From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma

Immunotherapy has revolutionized the treatment landscape for many cancer types. The treatment for renal cell carcinoma (RCC) has especially evolved in recent years, from cytokine-based immunotherapies to immune checkpoint inhibitors. Although clinical benefit from immunotherapy is limited to a subset of patients, many combination-based approaches have led to improved outcomes. The success of such approaches is a direct result of the tumor immunology knowledge accrued regarding the RCC microenvironment, which, while highly immunogenic, demonstrates many unique characteristics. Ongoing translational work has elucidated some of the mechanisms of response, as well as primary and secondary resistance, to immunotherapy. Here, we provide a comprehensive review of the RCC immunophenotype with a specific focus on how preclinical and clinical data are shaping the future of immunotherapy.

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Resistance to Systemic Agents in Renal Cell Carcinoma Predict and Overcome Genomic Strategies Adopted by Tumor

Cancers ◽

10.3390/cancers11060830 ◽

2019 ◽

Vol 11 (6) ◽

pp. 830 ◽

Cited By ~ 10

Author(s):

Veronica Mollica ◽

Vincenzo Di Nunno ◽

Lidia Gatto ◽

Matteo Santoni ◽

Marina Scarpelli ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Secondary Resistance ◽

Systemic Treatments ◽

Clinical Scenarios ◽

Systemic Agents

The development of new systemic agents has led us into a “golden era” of management of metastatic renal cell carcinoma (RCC). Certainly, the approval of immune-checkpoint inhibitors and the combination of these with targeted compounds has irreversibly changed clinical scenarios. A deeper knowledge of the molecular mechanisms that correlate with tumor development and progression has made this revolution possible. In this amazing era, novel challenges are awaiting us in the clinical management of metastatic RCC. Of these, the development of reliable criteria which are able to predict tumor response to treatment or primary and acquired resistance to systemic treatments still remain an unmet clinical need. Thanks to the availability of data provided by studies evaluating genomic assessments of the disease, this goal may no longer be out of reach. In this review, we summarize current knowledge about genomic alterations related to primary and secondary resistance to target therapy and immune-checkpoint inhibitors in RCC.

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Acute interstitial nephritis, a potential predictor of response to immune checkpoint inhibitors in renal cell carcinoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001198 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001198

Author(s):

Viral Patel ◽

Roy Elias ◽

Joseph Formella ◽

William Schwartzman ◽

Alana Christie ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Interstitial Nephritis ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Acute Interstitial Nephritis ◽

First Line ◽

Improved Outcomes

Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab have improved outcomes in metastatic renal cell carcinoma (mRCC) patients, but they are also associated with immune-related adverse events (irAEs). As observed in melanoma, we hypothesized that patients experiencing an autoimmune reaction directed against the tissue of origin may be more likely to benefit from ICI. Specifically, we asked whether patients with immune-related acute interstitial nephritis (irAIN) exhibited improved outcomes. Using Kidney Cancer Explorer (KCE), a data portal and i2b2-based central database for clinical, pathological and experimental genetic data, we systematically identified all patients with mRCC at UT Southwestern Medical Center (UTSW) from 2014–2018 who received at least one dose of ICI. More recent cases were identified through a provider query. We extracted creatinine (Cr) values at baseline and over the entirety of each patient ICI treatment course using KCE. Patients with ≥ 1.5-fold Cr increase over baseline were investigated. The likelihood of irAIN was determined based on the work-up (biopsy, if available), or by clinical criteria (timing of kidney injury, exclusion of other etiologies, treatment with immunosuppressants and response). We identified 177 mRCC patients who received at least one dose of ICI, 36 of whom had ≥ 1.5-fold increase in Cr over baseline while on treatment. Of those, two had biopsy-proven irAIN and one was clinically diagnosed, resulting in an incidence of 1.7%. One additional biopsy-proven case past 2018 was identified through a provider query, for a total of four patients. Two received combination nivolumab and ipilimumab in the first line, whereas the remaining received nivolumab after first line therapy. irAIN onset ranged from 1.5 to 12 months. All four patients stopped ICI with recovery of renal function, at least partially, three after receiving systemic steroids. Notably, all four patients had a deep response. In conclusion, irAIN is a rare event, but it may portend a higher likelihood of response. One possible explanation is antigenic overlap between normal renal tubular cells and tumor cells.

