Articles

Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma

Bi K, Xiao He M, Bakouny Z, et al.
Cancer Cell. 2021 May 10;39(5):649-661.e5.
DOI: 10.1016/j.ccell.2021.02.015.

Abstract

Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.

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Efficacy of immune-checkpoint inhibitors (ICI) in the treatment of older adults with metastatic renal cell carcinoma (mRCC) – an International mRCC Database Consortium (IMDC) analysis

Araujo DV, Wells JC, Hansen AR, et al.
J Geriatr Oncol.2021 Mar 2;S1879-4068(21)00046-1.
DOI: 10.1016/j.jgo.2021.02.022.

Abstract

Objective

Older adults with metastatic renal cell carcinoma(mRCC) are underrepresented in immune-checkpoint inhibitor(ICI) registration trials. Here we compare the efficacy of ICI treatments in older vs. younger adults with mRCC.

Methods

Using the International mRCC Database Consortium(IMDC), patients treated with a PD(L)-1 based ICI were identified. Older adult was defined as ≥70-years at the time of treatment. Descriptive statistics were summarized in means, medians, and proportions. Effectiveness endpoints included overall survival (OS), time-to-treatment failure(TTF), time-to-next treatment(TNT), and overall response rate(ORR). Hazards ratios were adjusted(aHR) for IMDC risk factors, histology, line of treatment and older age.

Results

Of 1427 included patients, 397(28%) were older adults. ICI was used as 1st line(1 L) in 40%, 2nd line(2 L) in 49% and 3rd line(3 L) in 11% of patients. In univariable analysis, older adults had inferior OS compared to younger adults(25.1 m vs. 30.8 m, p < 0.01). There were no significant differences in TTF (6.9 m vs. 6.9 m, p = 0.4) or TNT(9.1 m vs 10 m, p = 0.3) between groups. In multivariable analyses, older age was not independently associated with worse OS(aHR = 1.02, p = 0.8), TTF(aHR = 0.95, p = 0.6) or TNT(aHR = 0.93, p = 0.5). Older adults had a lower ORR compared to younger adults(24% vs. 31%, p = 0.01), which was mainly driven by responses in 1 L(31% vs. 44%, p = 0.02) and not observed in 2 L/3 L.

Conclusions

After multivariable analyses, older adults with mRCC treated with ICI had no difference in OS, TTF or TNT when compared to younger adults. Our data support that chronological older age should not preclude patients from receiving ICI based therapies.

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Prognostic effect of preoperative serum albumin to globulin ratio in patients treated with cytoreductive nephrectomy for metastatic renal cell carcinoma

Laukhtina E, Pradere B, D’Andrea D, et al.
Transl Androl Urol.2021 Feb;10(2):609-619.
DOI: 10.21037/tau-20-1101.

Abstract

Background

Accurate identification of ideal candidates for cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is an unmet need. We tested the association between preoperative value of systemic albumin to globulin ratio (AGR) and overall survival (OS) as well as cancer-specific survival (CSS) in mRCC patients treated with CN.

Methods

mRCC patients treated with CN were included. The overall population was therefore divided into two AGR groups using cut-off of 1.43 (low, <1.43 vs. high, ≥1.43). Univariable and multivariable Cox regression analyses tested the association between AGR and OS as well as CSS. The discrimination of the model was evaluated with the Harrel’s concordance index (C-index). The clinical value of the AGR was evaluated with decision curve analysis (DCA).

Results

Among 613 mRCC patients, 159 (26%) patients had an AGR <1.43. Median follow-up was 31 (IQR: 16-58) months. On univariable analysis, low preoperative serum AGR was significantly associated with both OS (HR: 1.55, 95% CI: 1.26-1.89, P<0.001) and CSS (HR: 1.55, 95% CI: 1.27-1.90, P<0.001). On multivariable analysis, AGR <1.43 was associated with worse OS (HR: 1.51, 95% CI: 1.23-1.85, P<0.001) and CSS (HR: 1.52, 95% CI: 1.24-1.86, P<0.001). The addition of AGR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index=0.640 vs. C-index=0.629). On DCA, the inclusion of AGR marginally improved the net benefit of the prognostic model. Low AGR remained independently associated with OS and CSS in the IMDC intermediate risk group (HR: 1.52, 95% CI: 1.16-1.99, P=0.002).

Conclusions

In our study, low AGR before CN was associated with worse OS and CSS, particularly in intermediate risk patients.

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Cytoreductive nephrectomy in the era of targeted- And immuno- therapy for metastatic renal cell carcinoma: An elusive issue? A systematic review of the literature

Mazzaschi G, Quaini F, Bersanelli M, et al.
Crit Rev Oncol Hematol. 2021 Apr;160:103293.
DOI: 10.1016/j.critrevonc.2021.103293.

Abstract

Background

The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) in the era of targeted- (TT) and immuno- (IT) therapy remains controversial.

