Option For Renal Cell Carcinoma Research Articles

RCC-Supporter: supporting renal cell carcinoma treatment decision-making using machine learning

BackgroundThe population diagnosed with renal cell carcinoma, especially in Asia, represents 36.6% of global cases, with the incidence rate of renal cell carcinoma in Korea steadily increasing annually. However, treatment options for renal cell carcinoma are diverse, depending on clinical stage and histologic characteristics. Hence, this study aims to develop a machine learning based clinical decision-support system that recommends personalized treatment tailored to the individual health condition of each patient.ResultsWe reviewed the real-world medical data of 1,867 participants diagnosed with renal cell carcinoma between November 2008 and June 2021 at the Pusan National University Yangsan Hospital in South Korea. Data were manually divided into a follow-up group where the patients did not undergo surgery or chemotherapy (Surveillance), a group where the patients underwent surgery (Surgery), and a group where the patients received chemotherapy before or after surgery (Chemotherapy). Feature selection was conducted to identify the significant clinical factors influencing renal cell carcinoma treatment decisions from 2,058 features. These features included subsets of 20, 50, 75, 100, and 150, as well as the complete set and an additional 50 expert-selected features. We applied representative machine learning algorithms, namely Decision Tree, Random Forest, and Gradient Boosting Machine (GBM). We analyzed the performance of three applied machine learning algorithms, among which the GBM algorithm achieved an accuracy score of 95% (95% CI, 92–98%) for the 100 and 150 feature sets. The GBM algorithm using 100 and 150 features achieved better performance than the algorithm using features selected by clinical experts (93%, 95% CI 89–97%).ConclusionsWe developed a preliminary personalized treatment decision-support system (TDSS) called “RCC-Supporter” by applying machine learning (ML) algorithms to determine personalized treatment for the various clinical situations of RCC patients. Our results demonstrate the feasibility of using machine learning-based clinical decision support systems for treatment decisions in real clinical settings.

Calcium saccharate/DUSP6 suppresses renal cell carcinoma glycolytic metabolism and boosts sunitinib efficacy via the ERK-AKT pathway

Current therapeutic options for renal cell carcinoma (RCC) are very limited, which is largely due to inadequate comprehension of molecular pathological mechanisms as well as RCC's resistance to chemotherapy. Dual-specificity phosphatase 6 (DUSP6) has been associated with numerous human diseases. However, its role in RCC is not well understood. Here, we show that diminished DUSP6 expression is linked to RCC progression and unfavorable prognosis. Mechanistically, DUSP6 serves as a tumor suppressor in RCC by intervening the TAF10 and BSCL2 via the ERK-AKT pathway. Further, DUSP6 is also transcriptionally regulated by HNF-4a. Moreover, docking experiments have indicated that DUSP6 expression is enhanced when bound by Calcium saccharate, which also inhibits RCC cell proliferation, metabolic rewiring, and sunitinib resistance. In conclusion, our study identifies Calcium saccharate as a prospective pharmacological therapeutic approach for RCC.

Current Treatment Options for Renal Cell Carcinoma: Focus on Cell-Based Immunotherapy.

Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space.

Treatment of localized renal cell carcinoma

Both partial nephrectomy (pNx) and total nephrectomy (TNx) are the mainstay of the surgical treatment of renal cell carcinoma. In smaller masses, ablative treatment as well as surveillance are possible options. The aim of this article is to provide acloser look at the surgical methods, active surveillance and ablative options as well as the current evidence to support their use. This study is based on aselective literature review regarding pNx and TNx for renal cell carcinoma using the PubMed database and the review of current European and American guidelines on surgical treatment and conservative options for renal cell carcinoma. The choice of surgical method depends on the intrarenal tumor configuration as well as patient comorbidities. While pNx is used for smaller localized masses TNx is usually performed in larger more complex tumors. Both methods can be performed using aminimally invasive (laparoscopic or robotically assisted) or an open approach. In patients with severe comorbidities or alimited life expectancy, local ablative treatment options as well as surveillance strategies are suitable strategies.