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Pembrolizumab plus axitinib combination and the paradigm change in the treatment of advanced renal cell carcinoma

Future Oncology ◽

10.2217/fon-2020-0079 ◽

2020 ◽

Author(s):

Martina Spisarová ◽

Bohuslav Melichar ◽

Denisa Vitásková ◽

Hana Študentová

Keyword(s):

Renal Cell Carcinoma ◽

Drug Resistance ◽

Cell Carcinoma ◽

Renal Cell ◽

Checkpoint Inhibitors ◽

Paradigm Change ◽

Improved Outcomes ◽

Sequential Administration ◽

Treatment Paradigm ◽

Combination Regimens

Sequential administration of single targeted agents has been challenged as the dominant treatment paradigm in patients with metastatic renal cell carcinoma by improved outcomes obtained with combination regimens based on immune checkpoint inhibitors. Most patients treated with sequential monotherapy eventually develop drug resistance and succumb to progressive disease, leading to the search for therapies that would overcome drug resistance and result in a more durable treatment response. Improved outcomes have been demonstrated in Phase 3 trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab and ipilimumab plus nivolumab. A statistically significant improvement of both progression-free and overall survival has been demonstrated for the axitinib plus pembrolizumab combination.

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Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920907504 ◽

2020 ◽

Vol 12 ◽

pp. 175883592090750 ◽

Cited By ~ 10

Author(s):

Elie Rassy ◽

Ronan Flippot ◽

Laurence Albiges

Keyword(s):

Renal Cell Carcinoma ◽

Tyrosine Kinase ◽

Cell Carcinoma ◽

Tyrosine Kinase Inhibitors ◽

Renal Cell ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Predictive Biomarkers ◽

Improved Outcomes

The treatment landscape of metastatic renal cell carcinoma (mRCC) has been transformed with the advent of antiangiogenics, notably tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR), and immune checkpoint inhibitors (ICIs). Both treatment options have improved outcomes of patients and modified the natural history of mRCC. Clinical investigations have focused on evaluating combination regimens containing ICIs and VEGFR-directed TKIs. Namely, the combinations of axitinib plus pembrolizumab (KEYNOTE-426) and axitinib plus avelumab (JAVELIN RENAL 101) have shown improved outcomes compared with sunitinib in treatment-naïve patients with mRCC. In this review, we discuss the clinical data of single-agent TKIs and ICIs in mRCC and the rationale for the combination ICIs and TKIs based on preclinical and clinical evidence. We also explore the current challenges for regimen selection and development of predictive biomarkers.

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Adjuvant Therapy in Renal Cell Carcinoma: Current Stance and Future Directions

Kidney Cancer ◽

10.3233/kca-200105 ◽

2021 ◽

pp. 1-12

Author(s):

Austin G. Kazarian ◽

Neal S. Chawla ◽

Ramya Muddasani ◽

Sumanta K. Pal

Keyword(s):

Renal Cell Carcinoma ◽

Adjuvant Therapy ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Unmet Need ◽

