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Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab–ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab–ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05–0.47, P  = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P  = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab–ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments. A randomized trial in treatment-naive patients with metastatic renal cell carcinoma shows that the addition of a live bacterial product to an immunotherapy combination elicits promising clinical benefit in association with an enrichment of bacterial species, circulating cytokines and immune cell populations in responders.

Abstract Background In addition to the previously studied socioeconomic factors associated with health disparities, insurance status can serve as a prognostic factor associated with overall survival in RCC patients (Zhang et al., Future Oncol 2019). Moreover, within this population, having access to health insurance has been reported to result in earlier detection of disease (Javier-DesLoges et al., JAMA Netw Open 2021). In this study, we explored the impact of primary and secondary insurance status on PFS and OS in patients receiving first line systemic therapy for mRCC. Methods Patients with mRCC from two NCI-designated comprehensive cancer centers diagnosed between 1990 and 2022 with available insurance information were retrospectively identified using institutional databases. Primary insurance information was categorized into three groups—Medicare, private insurance, and Medicaid/no insurance—while secondary insurance was defined by the presence or absence of secondary coverage. PFS and OS were estimated by Kaplan-Meier method and compared based on insurance status using log-rank tests. Univariate and multivariate Cox proportional hazard regression models were used to examine the impact of insurance status on PFS and OS. Results In total, 645 patients with mRCC had accessible information and were included in our analysis. Of these, 344 (53.3%), 250 (38.8%), and 51 (7.9%) had primary Medicare, private insurance, and Medicaid/no insurance, respectively. Overall, most patients were male (73.0%), with a median age of 60.0 (22.0-94.0) at time of diagnosis. The most commonly rendered first-line treatments were monotherapy with targeted agents (66.4%), dual immunotherapy (13.6%), and targeted/immunotherapy combinations (10.2%). Median PFS for the entire cohort was 6.6 months (95% CI, 5.9-7.7). Median PFS for patients with primary Medicare was 7.7 months (95%, CI 7.0-9.0), 5.5 months (95% CI, 4.0-7.0) for patients with private insurance, and 4.9 months (95% CI, 3.8-8.1) for Medicaid/uninsured patients. Using an overall log-rank test, a significant difference in PFS among the three groups with different primary insurance was observed (p<0.0001). The median PFS for patients with secondary insurance was 8.1 months (95% CI, 6.6-11.3) compared to 6.1 months (95% CI, 5.5-7.4) for patients without secondary insurance. A multivariate Cox model with adjustment for other factors (such as age, gender, and ethnicity) revealed a statistically significant difference in PFS between patients with and without secondary insurance (p=0.0281). Median OS for the entire cohort was 36.8 months (95% CI, 32.4-44.3). Median OS for patients with primary Medicare, private insurance, and Medicaid/no insurance was 49.0 months (95%, CI 41.8-55.3), 28.5 months (95% CI, 24.1-35.7), and 21.6 months (95% CI, 17.5-42.3), respectively. By an overall log-rank test, a significant difference in OS across the three groups of primary insurance was observed (p=0.0003). No statistically significant differences in OS were observed between patients with and without secondary insurance. Overall, patients with primary Medicare had superior median PFS (p=0.0327) and OS (p=0.0004) compared to those with Medicaid/no insurance; although patients with private insurance had a lower risk of progression and death compared to those with Medicaid/no insurance, the result was not statistically significant. Conclusions In this real-world study, we investigated the impact of insurance status on clinical outcomes in patients with mRCC receiving systemic therapy. mRCC patients with primary Medicaid/no insurance or private insurance had inferior median PFS and OS compared to those with primary Medicare. Moreover, patients with secondary insurance had superior PFS over those with primary insurance alone. Overall, our findings suggest that insurance status may serve as a determinant of clinical outcomes. These hypothesis-generating data warrant external validation in prospective studies.

