Antibody-Based Therapeutics for the Treatment of Renal Cell Carcinoma: Challenges and Opportunities.

Renal cell carcinoma (RCC) is among the top 10 most common cancers in both men and women with an estimated 75 000 cases each year in the US. Over the last decade, the therapeutic landscape for patients with metastatic RCC has significantly evolved, with immunotherapy emerging as the new front-line therapy. Despite significant improvement in toxicity profile and survival outcomes, key concerns such as patient selection, treatment sequencing, and intrinsic and acquired resistance remain unresolved. Emerging options such as antibody-based therapeutics (eg, anti-CD70, anti-CA9, and anti-ENPP3) are being explored in clinical trials for patients with cancer resistant or refractory to current immunotherapies. Despite positive results for hematological cancers, breast cancer, and more recently bladder cancer, most antibody-based therapies failed to improve the outcomes in patients with advanced RCC. This underscores the need to understand the underlying causes of failed responses to this treatment class, which will ultimately support the rational design of more effective and tolerable treatments. In this review, we summarize the evolving landscape of RCC therapeutics and describe recent clinical trials with emerging antibody-based therapeutics. We also describe the challenges that need to be overcome for the successful creation of therapeutic antibodies for treating RCC.

Circulating antigen-primed cytotoxic T-cells in patients with renal tumors treated with surgery.

INTRODUCTION: Systemic immunotherapy has changed the paradigm of treatment of advanced renal cell carcinoma, but nephrectomy continues to benefit selected patients. While we continue to identify mechanisms behind drug resistance, the effect of surgery on natural anti-tumor immunity is poorly understood. Specifically, peripheral blood mononuclear cell (PBMC) profile and tumor reactive cytotoxic T lymphocytes changes secondary to tumor resection have not been extensively characterized. Hence, we aimed to evaluate the effect of nephrectomy on PMBC profile and circulating antigen-primed CD8+ T-cells for patients undergoing solid renal mass resection. METHODS: Patients with localized or metastatic solid renal masses who underwent nephrectomy from 2016 to 2018 were enrolled. Blood samples were collected at 3 timepoints for PBMCs analysis (pre-op, 1 day, and 3 months post-op). Flow cytometry was used to identify CD11ahigh CD8+ T lymphocytes that were then further characterized according to the expression of CX3CR1/GZMB, Ki67, Bim, and PD-1. Changes in circulating CD8+ T-cells from pre-op to 1 day and 3 months post-op were evaluated using Wilcoxon signed rank tests. RESULTS: Antigen-primed CX3CR1+GZMB+ T-cells significantly increased by 3 months after surgery among patients with RCC (0.8 × 109 cells; P = 0.01). In contrast, there was a decrease in absolute numbers of Bim+ T-cells at 3 months (-1.9 × 109 cells; P = 0.02). There were no significant absolute changes in PD-1+ (-1.4 × 109; P = 0.7) and CD11ahigh CD8+ T lymphocytes (1.3 × 109; P = 0.9). Ki67+ T-cells decreased by 3 months (-0.8 × 109; P < 0.001). CONCLUSIONS: Nephrectomy is associated with an increase in cytolytic antigen-primed CD8+ T-cells and specific PBMC profile changes. Further studies are warranted to ascertain the role surgery may have in the restoration of anti-tumor immunity.

Cutaneous Ureterostomy Following Radical Cystectomy for Bladder Cancer: A Contemporary Series.

OBJECTIVE: To report peri-operative outcomes of a contemporary series of bladder cancer patients undergoing radical cystectomy (RC) with cutaneous ureterostomy (CU) urinary diversion at a tertiary referral center. METHODS: We retrospectively identified patients who underwent RC with CU at Mayo Clinic between 2016 and 2021. Clinicopathologic and perioperative characteristics were analyzed using standard descriptive statistics. RESULTS: A total of 31 patients underwent RC with CU at our institution. Median age was 72years and 21 were male. This was highly comorbid cohort (83% had an American Society of Anesthesiologists [ASA] Physical Status Classification System ≥3; median Charlson Comorbidity index= 8). Median time to flatus, tolerating regular diet, and length of stay were 3 (interquartile range [IQR] 3-3), 3 (IQR 3-4), and 4days (IQR 4-7), respectively. A total of 14 patients experienced a high-grade complication (Clavien-Dindo ≥3) within 30days of surgery, and 8 were readmitted. The most common 30-day complication was sepsis, which affected 13% (4/31) of patients. At 90days postsurgery, the readmission rate was 32% (10/31), most commonly for sepsis. Three patients required reoperation within 90days, including one patient who required CU revision due to stomal ischemia. One patient died within this time frame from causes unrelated to bladder cancer. CONCLUSION: In a comorbid, relatively elderly bladder cancer cohort undergoing RC, the use of CU was associated with expeditious surgery and postoperative recovery. CU represents an option for urinary diversion in high-risk patients undergoing RC. Higher rate of postoperative ureteral obstruction can be pre-emptively addressed with chronic stent placement.