Disease Free Survival ◽

Adjuvant Setting ◽

Metastatic Setting

In recent years, incredible progress has been made in the treatment of metastatic renal cell carcinoma, with a paradigm shift from the use of cytokines to tyrosine kinase inhibitors, and more recently, immune checkpoint inhibitors (ICIs). Despite advances in the metastatic setting, effective therapies in the adjuvant setting are a largely unmet need. Currently, sunitinib (Sutent, Pfizer) is the only therapy for the adjuvant treatment of RCC included in the National Comprehensive Cancer Network guidelines, which was approved by the FDA based on the improvement in disease-free survival (DFS) seen in the S-TRAC trial. However, improvement in DFS has not translated into an overall survival (OS) benefit for patients at high-risk of relapse post-nephrectomy, illustrating the need for more effective therapies. This manuscript will highlight attributes of both historical and current drug trials and their implications on the landscape of adjuvant therapy. Additionally, we will outline strategies for selecting patients in whom treatment would be most beneficial, as optimal patient selection is a crucial step towards improving outcomes in the adjuvant setting. This is especially critical, given the financial cost and pharmacological toxicity of therapeutic agents. Furthermore, we will review the design of clinical trials including the value of utilizing OS as an endpoint over DFS. Finally, we will discuss how the incorporation of genomic data into predictive models, the use of more sensitive imaging modalities for more accurate staging, and more extensive surgical intervention involving lymph node dissection, may impact outcomes.

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Modified Glasgow Prognostic Score associated with survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002851 ◽

2021 ◽

Vol 9 (7) ◽

pp. e002851

Author(s):

Jacqueline T Brown ◽

Yuan Liu ◽

Julie M Shabto ◽

Dylan Martini ◽

Deepak Ravindranathan ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Immune Checkpoint ◽

Renal Cell ◽

Checkpoint Inhibitors ◽

Prognostic Score ◽

Univariate Analysis ◽

Glasgow Prognostic Score ◽

Modified Glasgow Prognostic Score

BackgroundThe modified Glasgow Prognostic Score (mGPS) is a composite biomarker that uses albumin and C reactive protein (CRP). There are multiple immune checkpoint inhibitor (ICI)-based combinations approved for metastatic renal cell carcinoma (mRCC). We investigated the ability of mGPS to predict outcomes in patients with mRCC receiving ICI.MethodsWe retrospectively reviewed patients with mRCC treated with ICI as monotherapy or in combination at Winship Cancer Institute between 2015 and 2020. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical/radiographical progression, respectively. The baseline mGPS was defined as a summary score based on pre-ICI values with one point given for CRP>10 mg/L and/or albumin<3.5 g/dL, resulting in possible scores of 0, 1 and 2. If only albumin was low with a normal CRP, no points were awarded. Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard model. Outcomes were also assessed by Kaplan-Meier analysis.Results156 patients were included with a median follow-up 24.2 months. The median age was 64 years and 78% had clear cell histology. Baseline mGPS was 0 in 36%, 1 in 40% and 2 in 24% of patients. In UVA, a baseline mGPS of 2 was associated with shorter OS (HR 4.29, 95% CI 2.24 to 8.24, p<0.001) and PFS (HR 1.90, 95% CI 1.20 to 3.01, p=0.006) relative to a score of 0; this disparity in outcome based on baseline mGPS persisted in MVA. The respective median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (95% CI 27.3 to not evaluable), 15.3 (95% CI 11.0 to 24.2) and 10 (95% CI 4.6 to 17.5) months (p<0.0001). The median PFS of these three cohorts was 6.7 (95% CI 3.6 to 13.1), 4.2 (95% CI 2.9 to 6.2) and 2.6 (95% CI 2.0 to 5.6), respectively (p=0.0216). The discrimination power of baseline mGPS to predict survival outcomes was comparable to the IMDC risk score based on Uno’s c-statistic (OS: 0.6312 vs 0.6102, PFS: 0.5752 vs 0.5533).ConclusionThe mGPS is prognostic in this cohort of patients with mRCC treated with ICI as monotherapy or in combination. These results warrant external and prospective validation.

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Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22126290 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6290

Author(s):

Hye-Won Lee

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Imaging Techniques ◽

Predictive Biomarkers ◽

Effective Control ◽

Extrinsic Factors ◽

Medical Needs

Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME.

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Low intratumor heterogeneity correlates with increased response to PD-1 blockade in renal cell carcinoma

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920977117 ◽

2020 ◽

Vol 12 ◽

pp. 175883592097711

Author(s):

Xia Ran ◽

Jinyuan Xiao ◽

Yi Zhang ◽

Huajing Teng ◽

Fang Cheng ◽

...