Treatment Options for Renal Cell Carcinoma: Mechanisms and Outcomes

Renal Cell Carcinoma (RCC), cancer of the tubules of the kidneys, has historically been one of the most difficult cancers to treat due to its ability to remain hidden in the body for longer than other cancers and its tendency to resist traditional forms of chemotherapy and radiation therapy. However, both traditional and nontraditional treatments of RCC have seen both significant biomedical advancements and clinical instances of use in recent years. In this review, we analyze five treatments of RCC: Nephrectomy, Immunotherapy, Anti-Angiogenesis, Chemotherapy, and Radiation Therapy, providing background on their mechanisms and clinical outcomes. Through our review of studies of clinical outcomes, we reaffirm the existing thought that nephrectomy remains the most effective treatment for RCC, while radiation therapy and chemotherapy are generally less effective and not recommended for treatment on their own. Immunotherapy and anti-angiogenic therapy have been shown to be effective treatments in the modern healthcare landscape and show great potential for the future as the techniques are better developed and optimized.

Onconephrology: Renal cancer

Renal cancer (RC) ranks eighth among the most prevalent oncopathologies, making it one of the most widespread types of cancer. Over the last decade, there has been an average annual increase in morbidity of 2 percent. RC is a collective term that encompasses parenchymal tumors and pelvis tumors with distinct histologic characteristics.
 Renal cancer can appear in intact kidneys and cause additional damage except for the actual tumor process, or in patients with previously affected kidneys.
 The main treatment option for renal cell carcinoma (RCC) is surgery, which can be performed through various approaches, including open-access surgery, laparoscopic surgery, and robotic-assisted surgery. These surgical techniques enable the performance of radical nephrectomy, partial nephrectomy, and cytoreductive nephrectomy. The selection of the surgical method and the extent of the intervention fall within the expertise of oncourologists.
 Anti-angiogenic drugs, including tyrosine kinase inhibitors, humanized monoclonal antibodies, and immune checkpoint inhibitors, as well as mTOR inhibitors, are commonly utilized in the treatment of advanced-stage RCC (II-IV) or its relapse. However, it is important to note that these drugs possess considerable nephrotoxicity. Therefore, kidney status plays a crucial role in determining the appropriate treatment options, the dosage of antitumor drugs, and the potential nephrotoxicity associated with them, thereby becoming the main limiting factor affecting the quality and duration of life for RCC patients.
 The present review focuses on the analysis of recent data concerning the issues mentioned above, primarily in relation to RCC, and provides recommendations for the investigation and treatment of this specific category of patients.

Renal Biopsy

The extent of renal biopsy indication is being widened because of the increasing incidence of incidental renal masses; the increasing treatment options for renal cell carcinoma, including ablation therapy and novel targeted treatment; and the increasing incidence of kidney transplantation. However, percutaneous renal biopsy is technically difficult, particularly for beginners, because the skin-to-organ distance is relatively longer than those associated with other organs. In the present review, we will discuss the indications, technical considerations, efficacy, and complications of renal biopsy. Furthermore, we share practical tips of renal biopsy through many examples to help radiologists perform renal biopsy safely and effectively in various situations.