Design

The primary objective of the present systematic, performed according to PRISMA guidelines review, was to assess the prevalence of nephrectomy in mRCC patients enrolled in TT/IT randomized phase II/III clinical trials (RCTs) or expanded access programs (EAPs). Medline database was searched from 2003 to 2019 for studies with available nephrectomy data.

Results

We identified 609 studies, subsequently restricted to 57 randomized phase II/III clinical trials and 6 EAPs. Overall, 33,196 patients with mRCC were included, among whom 28,700 (86.4 %) underwent nephrectomy. The trends over time of nephrectomy occurrence remained substantially stable from 2003 to 2019.

Conclusions

Our analysis highlighted that data from RCTs and EAPs driving the clinical practice originate from nephrectomized patient populations. This evidence supports the clinical relevance of CN also in mRCC patients candidate to receive TT/IT.

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Development of a Histopathology Informatics Pipeline for Classification and Prediction of Clinical Outcomes in Subtypes of Renal Cell Carcinoma

Marostica E, Barber R, Denize T, et al.
Clin Cancer Res. 2021 May 15;27(10):2868-2878.
DOI: 10.1158/1078-0432.CCR-20-4119.

Abstract

Purpose

Histopathology evaluation is the gold standard for diagnosing clear cell (ccRCC), papillary, and chromophobe renal cell carcinoma (RCC). However, interrater variability has been reported, and the whole-slide histopathology images likely contain underutilized biological signals predictive of genomic profiles.

Experimental design

To address this knowledge gap, we obtained whole-slide histopathology images and demographic, genomic, and clinical data from The Cancer Genome Atlas, the Clinical Proteomic Tumor Analysis Consortium, and Brigham and Women’s Hospital (Boston, MA) to develop computational methods for integrating data analyses. Leveraging these large and diverse datasets, we developed fully automated convolutional neural networks to diagnose renal cancers and connect quantitative pathology patterns with patients’ genomic profiles and prognoses.

Results

Our deep convolutional neural networks successfully detected malignancy (AUC in the independent validation cohort: 0.964-0.985), diagnosed RCC histologic subtypes (independent validation AUCs of the best models: 0.953-0.993), and predicted stage I ccRCC patients’ survival outcomes (log-rank test P = 0.02). Our machine learning approaches further identified histopathology image features indicative of copy-number alterations (AUC > 0.7 in multiple genes in patients with ccRCC) and tumor mutation burden.

Conclusions

Our results suggest that convolutional neural networks can extract histologic signals predictive of patients’ diagnoses, prognoses, and genomic variations of clinical importance. Our approaches can systematically identify previously unknown relations among diverse data modalities.

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Real-world outcomes in patients with metastatic renal cell carcinoma according to risk factors: the STAR-TOR registry

Strauss A, Schmid M, Rink M, et al.
Future Oncol. 2021 Mar 16.
DOI: 10.2217/fon-2020-1020

Abstract

Aim

Examine outcomes in sunitinib-treated patients by International Metastatic RCC Database Consortium (IMDC) or Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors

Patients & methods

Patients enrolled in STAR-TOR registry (n = 327). End points included overall survival, progression-free survival and objective response rate.

Results

Overall survival was similar for IMDC 0 versus 1 (p = 0.238) or 2 versus ≥3 (p = 0.156), but different for MSKCC (0 vs 1, p = 0.037; 2 vs ≥3, p = 0.001). Progression-free survival was similar for IMDC 2 versus 3 (p = 0.306), but different for MSKCC (p = 0.009). Objective response rate was different for IMDC 1 (41.9%) and 2 (29.5%) and similar for MSKCC 1 (34.4%) and 2 (31.0%). Conclusion: Outcome data varied according to IMDC or MSKCC. MSKCC model accurately stratify patients into risk groups. Clinical trial registration: NCT00700258 (ClinicalTrials.gov).

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Predicting Disease Recurrence, Early Progression, and Overall Survival Following Surgical Resection for High-risk Localized and Locally Advanced Renal Cell Carcinoma

Correa AF, Jegede OA, Haas NB, et al.
Eur Urol. 2021 Mar 8;S0302-2838(21)00145-7.
DOI: 10.1016/j.eururo.2021.02.025.

Abstract

Background

Risk stratification for localized renal cell carcinoma (RCC) relies heavily on retrospective models, limiting their generalizability to contemporary cohorts.

Objective

To introduce a contemporary RCC prognostic model, developed using prospective, highly annotated data from a phase III adjuvant trial.

Design, setting, and participants

The model utilizes outcome data from the ECOG-ACRIN 2805 (ASSURE) RCC trial.

Outcome measurements and statistical analysis

The primary outcome for the model is disease-free survival (DFS), with overall survival (OS) and early disease progression (EDP) as secondary outcomes. Model performance was assessed using discrimination and calibration tests.