Relative impact of lymph-node metastasis and seminal vesical invasion on oncologic outcomes following radical prostatectomy.

BACKGROUND: While both seminal vesicle (SVI) and lymph-node invasion (LNI) have been identified as adverse prognostic variables among men undergoing radical prostatectomy (RP), the relative impact of each of these features on subsequent oncologic outcomes has not been well defined. We assessed the impact of LNI on long-term oncologic outcomes among patients with SVI at RP. METHODS: We reviewed 19,519 patients who underwent RP and identified 2043 with SVI. Metastasis-free (MFS), cancer-specific (CSS), and overall survival (OS) were estimated for patients with SVI, stratified by the presence and number of pelvic lymph node metastases. Cox proportional hazards models were used to evaluate the independent association of the number of metastatic nodes and lymph node density with oncologic outcomes among patients with SVI, controlling for age, year of surgery, margin status, preoperative PSA, pathologic Gleason score, extraprostatic extension, and use of adjuvant therapies. RESULTS: At a median follow up of 12.1 years (IQR 7.0,18.6), 548 patients developed metastatic disease and 1331 died, including 406 who died from prostate cancer (PCa). We found that, among patients with SVI, the presence of a single positive lymph node was not associated with incrementally adverse oncologic outcomes compared to no nodal metastasis at RP, with 10-year MFS, CSS, and OS rates of 81.3% versus 78.3%(p = 0.18), 86.5% versus 89.8%(p = 0.32), and 72.8% versus 76.7%(p = 0.53), respectively. In contrast, on multivariable analyses, the presence of ≥2 metastatic nodes and a 20% lymph-node density cut off remained independently associated with worse survival. CONCLUSIONS: SVI represents an adverse pathologic feature such that the presence of a single positive pelvic lymph node did not further adversely impact prognosis. Meanwhile, a significant number of involved nodes was associated with decreased survival. These findings may aid in risk-stratification as well as clinical trial design for such high-risk patients following surgery.

Extrarenal, Soft Tissue Malignant Rhabdoid Tumor Arising in the Mons Pubis.

Extrarenal, extracranial malignant rhabdoid tumors (MRT) are uncommon malignancies with poor prognoses that may be diagnostically challenging. Reports of soft tissue MRTs in children are rare. For this reason, there are no standard treatment protocols. Historically, an aggressive multimodal approach has been taken. Here, we present a case of metastatic superficial pelvic MRT in a 16-year-old girl who remains disease-free after aggressive multi-modal therapy.

Boosting immune response with GM-CSF optimizes primary cryotherapy outcomes in the treatment of prostate cancer: a prospective randomized clinical trial.

OBJECTIVE: We explored the association of prostate cryotherapy and immunomodulation with granulocyte-macrophage colony-stimulating factor (GMCSF) in the generation of detectable tumor-specific T- and B-cell responses in men with prostate cancer. MATERIALS AND METHODS: A randomized pilot study of patients assigned to either cryotherapy alone (Control group) or in combination with GMCSF (Treatment group). The impact of therapy on the development of T- and B-cell responses against tumor-related antigens was studied using enzyme-linked immune absorbent spot (ELISpot) and protein microarray panels (Sematrix) assays, respectively. Fold changes in response to treatment were calculated by normalization of post-treatment ELISpot values against the mean pre-cryoablation response. Student t tests between treatment and control groups at 4 weeks and 12 weeks across all the antigens were performed. RESULTS: A total of 20 patients were randomized to either control or treatment arm. At 4 weeks after cryotherapy, the treatment group demonstrated an average fold change in cancer antigen-related antibodies of 2.8% above their mean baseline values, whereas controls averaged an 18% change below mean baseline (p < 0.05). At 12 weeks, antibody response in treatment group increased to 25% above baseline, while the average of control group patients remained 9% below baseline (p < 0.05). Patients in treatment group displayed, on average, higher ELISPOT readings for the 4- and 12-week times points (527 vs 481 for PSA and 748 vs 562 for PAP). CONCLUSIONS: GMCSF appeared to broadly elevate antibodies against prostate-specific and nonspecific antigens. Prostate antigen-specific T-cell responses were more enhanced over non-prostate-specific responses, preferentially in the treatment group. Our findings suggest a possible therapeutic effect of adjuvant immunotherapy in association with cryotherapy for the treatment of prostate cancer.