Selected Articles from This Issue

PD-1T tumor-infiltrating lymphocytes (TIL) are a dysfunctional T-cell population characterized by high PD-1 expression and tumor reactivity. To evaluate their potential as a biomarker for durable clinical benefit to PD-1 blockade, Hummelink and colleagues digitally quantified PD-1T TIL in 120 pretreatment samples from patients with advanced non-small cell lung cancer. PD-1T TIL showed a high sensitivity in predicting clinical benefit and survival to anti-PD-1 and were superior to PD-L1 or TLS as a biomarker. Importantly, the absence of PD-1T TIL reliably identified a patient group without benefit from PD-1 blockade, thereby providing a promising tool to reduce overtreatment.Immune checkpoint inhibitors (ICI) targeting programmed cell death protein 1 and its ligand (PD-1/PD-L1) have revolutionized therapeutic options for renal cell carcinoma (RCC). However, response rates to ICI vary widely (20–70%) in patients with RCC. Predicting responses using conventional tissue-based techniques evaluating PD-L1 expression is of limited value, owing to the dynamic and heterogenous nature of PD-L1 expression. Mulgaonkar and colleagues systematically examined the performance of immunoPET for PD-L1 imaging relative to immunohistochemistry in an RCC tumorgraft platform. This study demonstrates the promising potential of immunoPET for clinical real-time assessment of PD-L1 expression across tumor sites and heterogeneous intratumoral distribution.CSF1R inhibitor treatments have shown to be effective targeted therapies for TGCT. Trials are currently underway to study the effect of discontinuation and retreatment with CSF1R inhibitors. In this study, van IJzendoorn and colleagues investigate the tumor landscape in TGCT using single-cell sequencing and other molecular techniques. They show that the neoplastic cells are not targeted by CSF1R inhibitors, in contrast to what was previously postulated. The authors identify markers for the neoplastic cells and show the lack of an autocrine loop involving CSF1-CSF1R in the neoplastic cells. As a result, CSF1R inhibitor treatments are unlikely to affect the neoplastic cell population in TGCT as is currently assumed. Additionally, this work identifies two new pathways that could be targeted in future trials involving TGCT.The resistance of immunotherapy in renal cancer patients remains unclear despite the high infiltrations of CD8+T cells. Here, Benhamouda and colleagues show that baseline plasma soluble CD27 (sCD27) is associated with resistance to immunotherapy in renal cell carcinoma independently of clinical factors. sCD27 reflects the interaction between CD27 expressed by T lymphocytes and CD70 expressed by tumor cells, which associates with the apoptosis and dysfunction of T lymphocytes. Peripheral blood sCD27 could thus be considered as a marker of T-cell dysfunction due to the CD27-CD70 interaction in the tumor and predict the response to immunotherapy.

CyberKnife Stereotactic Body Radiotherapy as a treatment option for renal cell carcinoma: The complex case of a patient with unilateral renal agenesis

Surgery is the standard treatment for local renal cell carcinoma (RCC), but many patients are medically inoperable and local approaches such as radiofrequency ablation and cryoablation may be limited to smaller tumours. Conventional radiotherapy has not been effective in RCC, but higher dose-per-fraction radiotherapy has shown high local control rates accompanied by low toxicity. This is particularly important in the case of patients with a solitary kidney, either congenital or due to previous surgical history. Here, we present the case of a 68-year-old female patient with congenital right renal agenesis diagnosed with clear cell renal cell carcinoma in her left (solitary) kidney. Originally, the patient started treatment with sunitinib but 9 months later, due to important side effects, it was decided to treat her with CyberKnife Stereotactic Body Radiotherapy (SBRT) using a prescription dose of 45 Gy in five sessions. Ten months after her treatment, PET/CT images showed no signs of local hypermetabolism and more than a year after treatment, kidney function remains stable. Curiously, PET/CT also revealed the presence of percutaneous tumour seeding probably after renal biopsy. This case supports the growing body of evidence showing the value of Stereotactic Body Radiotherapy for renal cancer, especially for medically inoperable renal tumours in a solitary kidney.

Safety and efficacy of RFA versus MWA for T1a renal cell carcinoma: a propensity score analysis

ObjectivesPercutaneous radiofrequency ablation (RFA) is stated as a treatment option for renal cell carcinoma (RCC) smaller than 4 cm (T1a). Microwave ablation (MWA) is a newer technique and is still considered experimental in some guidelines. The objective of this study was to compare the safety and efficacy of RFA and MWA for the treatment of RCC.MethodsPatients with T1a RCC treated by RFA or MWA in two referral centers were retrospectively analyzed. Patient records were evaluated to generate mRENAL nephrometry scores. Local tumor progression (LTP) was considered when new (recurrence) or residual tumor enhancement within/adjacent to the ablation zone was objectified. Differences in LTP-free interval (residual + recurrence) between ablation techniques were assessed with Cox proportional hazards models and propensity score (PS) methods.ResultsIn 164 patients, 87 RFAs and 101 MWAs were performed for 188 RCCs. The primary efficacy rate was 92% (80/87) for RFA and 91% (92/101) for MWA. Sixteen patients had residual disease (RFA (n = 7), MWA (n = 9)) and 9 patients developed recurrence (RFA (n = 7), MWA (n = 2)). LTP-free interval was significantly worse for higher mRENAL nephrometry scores. No difference in LTP-free interval was found between RFA and MWA in a model with inverse probability weighting using PS (HR = 0.99, 95% CI 0.35–2.81, p = 0.98) and in a PS-matched dataset with 110 observations (HR = 0.82, 95% CI 0.16–4.31, p = 0.82). Twenty-eight (14.9%) complications (Clavien-Dindo grade I–IVa) occurred (RFA n = 14, MWA n = 14).ConclusionPrimary efficacy for ablation of RCC is high for both RFA and MWA. No differences in efficacy and safety were observed between RFA and MWA.Key Points• Both RFA and MWA are safe and effective ablation techniques in the treatment of T1a renal cell carcinomas.• High modified RENAL nephrometry scores are associated with shorter local tumor progression-free interval.• MWA can be used as heat-based ablation technique comparable to RFA for the treatment of T1a renal cell carcinomas.

