. Appropriate diagnostic and classification are crucial for the correct management of the patients and in order to avoid inappropriate pre-operative chemotherapy, which is usually recommended if a Wilms' tumour is suspected. METHODS AND RESULTS: A French-Italian series of 93 renal cell carcinomas collected from 1990 to 2019 in patients aged less than 18 years was reclassified according to the 2016 World Health Organization (WHO) classification and the latest literature. TFE3 and TFEB fluorescence in-situ hybridisation (FISH) analyses and a panel of immunohistochemical stains were applied. The median age at diagnosis was 11 years (range = 9 months-17 years). MiT family (MiTF) translocation RCCs accounted for 52% of the tumours, followed by papillary (20%) and unclassified RCCs (13%). Other subtypes, such as SDHB-deficient and fumarate hydratase-deficient RCCs, represented 1-3% of the cases. We also described a case of ALK-rearranged RCC with a metanephric adenoma-like morphology. CONCLUSION: A precise histological diagnosis is mandatory, as targeted therapy could be applied for some RCC subtypes, i.e. MiTF-translocation and ALK-translocation RCC. Moreover, some RCC subtypes may be associated with a predisposition syndrome that will impact patients' and family's management and genetic counselling. A precise RCC subtype is also mandatory for the clinical management of the patients and inclusion in new prospective clinical trials.
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Carcinoma de Células Renais , Neoplasias Renais , Tumor de Wilms , Adolescente , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Translocação GenéticaRESUMO
Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), which is the most common form of kidney cancer. The VHL tumor suppressor protein marks hypoxia-inducible factor 1 (HIF1) and HIF2 for proteasomal degradation when oxygen is present. The inappropriate accumulation of HIF2 drives tumor formation by VHL tumor suppressor protein (pVHL)defective ccRCC. Belzutifan, a first-in-class allosteric HIF2 inhibitor, has advanced to phase 3 testing for advanced ccRCC and is approved for ccRCCs arising in patients with VHL disease, which is caused by germline VHL mutations. HIF2 can suppress p53 function in some settings and preliminary data suggested that an intact p53 pathway, as measured by activation in response to DNA damage, was necessary for HIF2 dependence. Here, we correlated HIF2 dependence and p53 status across a broader collection of ccRCC cell lines. We also genetically manipulated p53 function in ccRCC lines that were or were not previously HIF2-dependent and then assessed their subsequent sensitivity to HIF2 ablation using CRISPR-Cas9 or the HIF2 inhibitor PT2399, which is closely related to belzutifan. From these studies, we conclude that p53 status does not dictate HIF2 dependence, at least in preclinical models, and thus is unlikely to be a useful biomarker for predicting which ccRCC patients will respond to HIF2 inhibitors.