ObjectiveTo characterize and further compare the immune cell populations of the tumor microenvironment (TME) in both clear cell and papillary renal cell carcinoma (RCC) using heavy metal-labeled antibodies in a multiplexed imaging approach (imaging mass cytometry).Materials and methodsFormalin-fixed paraffin-embedded (FFPE) baseline tumor tissues from metastatic patients with clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) were retrospectively requisitioned from an institutional biorepository. Pretreated FFPE samples from 33 RCC patients (10 ccRCC, 23 pRCC) were accessioned and stained for imaging mass cytometry (IMC) analysis. Clinical characteristics were curated from an institutional RCC database. FFPE samples were prepared and stained with heavy metal-conjugated antibodies for IMC. An 11-marker panel of tumor stromal and immune markers was used to assess and quantify cellular relationships in TME compartments. To validate our time-of-flight (CyTOF) analysis, we cross-validated findings with The Cancer Genome Atlas Program (TCGA) analysis and utilized the CIBERSORTx tool to examine the abundance of main immune cell types in pRCC and ccRCC patients.ResultsPatients with ccRCC had a longer median overall survival than did those with pRCC (67.7 vs 26.8 mo, respectively). Significant differences were identified in the proportion of CD4+ T cells between disease subtypes (ccRCC 14.1%, pRCC 7.0%, p<0.01). Further, the pRCC cohort had significantly more PanCK+ tumor cells than did the ccRCC cohort (24.3% vs 9.5%, respectively, p<0.01). There were no significant differences in macrophage composition (CD68+) between cohorts. Our results demonstrated a significant correlation between the CyTOF and TCGA analyses, specifically validating that ccRCC patients exhibit higher levels of CD4+ T cells (ccRCC 17.60%, pRCC 15.7%, p<0.01) and CD8+ T cells (ccRCC 17.83%, pRCC 11.15%, p<0.01). The limitation of our CyTOF analysis was the large proportion of cells that were deemed non-characterizable.ConclusionsOur findings emphasize the need to investigate the TME in distinct RCC histological subtypes. We observed a more immune infiltrative phenotype in the TME of the ccRCC cohort than in the pRCC cohort, where a tumor-rich phenotype was noted. As practical predictive biomarkers remain elusive across all subtypes of RCC, further studies are warranted to analyze the biomarker potential of such TME classifications.

Supplementation with CBM588, a bifidogenic live bacterial product, has been associated with improved clinical outcomes in persons with metastatic renal cell carcinoma (mRCC) receiving nivolumab and ipilimumab. However, its effect on those receiving tyrosine kinase inhibitor-based combinations is unknown. In this open-label, randomized, investigator-initiated, phase 1 study, 30 participants with locally advanced or mRCC with histological confirmation of clear cell, papillary or sarcomatoid component were randomized in a 2:1 fashion to receive cabozantinib (an inhibitor of vascular endothelial growth factor receptor, MET and AXL) and nivolumab (anti-programmed cell death protein 1) with or without CBM588 as first-line treatment. Metagenomic sequencing was performed on stool samples to characterize their gut microbiome at baseline and 13 weeks into treatment. The primary endpoint was a change in the relative abundance of Bifidobacterium spp.; secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and toxicity profile. The primary endpoint of the study was not met and the addition of CBM588 to cabozantinib and nivolumab did not result in a difference in the relative abundance of Bifidobacterium spp. or alpha diversity (as measured by the Shannon index). However, ORR was significantly higher in participants treated with CBM588 compared to those in the control arm (14 of 19, 74% versus 2 of 10, 20%; P  = 0.01). PFS at 6 months was 84% (16 of 19) and 60% (6 of 10) in the experimental and control arms, respectively. No significant difference in toxicity profile was seen between the study arms. Our results provide a preliminary signal of improved clinical activity with CBM588 in treatment-naive participants with mRCC receiving cabozantinib and nivolumab. Further investigation is needed to confirm these findings and better characterize the underlying mechanism driving this effect. ClinicalTrials.gov identifier: NCT05122546 In a randomized phase 1 trial, the addition of a live Clostridium species-containing product to a tyrosine kinase inhibitor and anti-programmed cell death protein 1 treatment combination did not increase bacterial abundance of Bifidobacterium spp. but enhanced clinical responses in participants with metastatic renal cell carcinoma.