Inhibition of DCLK1 with DCLK1-IN-1 Suppresses Renal Cell Carcinoma Invasion and Stemness and Promotes Cytotoxic T-Cell-Mediated Anti-Tumor Immunity.

Simple SummaryIn this study, we found that the novel small molecule kinase inhibitor DCLK1-IN-1 not only inhibited DCLK1 phosphorylation, stemness, and EMT-related properties of RCC cells but also revealed its potential as an immunotherapy agent and potential combination therapy with anti-PD1 against RCC in immune co-culture experiments.The approval of immune checkpoint inhibitors has expanded treatment options for renal cell carcinoma (RCC), but new therapies that target RCC stemness and promote anti-tumor immunity are needed. Previous findings demonstrate that doublecortin-like kinase 1 (DCLK1) regulates stemness and is associated with RCC disease progression. Herein, we demonstrate that small-molecule kinase inhibitor DCLK1-IN-1 strongly inhibits DCLK1 phosphorylation and downregulates pluripotency factors and cancer stem cell (CSC) or epithelial-mesenchymal transition (EMT)-associated markers including c-MET, c-MYC, and N-Cadherin in RCC cell lines. Functionally, DCLK1-IN-1 treatment resulted in significantly reduced colony formation, migration, and invasion. Additionally, assays using floating or Matrigel spheroid protocols demonstrated potent inhibition of stemness. An analysis of clinical populations showed that DCLK1 predicts RCC survival and that its expression is correlated with reduced CD8+ cytotoxic T-cell infiltration and increases in M2 immunosuppressive macrophage populations. The treatment of RCC cells with DCLK1-IN-1 significantly reduced the expression of immune checkpoint ligand PD-L1, and co-culture assays using peripheral blood monocytes (PBMCs) or T-cell expanded PBMCs demonstrated a significant increase in immune-mediated cytotoxicity alone or in combination with anti-PD1 therapy. Together, these findings demonstrate broad susceptibility to DCLK1 kinase inhibition in RCC using DCLK1-IN-1 and provide the first direct evidence for DCLK1-IN-1 as an immuno-oncology agent.

Antiangiogenic Properties of Axitinib versus Sorafenib Following Sunitinib Resistance in Human Endothelial Cells-A View towards Second Line Renal Cell Carcinoma Treatment.

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors predominate as first-line therapy options for renal cell carcinoma. When first-line TKI therapy fails due to resistance development, an optimal second-line therapy has not yet been established. The present investigation is directed towards comparing the anti-angiogenic properties of the TKIs, sorafenib and axitinib on human endothelial cells (HUVECs) with acquired resistance towards the TKI sunitinib. HUVECs were driven to resistance by continuously exposing them to sunitinib for six weeks. They were then switched to a 24 h or further six weeks treatment with sorafenib or axitinib. HUVEC growth, as well as angiogenesis (tube formation and scratch wound assay), were evaluated. Cell cycle proteins of the CDK-cyclin axis (CDK1 and 2, total and phosphorylated, cyclin A and B) and the mTOR pathway (AKT, total and phosphorylated) were also assessed. Axitinib (but not sorafenib) significantly suppressed growth of sunitinib-resistant HUVECs when they were exposed for six weeks. This axinitib-associated growth reduction was accompanied by a cell cycle block at the G0/G1-phase. Both axitinib and sorafenib reduced HUVEC tube length and prevented wound closure (sorafenib > axitinib) when applied to sunitinib-resistant HUVECs for six weeks. Protein analysis revealed diminished phosphorylation of CDK1, CDK2 and pAKT, accompanied by a suppression of cyclin A and B. Both drugs modulated CDK-cyclin and AKT-dependent signaling, associated either with both HUVEC growth and angiogenesis (axitinib) or angiogenesis alone (sorafenib). Axitinib and sorafenib may be equally applicable as second line treatment options, following sunitinib resistance.