Results and limitations

A total of 1735 patients were included in the analysis, with 887 DFS events occurring over a median follow-up of 9.6 yr. Five common tumor variables (histology, size, grade, tumor necrosis, and nodal involvement) were included in each model. Tumor histology was the single most powerful predictor for each model outcome. The C-statistics at 1 yr were 78.4% and 81.9% for DFS and OS, respectively. Degradation of the DFS, DFS validation set, and OS model’s discriminatory ability was seen over time, with a global c-index of 68.0% (95% confidence interval or CI [65.5, 70.4]), 68.6% [65.1%, 72.2%], and 69.4% (95% CI [66.9%, 71.9%], respectively. The EDP model had a c-index of 75.1% (95% CI [71.3, 79.0]).

Conclusions

We introduce a contemporary RCC recurrence model built and internally validated using prospective and highly annotated data from a clinical trial. Performance characteristics of the current model exceed available prognostic models with the added benefit of being histology inclusive and TNM agnostic.

Patient summary

Important decisions, including treatment protocols, clinical trial eligibility, and life planning, rest on our ability to predict cancer outcomes accurately. Here, we introduce a contemporary renal cell carcinoma prognostic model leveraging high-quality data from a clinical trial. The current model predicts three outcome measures commonly utilized in clinical practice and exceeds the predictive ability of available prognostic models.

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Circulating cytokines associated with clinical response to systemic therapy in metastatic renal cell carcinoma

Chehrazi-Raffle A, Meza L, Alcantara M, et al.
J Immunother Cancer. 2021 Mar;9(3):e002009.
DOI: 10.1136/jitc-2020-002009.

Abstract

Background

Circulating cytokines and angiogenic factors have been associated with clinical outcom es in patients with metastatic renal cell carcinoma (RCC) receiving systemic therapy. However, none have yet examined cytokine concentrations in parallel cohorts receiving either immunotherapy or targeted therapy.

Methods

In this prospective correlative study, we enrolled 56 patients who were planned for treatment with either a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI). Eligibility requirements permitted any RCC histologic subtype, International Metastatic Renal Cell Carcinoma risk classification, and line of therapy. Immunologic profile was assessed at baseline and after 1 month on treatment using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit was defined as complete response, partial response, or stable disease ≥6 months per RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria.

Results

Clinical benefit was similar between VEGF-TKI and ICI arms (65% vs 54%). Patients with clinical benefit from VEGF-TKIs had lower pretreatment levels of interleukin-6 (IL-6) (p=0.02), IL-1RA (p=0.03), and granulocyte colony-stimulating factor (CSF) (p=0.02). At 1 month, patients with clinical benefit from ICIs had higher levels of interferon-γ (IFN-γ) (p=0.04) and IL-12 (p=0.03). Among patients on VEGF-TKIs, those with clinical benefit had lower 1 month IL-13 (p=0.02) and granulocyte macrophage CSF (p=0.01) as well as higher 1 month VEGF (p=0.04) compared with patients with no clinical benefit.

Conclusions

For patients receiving VEGF-TKI or ICI therapy, distinct plasma cytokines were associated with clinical benefit. Our findings support additional investigation into plasma cytokines as biomarkers in metastatic RCC.

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Outcomes of Active Surveillance for Young Patients with Small Renal Masses: Prospective Data from the DISSRM Registry

Metcalf MR, Cheaib JG, Biles MJ, et al.
J Urol. 2021 May;205(5):1286-1293.
DOI: 10.1097/JU.0000000000001575.

Abstract

Purpose

A paradigm shift in the management of small renal masses has increased utilization of active surveillance. However, questions remain regarding safety and durability in younger patients.

Materials and methods

Patients aged 60 or younger at diagnosis were identified from the Delayed Intervention and Surveillance for Small Renal Masses registry. The active surveillance, primary intervention, and delayed intervention groups were evaluated using ANOVA with Bonferroni correction, χ2 and Fisher’s exact tests, and Kruskal-Wallis and Wilcoxon signed-rank tests. Survival outcomes were calculated using the Kaplan-Meier method and compared with the log-rank test.

Results

Of 224 patients with median followup of 4.9 years 30.4% chose surveillance. There were 20 (29.4%) surveillance progression events, including 4 elective crossovers, and 13 (19.1%) patients underwent delayed intervention. Among patients with initial tumor size ≤2 cm, 15.1% crossed over, compared to 33.3% with initial tumor size 2-4 cm. Overall survival was similar in primary intervention and surveillance at 7 years (94.0% vs 90.8%, log-rank p=0.2). Cancer-specific survival remained at 100% for both groups. There were no significant differences between primary and delayed intervention with respect to minimally invasive or nephron-sparing interventions. Recurrence-free survival at 5 years was 96.0% and 100% for primary and delayed intervention, respectively (log-rank p=0.6).

Conclusions

Active surveillance is a safe initial strategy in younger patients and can avoid unnecessary intervention in a subset for whom it is durable. Crucially, no patient developed metastatic disease on surveillance or recurrence after delayed intervention. This study confirms active surveillance principles can effectively be applied to younger patients.

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Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy

Krishna C, DiNatale RG, Kuo F, et al.
Cancer Cell. 2021 May 10;39(5):662-677.e6.
DOI: 10.1016/j.ccell.2021.03.007.

Abstract

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.

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