Systematic review and meta-analysis of radiation therapy for high-risk non-muscle invasive bladder cancer.

INTRODUCTION: Radiation therapy (XRT) has been investigated as a possible treatment for high-risk non-muscle invasive bladder cancer (NMIBC) with the goal of bladder preservation, especially with the ongoing Bacillus Calmette-Guerin (BCG) shortage. Yet, little is known about the clinical efficacy and the quality of evidence supporting XRT for NMIBC. Herein, we performed a systematic review and meta-analysis to evaluate XRT in the treatment of patients with high-risk NMIBC. METHODS: Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and Web of Science were searched for high-risk NMIBC (high grade T1, T1/Ta with associated risk features: carcinoma in-situ (CIS), multifocality, > 5cm in diameter, and/or multiple recurrences) treated with primary XRT. Outcomes evaluated were recurrence-free survival (RFS), cancer-specific-survival (CSS), overall survival (OS), and salvage cystectomy and progression to metastatic disease rates. A meta-analysis was performed to assess outcomes for XRT in NMIBC. RESULTS: Overall,13 studies including 746 patients met the search criteria. The 5-year rates of RFS, CSS and OS were 54% (95% CI = 38% - 70%), 86% (95% CI = 80% - 92%), and 72% (95% CI = 64% - 79%). Notably, 13% of patients proceeded to salvage radical cystectomy and 9% developed metastatic disease. All studies were of poor quality, comprising single institution and retrospective studies with only one clinical trial. CONCLUSION: XRT for high-risk NMIBC provides some degree of oncologic control, although distant progression was noted. In the setting of the low-quality evidence, a prospective clinical trial is needed to clearly define the risks and benefits of this approach.

National trends in clinical and pathologic staging for upper tract urothelial carcinoma: Implications for neoadjuvant chemotherapy.

INTRODUCTION: With growing support of perioperative chemotherapy for upper tract urothelial carcinoma (UTUC), current biopsy methods are challenging, and little is known as to the degree to which patients would appropriately receive neoadjuvant chemotherapy (NAC) from biopsy alone. Herein, we sought to assess the rates of appropriate clinical use of NAC and identify clinicopathologic factors associated with aggressive UTUC amongst patients undergoing radical nephroureterectomy (RNU) for clinically localized disease. METHODS: From 2004 to 2013, we identified all treatment naïve patients diagnosed with clinically localized, high grade UTUC (cTa-4Nx) who underwent RNU from the National Cancer Database (NCDB). Pathologic criteria for NAC (pT2-4N0,x; pTanyN1) from RNU represented the primary outcome. Bivariate and multivariable analyses were utilized to identify covariates associated with primary outcome to determine appropriate use of NAC. RESULTS: During the study interval, 5,362 patients were diagnosed with clinically localized UTUC and underwent RNU. Overall, 49.1% of patients presented with an unknown primary tumor stage (Tx) and 24.5% had invasive UTUC from biopsy. On multivariable analysis, upper tract tumor size was associated with invasive UTUC eligible for NAC (all P < 0.05). Amongst patients with cTx UTUC from biopsy, half of patients had pathologic noninvasive UTUC (pTa,is,1) from RNU and would be overtreated with NAC. CONCLUSION: Significant uncertainty persists in assigning primary upper tract tumor depth and represents a key barrier to widespread implementation of NAC for patients with high grade UTUC. Further research is needed to more accurately determine clinical criteria to identify patients for NAC.

Enhanced recovery after surgery review and urology applications in 2020.

Purpose: To explore enhanced recovery after surgery (ERAS) components and their current application to major urologic surgeries, barriers to implementation and maintenance of the associated quality improvement. Data Identification: An English language literature search was done using PubMed. Study Selection: After independent review, 55 of the original 214 articles were selected to specifically address the stated purpose. Data Extraction: Clinical trials were included, randomized trials were prioritized, but robust observational studies were also included. Results of Data Synthesis: Many ERAS components have good data to support usage in radical cystectomy (RC) patients. Most ERAS programs include multidisciplinary teams carrying out multimodal pathways to hasten recovery after a major operation. ERAS components generally include preoperative counseling and medical optimization, venous thromboembolism prophylaxis, ileus prevention, avoidance of fluid overload, normothermia maintenance, early mobilization, pain control and early feeding, all leading to early discharge without increased complications or readmissions. Although there may not be specific data pertaining to other major urologic operations, the principles remain similar and ERAS is easily applicable. Conclusion: The benefits of ERAS programs are well established for RC and principles are easily applicable to other major urology operations. Barriers to implantation and maintenance of ERAS must be recognized to continue to maintain the benefits of these programs.