Microwave Ablation of Renal Cell Carcinoma.

Management options for small renal masses include active surveillance, partial nephrectomy, radical nephrectomy, and thermal ablation. For tumors typically ≤3 cm in size, thermal ablation is a good option for those desiring an alternative to surgery or active surveillance, especially in patients who are considered high surgical risk. We favor microwave ablation because of the more rapid heating, higher temperatures that overcome the heat sink effect of vessels, reproducible cell kill, and a highly visible ablation zone formed by water vapor that corresponds well to the zone of necrosis. For central tumors, we favor cryoablation because of the slower formation of the ablation zone and less likelihood of damage to the collecting system. With microwaves, it is important to monitor the ablation zone in real time (ultrasound is the best modality for this purpose), avoid direct punctures of the collecting system, and to place probes tangential to the collecting system to avoid burning open a persistent tract between the urothelium and extrarenal spaces or causing strictures. The surgical steps described in this video cover our use of high-frequency jet ventilation with general anesthesia to minimize organ motion, initial imaging and targeting, probe insertion, hydrodissection (a technique that enables displacement of adjacent structures), the ablation itself, and finally our dressing. Postoperative cares typically consist of observation with a same-day discharge or an overnight stay. Follow-up includes a magnetic resonance imaging abdomen with and without contrast, chest X-ray, and laboratories (basic metabolic panel, complete blood count, and C-reactive protein) 6 months postablation. Overall, percutaneous microwave ablation is an effective and safe treatment option for renal cell carcinoma in both T1a and T1b tumors in selected patients with multiple studies showing excellent oncologic outcomes when compared with partial and radical nephrectomy.

Adaptive Magnetic Resonance-Guided Stereotactic Body Radiotherapy: The Next Step in the Treatment of Renal Cell Carcinoma.

Adaptive MR-guided radiotherapy (MRgRT) is a new treatment paradigm and its role as a non-invasive treatment option for renal cell carcinoma is evolving. The early clinical experience to date shows that real-time plan adaptation based on the daily MRI anatomy can lead to improved target coverage and normal tissue sparing. Continued technological innovations will further mitigate the challenges of organ motion and enable more advanced treatment adaptation, and potentially lead to enhanced oncologic outcomes and preservation of renal function. Future applications look promising to make a positive clinical impact and further the personalization of radiotherapy in the management of renal cell carcinoma.

An open-label phase II study comparing two doses of MK-6482 for the treatment of advanced renal cell carcinoma (RCC) following progression on prior systemic therapy.

TPS369 Background: Treatment options for RCC in the late-line setting after immunotherapy and vascular endothelial growth factor (VEGF)-targeted therapy are limited. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). The first-in-class small molecular HIF-2α inhibitor, MK-6482, recently showed promising antitumor activity in a cohort of heavily pretreated ccRCC patients (pts) and in pts with von Hippel-Lindau–disease-associated RCC for which the FDA granted Breakthrough Therapy Designation to MK-6482. Methods: This randomized, open-label, multicenter phase II trial will evaluate the efficacy and safety of 2 doses of MK-6482 in pts with advanced RCC who have experienced progression after prior systemic therapy (NCT04489771). Eligible pts are male or female aged ≥18 years with histologically confirmed locally advanced or metastatic ccRCC (measurable disease per RECIST v1.1) who have experienced progression after 1-3 prior systemic therapies comprising an anti-PD-1/L1 agent combined with a VEGF-targeted tyrosine kinase inhibitor (TKI) or an anti-cytotoxic T lymphocyte-associated antigen-4 agent and have undergone no more than 3 prior systemic regimens; and a Karnofsky Performance Scale ≥70. Treatment progression on anti-PD-1/L1 combination therapy was defined as pts who received at least 2 doses of anti-PD-1/L1 therapy and demonstrated radiographic disease progression as assessed by the investigator. Pts who have received prior treatment with MK-6482 or another HIF-2α inhibitor, and those requiring intermittent or chronic supplemental oxygen, or with a baseline hemoglobin less than 10 g/dL, a history of human immunodeficiency virus, hepatitis B or hepatitis C infection, or active central nervous system metastases will be excluded. Approximately 150 pts will be randomly assigned 1:1 to oral MK-6482 120 mg once daily (QD) or 200 mg QD; treatment will continue until progression, unacceptable toxicity, or withdrawal. Pts will be stratified by International Metastatic RCC Database Consortium prognostic scores (0, 1-2, 3-6) and the number of prior TKI-containing therapies (0, 1, or 2-3). Imaging with computed tomography or magnetic resonance imaging will be undertaken on Week 9 from the date of randomization, every 8 weeks through Week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). The primary end point is objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are progression-free survival, duration of response and clinical benefit rate per RECIST v1.1 by BICR, overall survival, pharmacokinetics, and safety. Safety will be analyzed using a tiered approach. This study is recruiting. Clinical trial information: NCT04489771 .

