The most common subtype of renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). While localized ccRCC can be cured with surgery, metastatic disease has a poor prognosis. Recently, immunotherapy has emerged as a promising approach for advanced ccRCC. This review provides a comprehensive overview of the evolving immunotherapeutic landscape for metastatic ccRCC. Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 and CTLA-4 inhibitors have demonstrated clinical efficacy as monotherapies and in combination regimens. Combination immunotherapies pairing ICIs with antiangiogenic agents, other immunomodulators, or novel therapeutic platforms such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy are areas of active research. Beyond the checkpoint blockade, additional modalities including therapeutic vaccines, cytokines, and oncolytic viruses are also being explored for ccRCC. This review discusses the mechanisms, major clinical trials, challenges, and future directions for these emerging immunotherapies. While current strategies have shown promise in improving patient outcomes, continued research is critical for expanding and optimizing immunotherapy approaches for advanced ccRCC. Realizing the full potential of immunotherapy will require elucidating mechanisms of response and resistance, developing predictive biomarkers, and rationally designing combination therapeutic regimens tailored to individual patients. Advances in immunotherapy carry immense promise for transforming the management of metastatic ccRCC.

Purpose: Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa. Experimental design: This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/− salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints. Results: Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1–2), 25% nausea (grade 1–2), and 20% fatigue (grade 1–2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved). Conclusion: Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

Prostate cancer (PCa) remains a leading cause of mortality among American men, with metastatic and recurrent disease posing significant therapeutic challenges due to a limited comprehension of the underlying biological processes governing disease initiation, dormancy, and progression. The conventional use of PCa cell lines has proven inadequate in elucidating the intricate molecular mechanisms driving PCa carcinogenesis, hindering the development of effective treatments. To address this gap, patient-derived primary cell cultures have been developed and play a pivotal role in unraveling the pathophysiological intricacies unique to PCa in each individual, offering valuable insights for translational research. This review explores the applications of the conditional reprogramming (CR) cell culture approach, showcasing its capability to rapidly and effectively cultivate patient-derived normal and tumor cells. The CR strategy facilitates the acquisition of stem cell properties by primary cells, precisely recapitulating the human pathophysiology of PCa. This nuanced understanding enables the identification of novel therapeutics. Specifically, our discussion encompasses the utility of CR cells in elucidating PCa initiation and progression, unraveling the molecular pathogenesis of metastatic PCa, addressing health disparities, and advancing personalized medicine. Coupled with the tumor organoid approach and patient-derived xenografts (PDXs), CR cells present a promising avenue for comprehending cancer biology, exploring new treatment modalities, and advancing precision medicine in the context of PCa. These approaches have been used for two NCI initiatives (PDMR: patient-derived model repositories; HCMI: human cancer models initiatives).

Prostate cancer exhibits significant racial disparities, with African American (AA) individuals showing ∼64% higher incidence and 2.3 times greater mortality rates compared to their Caucasian (CA) counterparts. Understanding the complex interplay of genetic, environmental, lifestyle, socioeconomic, and healthcare access factors is crucial for developing effective interventions to reduce this disproportionate burden. This study aims to uncover the genetic and transcriptomic differences driving these disparities through a comprehensive analysis using RNA sequencing (RNA-seq) and exome sequencing of prostate cancer tissues from both Black and White patients. Our transcriptomics analysis revealed enhanced activity in pathways linked to immune response and cellular interactions in AA prostate cancer samples, with notable regulation by histone-associated transcription factors (HIST1H1A, HIST1H1D, and HIST1H1B) suggests potential involvement of histone modification mechanisms. Additionally, pseudogenes and long non-coding RNAs (lncRNAs) among the regulated genes indicate non-coding elements' role in these disparities. Exome sequencing identified unique variants in AA patient samples within key genes, including TP73 (tumor suppression), XYLB (metabolism), ALDH4A1 (oxidative stress), PTPRB (cellular signaling), and HLA-DRB5 (immune response). These genetic variations likely contribute to disease progression and therapy response disparities. This study highlights the importance of considering genetic and epigenetic variations in developing tailored therapeutic approaches to improve treatment efficacy and reduce mortality rates across diverse populations.