Keyword(s):

Clinical Trial ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Checkpoint Inhibitors ◽

Simulated Data ◽

The Cancer Genome Atlas ◽

Intratumor Heterogeneity ◽

Cell Renal Cell Carcinoma ◽

Immune Activity

Background: Intratumor heterogeneity (ITH) has been shown to be inversely associated with immune infiltration in several cancers including clear cell renal cell carcinoma (ccRCC), but it remains unclear whether ITH is associated with response to immunotherapy (e.g. PD-1 blockade) in ccRCC. Methods: We quantified ITH using mutant-allele tumor heterogeneity, investigated the association of ITH with immune parameters in patients with ccRCC ( n = 336) as well as those with papillary RCC (pRCC, n = 280) from The Cancer Genome Atlas, and validations were conducted in patients with ccRCC from an independent cohort ( n = 152). The relationship between ITH and response to anti-PD-1 immunotherapy was explored in patients with metastatic ccRCC from a clinical trial of anti-PD-1 therapy ( n = 35), and validated in three equal-size simulated data sets ( n = 60) generated by random sampling with replacement based on this clinical trial cohort. Results: In ccRCC, low ITH was associated with better survival, more reductions in tumor burden, and clinical benefit of anti-PD-1 immunotherapy through modulating immune activity involving more neoantigens, elevated expression of HLA class I genes, and higher abundance of dendritic cells. Furthermore, we found that the association between the level of ITH and response to PD-1 blockade was independent of the mutation status of PBRM1 and that integrating both factors performed better than the individual predictors in predicting the benefit of anti-PD-1 immunotherapy in ccRCC patients. In pRCC, increased immune activity was also observed in low- versus high-ITH tumors, including higher neoantigen counts, increased abundance of monocytes, and decreased expression of PD-L1 and PD-L2. Conclusions: ITH may be helpful in the identification of patients who could benefit from PD-1 blockade in ccRCC, and even in pRCC where no genomic metrics has been found to correlate with response to immune checkpoint inhibitors.

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

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01961-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Revati Sharma ◽

Elif Kadife ◽

Mark Myers ◽

George Kannourakis ◽

Prashanth Prithviraj ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Checkpoint ◽

Renal Cell ◽

Immune Checkpoint Inhibitors ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Resistance Mechanisms ◽

Number Of Patients ◽

Angiogenesis Pathway

AbstractVascular 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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Hyperprogressive disease after radiotherapy combined with anti-PD-1 therapy in renal cell carcinoma: a case report and review of the literature

BMC Urology ◽

10.1186/s12894-021-00813-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chao Liu ◽

Jingjing Piao ◽

Zhiyang Shang

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

General Condition ◽

Renal Cell ◽

Checkpoint Inhibitors ◽

Lung Metastases ◽

Left Lung ◽

The Third ◽

Bidirectional Regulation ◽

Hyperprogressive Disease

Abstract Background Studies have shown that immune checkpoint inhibitors (ICIs) have limited efficacy and can even increase tumour burden in short time periods. This is usually called hyperprogressive disease (HPD). To date, there are few reports regarding HPD; fewer have analysed the relationship between HPD and radiotherapy combined with ICIs, and their conclusions are controversial. Case presentation A 42-year-old woman was diagnosed with stage IV renal clear cell carcinoma. The patient had previously received sorafenib and pazopanib as first- and second-line therapies, respectively. She received radiotherapy combined with nivolumab. Eighteen days after administration of the third dose of nivolumab, the patient’s general condition deteriorated; this was associated with immune-related adverse events. Computed tomography showed that the diameter of left lung metastases had sharply increased. A biopsy of the lung metastasis showed no infiltration of lymphocytes. The patient’s general condition worsened and she died of the disease on the 70th day after administration of the third dose of nivolumab. Conclusions This report describes the development of HPD following the administration of radiotherapy combined with ICIs in a case of advanced renal cell carcinoma. The case indicates that radiotherapy may show bidirectional regulation effects on anti-tumour immune response. If the immunosuppressive function of radiotherapy is dominant, combined with ICIs, it could result in HPD.

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