A new approach that combines CAR T cells with serial mRNA vaccine injections facilitates robust anti-neoplastic activity in patients with genitourinary cancers, which will pave the way for a promising new targeted treatment strategy.

Abstract Background Two recent randomized phase I clinical trials have provided compelling evidence that CBM588, a Clostridium butyricum-based live biotherapeutic, holds potential to enhance clinical outcomes in patients with mRCC receiving frontline ICI combinations (Dizman et al Nature Medicine 2022; Ebrahimi et al ASCO 2023). We examined the impact of CBM588 on gut microbiome composition in a combined cohort of these two studies to further investigate its impact on gut microbiome Methods We analyzed stool samples from two phase I randomized clinical trials that enrolled patients with mRCC treated with (1) nivolumab/ipilimumab (nivo/ipi) +/- CBM588 and (2) cabozantinib/nivolumab (cabo/nivo) +/- CBM588. We compared gut microbiome diversity and composition at baseline and week 12 between patients in the standard of care (SOC) arms (nivo/ipi or cabo/nivo) and those who received CBM588 in combination with a SOC regimen (SOC/CBM). Taxonomic profiling was performed using MetaPhlan v4, and changes in the abundances of clinically relevant microbial species from baseline to week 12 were assessed using the Wilcoxon matched pairs test. The ratio of Firmicutes/Bacteroidetes, a measure of gut dysbiosis, was computed across time points in the two cohorts. Results Among 58 patients included in the analysis, 38 received SOC/CBM588 as first-line treatment. The median age was 60 years (range: 36-90) and the majority of patients were male (71%), had clear cell mRCC (88%), and intermediate/poor risk disease (79%). In both the SOC and SOC/CBM cohorts, there were no statistically significant differences in alpha and beta diversity between baseline and week 12. Among clinically relevant species compared between baseline and week 12, Alistipes senegalensis was found to decrease in both the SOC and SOC/CBM cohorts (log fold change [LFC] -0.82 [P=0.004] and LFC -0.36 [P=0.007], respectively), while Eubacterium siraeum decreased only in the SOC cohort (LFC -1.75 [P=0.005]). The Firmicutes/Bacteroidetes ratio increased from 89.0% to 96.4% in the SOC cohort, whereas a notable decrease was observed in this ratio from 100.0% to 75.7%. in the SOC/CBM cohort. Conclusions CBM588 leads to a marked correction of gut dysbiosis and prevents the depletion of species previously associated with ICI response (i.e., Eubacterium siraeum). These findings provide a plausible mechanism for the enhanced clinical outcome with CBM588 now seen across two small, randomized trials. A phase III study is planned within the cooperative groups to evaluate the clinical activity and gut microbiome modulation capacity of CBM588 in combination with ICIs in mRCC.

Background Vaccinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have had a transformative impact on morbidity and mortality. However, the long-term impact of vaccination on patients with genitourinary cancers is currently unknown. Materials and Methods This study aimed to assess seroconversion rates in patients with genitourinary cancers receiving COVID-19 vaccination. Patients with prostate cancer, renal cell carcinoma, or urothelial cancer who had not been vaccinated for COVID-19 were included. Blood samples were obtained at baseline and after 2, 6, and 12 months of one dose of an FDA-approved COVID-19 vaccine. Antibody titer analysis was performed using the SCoV-2 Detect IgG ELISA assay, and the results were reported as immune status ratio (ISR). A paired t-test was used for comparison of ISR values between timepoints. In addition, T-cell receptor (TCR) sequencing was performed to assess for differences in TCR repertoire 2 months after vaccination. Results Out of 133 patients enrolled, 98 baseline blood samples were collected. At 2-, 6-, and 12-month time points 98, 70, and 50 samples were collected, respectively. Median age was 67 (IQR, 62-75), with the majority of patients diagnosed with prostate (55.1%) or renal cell carcinoma (41.8%). Compared to baseline (0.24 [95% CI, 0.19-0.31]) a significant increase in the geometric mean ISR values was observed at the 2-month timepoint (5.59 [4.76-6.55]) (P < .001). However, at the 6-month timepoint, a significant decrease in the ISR values was observed (4.66 [95% CI, 4.04-5.38]; P < .0001). Notably, at the 12-month timepoint, the addition of a booster dose resulted in an absolute increase in the ISR values compared to those who did not receive a booster dose (P = .04). Conclusions Only a minority of patients with genitourinary cancers did not ultimately achieve satisfactory seroconversion after receiving commercial COVID-19 vaccination. Cancer type or treatment rendered did not appear to affect the immune response mounted after vaccination. The long-term effect of vaccination against SARS-CoV-2 on patients with genitourinary cancers is currently unknown. This study assessed the long-term effect of commercially available COVID-19 vaccination in patients with renal cell carcinoma, urothelial carcinoma, and prostate cancer.