Background: Sarcomatoid renal cell carcinoma (sRCC) is an aggressive RCC subtype with a poor prognosis. Although racial disparities in RCC outcomes are reported, survival patterns across racial and ethnic groups in metastatic sRCC (msRCC) remain unclear. Methods: We conducted a retrospective analysis of 2122 patients with msRCC diagnosed between 2010 and 2020 using the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized by race and ethnicity as non-Hispanic White, non-Hispanic Black, Hispanic, Asian/Pacific Islander, or American Indian/Alaska Native. Three-year cancer-specific survival (CSS) and overall survival (OS) were estimated using Kaplan–Meier methods. Multivariable Cox proportional hazards regression models were used to evaluate racial disparities in survival. Results: Non-Hispanic Black patients experienced the poorest outcomes, with 3-year CSS and OS of 9.3% and 8.6%, compared with 23.3% and 20.9% in non-Hispanic White, 22.1% and 19.0% in Hispanic, 21.2% and 19.4% in Asian/Pacific Islander, and 23.4% and 20.7% in American Indian/Alaska Native patients. Non-Hispanic Black patients were associated with higher estimated hazards of cancer-specific mortality (HR = 1.5, p < 0.0001) and overall mortality (HR = 1.5, p < 0.0001) versus non-Hispanic White. From 2010–2015 to 2016–2020, survival improved across most racial groups with the introduction of immune checkpoint inhibitors. However, non-Hispanic Black patients remained the only group with persistently inferior survival. Subgroup analysis further demonstrated worse survival for non-Hispanic Black patients in both clear cell msRCC and non-clear cell msRCC subgroups. Conclusions: Although survival was higher during the later diagnosis period, non-Hispanic Black patients with msRCC continued to have the poorest observed survival. These differences may be associated with unmeasured social, structural, socioeconomic, healthcare access, treatment, or clinical factors, but their causes cannot be determined from this observational study. Further research is needed to identify the factors underlying these survival differences.

Background/Objectives: Enfortumab vedotin plus pembrolizumab (EV+pembro) is the standard first-line treatment for metastatic urothelial carcinoma (mUC), yet no validated on-treatment biomarker identifies patients deriving a durable benefit. We evaluated whether circulating tumor DNA (ctDNA) clearance is associated with response and survival with this regimen alone. Methods: This single-center retrospective study included 25 patients with mUC receiving first-line EV+pembro. A tumor-informed assay (Signatera) measured ctDNA longitudinally. Responses were assessed by RECIST 1.1. Progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) were estimated by Cox regression and, to address immortal time bias, with clearance as a time-dependent covariate. Results: Fifteen of 25 patients (60%) achieved ctDNA clearance (ever undetectable). The objective response rate was 76% overall and 100% (15/15) with clearance versus 40% (4/10) without (p = 0.0012). Clearance was associated with longer PFS (HR 0.16, 95% CI 0.05–0.54; p = 0.003) and OS (HR 0.08, 95% CI 0.01–0.68; p = 0.021), with similar Firth penalized HRs (0.17 and 0.11). In the time-dependent analysis, the associations were attenuated (PFS HR 0.35, 95% CI 0.09–1.15, p = 0.085; OS HR 0.14, 95% CI 0.01–0.84, p = 0.029; profile likelihood CIs). A post-nadir ctDNA rise preceded progression or death by a median of 95 days in four patients (death in two). Conclusions: In this first-line EV+pembro cohort, all patients who cleared ctDNA responded, and clearance was associated with longer survival, although this association was attenuated in the time-dependent analysis. These hypothesis-generating findings support the prospective evaluation of ctDNA-guided monitoring.