Safety and Efficacy of Robotic Radiosurgery for Visceral and Lymph Node Metastases of Renal Cell Carcinoma: A Retrospective, Single Center Analysis.

Simple SummaryIn metastatic renal cell carcinoma (mRCC), systemic treatment with checkpoint inhibitors or tyrosine kinase inhibitors is recommended in guidelines. However, the treatment of patients with oligometastatic disease or mixed responses remains challenging. We aimed to investigate the safety and efficacy of robotic radiosurgery in patients with mRCC. Sixty patients with visceral and lymph node metastases were selected for robotic radiosurgery. The median progression free survival of all patients was 17.4 months, local tumor control was achieved in 96.7% of patients, and only 8.3% of patients experienced adverse events. Robotic radiosurgery might be a powerful tool in addition to systemic treatment for patients with mRCC, but additive effects of both treatments require further investigation.Despite rapid advances of systemic therapy options in renal cell carcinoma (RCC), local tumor or metastases treatment remains important in selected patients. Here, we assess the safety and efficacy of robotic radiosurgery (RRS) as an ablative therapy for visceral and lymph node metastases of RCC. Patients with histologically confirmed RCC and radiologically confirmed progression of visceral or lymph node metastases underwent RRS and were retrospectively analyzed. Overall survival and progression free survival were calculated by the Kaplan–Meier method and log-rank test. Sixty patients underwent RRS and were included in the analysis. Patients presented for RRS treatment with a median age at RRS treatment of 64 years (range 42–83), clear cell histology (88.3%) and favorable international metastatic renal cell carcinoma database (IMDC) risk score (58.3%). Treatment parameters differed for the number of fractions (median visceral metastases: 1, range 1–5; median lymph node metastases: 1, range 0–5; p = 0.003) and prescription dose (median visceral metastases 24 Gy, range 8–26; median lymph node metastases 18 Gy, range 7–26, p < 0.001). The median overall survival was 65.7 months (range: 2.9–108.6), the median progression free survival was 17.4 months (range: 2.7–70.0) and local tumor control was achieved in 96.7% of patients. Adverse events were limited to 8.3% of patients, with one grade 4 toxicity within 6 weeks after RRS therapy. RRS is a safe and effective treatment option in selected patients with metastatic RCC in a multimodal approach. Further research is warranted to confirm our findings prospectively.

Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities.

Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard of care in multiple cancers. However, durable antitumor responses have been observed in only a minority of patients, indicating the presence of other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against other immune suppressive mechanisms are needed to enhance anticancer immunity and maximize the clinical benefit of CIT in patients who are resistant to immune checkpoint inhibition. Preclinical and clinical studies have identified abnormalities in the tumor microenvironment (TME) that can negatively impact the efficacy of PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immune suppressive activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. In turn, immunosuppressive cells can drive angiogenesis, thereby creating a vicious cycle of suppressed antitumor immunity. VEGF-mediated immune suppression in the TME and its negative impact on the efficacy of CIT provide a therapeutic rationale to combine PD-1/PD-L1 antibodies with anti-VEGF drugs in order to normalize the TME. A multitude of clinical trials have been initiated to evaluate combinations of a PD-1/PD-L1 antibody with an anti-VEGF in a variety of cancers. Recently, the positive results from five Phase III studies in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma have shown that combinations of PD-1/PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared with respective standards of care. Such combinations have been approved by health authorities and are now standard treatment options for renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. A plethora of other randomized studies of similar combinations are currently ongoing. Here, we discuss the principle mechanisms of VEGF-mediated immunosuppression studied in preclinical models or as part of translational clinical studies. We also discuss data from recently reported randomized clinical trials. Finally, we discuss how these concepts and approaches can be further incorporated into clinical practice to improve immunotherapy outcomes for patients with cancer.

CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation.

Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to other frequently used cell lines such as HEK293, A549, Hela and DLD1. Ablation of EGFR by CRISPR/Cas9 significantly restrained tumor cell growth and activated the MAPK (pERK1/2) pathway. The VEGFR and PDGFR inhibitor, sunitinib, attenuated the expression of MAPK (pERK1/2) and pAKT induced by EGFR loss and further inhibited EGFR-/- cell proliferation. We showed that loss of EGFR eventually leads to resistance to SAHA and cisplatin. Furthermore, EGFR loss induced G2/M phase arrest and resulted in an increased resistance to TNF-related apoptosis-inducing ligand (TRAIL) in renal cell carcinoma. Thus, ablation of overexpressed EGFR by CRISPR/Cas9 alone or in combination with sunitinib may be a new treatment option for renal cell carcinoma.

Thymoquinone induces apoptosis of human renal carcinoma Caki-1 cells by inhibiting JAK2/STAT3 through pro-oxidant effect

Currently, there are limited effective treatment options for renal cell carcinoma (RCC), due to its poor responses to conventional therapies. Instead of using extrinsic anti-cancer drugs, cancer cell-intrinsic reactive oxygen species (ROS) can be a weapon of RCC treatment. In the present study, we found that the phytochemical thymoquinone (TQ), a bioactive natural product obtained from the black cumin seeds of Nigella sativa, generates intracellular ROS in human renal cancer Caki-1 cells. Treatment of Caki-1 cells with high concentration of TQ up-regulated pro-apoptotic p53 and Bax expression, while downregulated anti-apoptotic Bcl-2 and Bcl-xl expression. Simultaneously, TQ suppressed the pro-oncogenic JAK2/STAT3 pathway, resulting in decreased expression of Bcl-2, Bcl-xl, cyclin D1, cyclin D2, and survivin. Thus, TQ can integrate between apoptosis and the pro-survival JAK2/STAT3 pathway through the Bcl family members, collectively magnifying Caki-1 cell apoptosis. However, treatment with the ROS scavenger N-acetyl cysteine significantly blocked TQ-induced apoptosis as well as incorporated signaling pathways, supporting that its pro-oxidant property is crucial for Caki-1 cell apoptosis. Moreover, TQ reduced the tumor xenograft growth of Caki-1 cells in nude mice. Taken together, these data suggest that TQ is a prominent anti-cancer drug to treat human RCC by enhancing apoptosis through its pro-oxidant nature.

Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema in a patient with renal cell carcinoma

Immune checkpoint inhibitors and angiogenesis inhibitors are novel treatment options for renal cell carcinoma and widely used in clinical practice. They are related with adverse events that occur as a consequence of immune system activation and inhibition of angiogenesis. Herein, we report a rare case of inflammatory arthritis seen in a patient treated with an anti Programmed cell death-1 pembrolizumab and an anti-vascular endothelial growth factor pazopanib. A 60-year-old Caucasian male presented to our clinic with inflammatory arthritis with pitting edema. He had been started on pembrolizumab therapy for metastatic renal cell carcinoma after enrolling in the KEYNOTE-679 study. After six cycles of treatment with pembrolizumab, metastasis had been determined in the lung. Then, the patient's therapy was changed to pazopanib. While the patient was on pazopanib treatment, he noticed a gradual swelling of both hands. Rheumatoid factor, anti-nuclear antibody and anti-cyclic citrullinated peptide were negative. Joint ultrasonography revealed acute tenosynovitis and soft tissue swelling with pitting edema, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made. Management and outcome: He was started on 10 mg prednisolone daily. His symptoms dramatically responded to corticosteroid. He continued to take pazopanib. Then, the patient was discharged with 10 mg prednisolone daily. Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema can be among the rare rheumatic immune-related adverse events that clinicians may encounter as the immune check point inhibitors and anti-VEGF use increases. Corticosteroid therapy can relieve symptoms and cessation of therapy may not be necessary.