Abstract Background Patients with metastatic renal cell carcinoma (mRCC) experience emotional distress and limited supportive care access. This study assesses a mindfulness app’s feasibility, acceptability, and preliminary efficacy in improving emotional symptoms, trait mindfulness, and overall quality of life for patients with mRCC on immunotherapy. Methods This multinational study recruited patients with mRCC undergoing immunotherapy from Brazil and the United States. Participants were required to engage in mindfulness app-based activities for 20–30 min daily, at least 4 days per week, over a 4-week period. Assessments were conducted at weeks 0, 2, 4, and 12 to evaluate emotional symptoms (PROMIS-Anxiety and Depression, Fear of Cancer Recurrence-7), fatigue (Brief Fatigue Inventory), trait mindfulness (Mindfulness Attention Awareness Scale), and quality of life (Functional Assessment of Chronic Illness Therapy-General). Self-reported data were used to assess adherence. Linear mixed-effects models were used to evaluate changes over time for the measured outcomes. Results Among 50 patients with mRCC, the feasibility of this intervention was demonstrated; 96% of patients were assessed at week 4, with high adherence rates reported by 75% of patients. Participants expressed positive feedback on the smartphone-based approach. Significant improvements were observed in emotional symptoms, fatigue, and quality of life scores from baseline to post-intervention (P = .001 for each), suggesting the positive impact of this intervention. Conclusion Our findings provide encouraging evidence for the feasibility and acceptability of a mindfulness app-based intervention among patients with mRCC. This intervention may offer a viable and accessible means of providing psychosocial support to patients with mRCC.

Many patients diagnosed with cancer adopt dietary changes and supplement use, and a growing body of evidence suggests that such modifications can affect outcomes to cancer therapy. We sought to assess the prevalence of these practices and the surrounding physician-patient dialogue among patients with metastatic renal cell carcinoma. An online survey was administered by Kidney Cancer Research Alliance (KCCure), interrogating dietary modification patterns, supplement usage, out-of-pocket expenditure related to supplements, and patients’ views toward alternative medicine practices. Patients with metastatic renal cell carcinoma receiving combination therapy were actively solicited. In total, 289 unique responses were collected. The most common first-line treatments were nivolumab/ipilimumab (32.4%) and axitinib/pembrolizumab (13.1%). Within the cohort, 147 (50.9%) started using supplements following diagnosis of renal cell carcinoma; the most utilized supplements were probiotics, cannabidiol (CBD) oil/marijuana, and Vitamin C, reported by 70 (47.6%), 61 (41.4%), and 54 (36.7%), respectively. Dietary modifications following cancer diagnosis were reported by 101 (34.9%) respondents, of which 19.8% followed the Mediterranean diet and 18.8% adopted a ketogenic diet. Most respondents (71.3%) noted that they consistently report supplement usage to their physicians. A substantial proportion of patients with metastatic renal cell carcinoma utilize dietary modification and supplements as an adjunct to antineoplastic therapy. Considering the widespread adoption of these practices and the reported effects on cancer treatment, it is crucial for healthcare providers to engage in discussions with patients regarding supplement use.