T-Cell redirecting bispecific antibodies: a review of a novel class of immuno-oncology for advanced prostate cancer.

Novel T-cell immunotherapies such as bispecific T-cell engagers (BiTEs) are emerging as promising therapeutic strategies for prostate cancer. BiTEs are engineered bispecific antibodies containing two distinct binding domains that allow for concurrent binding to tumor-associated antigens (TAAs) as well as immune effector cells, thus promoting an immune response against cancer cells. Prostate cancer is rich in tumor associated antigens such as, but not limited to, PSMA, PSCA, hK2, and STEAP1 and there is strong biologic rationale for employment of T-cell redirecting BiTEs within the prostate cancer disease space. Early generation BiTE constructs employed in clinical study have demonstrated meaningful antitumor activity, but challenges related to drug delivery, immunogenicity, and treatment-associated adverse effects limited their success. The ongoing development of novel BiTE constructs continues to address these barriers and to yield promising results in terms of efficacy and safety. This review will highlight some of most recent developments of BiTE therapies for patients with advanced prostate cancer and the evolving data surrounding BiTE constructs undergoing clinical evaluation.

Predictive and Prognostic Biomarkers and Tumor Antigens for Targeted Therapy in Urothelial Carcinoma.

Urothelial carcinoma (UC) is the fourth most prevalent cancer amongst males worldwide. While patients with non-muscle-invasive disease have a favorable prognosis, 25% of UC patients present with locally advanced disease which is associated with a 10-15% 5-year survival rate and poor overall prognosis. Muscle-invasive bladder cancer (MIBC) is associated with about 50% 5 year survival when treated by radical cystectomy or trimodality therapy; stage IV disease is associated with 10-15% 5 year survival. Current therapeutic modalities for MIBC include neoadjuvant chemotherapy, surgery and/or chemoradiation, although patients with relapsed or refractory disease have a poor prognosis. However, the rapid success of immuno-oncology in various hematologic and solid malignancies offers new targets with tremendous therapeutic potential in UC. Historically, there were no predictive biomarkers to guide the clinical management and treatment of UC, and biomarker development was an unmet need. However, recent and ongoing clinical trials have identified several promising tumor biomarkers that have the potential to serve as predictive or prognostic tools in UC. This review provides a comprehensive summary of emerging biomarkers and molecular tumor targets including programmed death ligand 1 (PD-L1), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor (FGFR), DNA damage response and repair (DDR) mutations, poly (ADP-ribose) polymerase (PARP) expression and circulating tumor DNA (ctDNA), as well as their clinical utility in UC. We also evaluate recent advancements in precision oncology in UC, while illustrating limiting factors and challenges related to the clinical application of these biomarkers in clinical practice.

Natural Killer Cell Infiltration in Prostate Cancers Predict Improved Patient Outcomes.

BACKGROUND: Natural killer (NK) cells are non-antigen specific innate immune cells that can be redirected to targets of interest using multiple strategies, although none are currently FDA-approved. We sought to evaluate NK cell infiltration into tumors to develop an improved understanding of which histologies may be most amenable to NK cell-based therapies currently in the developmental pipeline. METHODS: DNA (targeted/whole-exome) and RNA (whole-transcriptome) sequencing was performed from tumors from 45 cancer types (N = 90,916 for all cancers and N = 3365 for prostate cancer) submitted to Caris Life Sciences. NK cell fractions and immune deconvolution were inferred from RNA-seq data using quanTIseq. Real-world overall survival (OS) and treatment status was determined and Kaplan-Meier estimates were calculated. Statistical significance was determined using X2 and Mann-Whitney U tests, with corrections for multiple comparisons where appropriate. RESULTS: In both a pan-tumor and prostate cancer (PCa) -specific setting, we demonstrated that NK cells represent a substantial proportion of the total cellular infiltrate (median range 2-9% for all tumors). Higher NK cell infiltration was associated with improved OS in 28 of 45 cancer types, including (PCa). NK cell infiltration was negatively correlated with common driver mutations and androgen receptor variants (AR-V7) in primary prostate biopsies, while positively correlated with negative immune regulators. Higher levels of NK cell infiltration were associated with patterns consistent with a compensatory anti-inflammatory response. CONCLUSIONS: Using the largest available dataset to date, we demonstrated that NK cells infiltrate a broad range of tumors, including both primary and metastatic PCa. NK cell infiltration is associated with improved PCa patient outcomes. This study demonstrates that NK cells are capable of trafficking to both primary and metastatic PCa and are a viable option for immunotherapy approaches moving forward. Future development of strategies to enhance tumor-infiltrating NK cell-mediated cytolytic activity and activation while limiting inhibitory pathways will be key.

Therapy With Metronomic Cyclophosphamide (mCyc) for Previously-Treated Metastatic Castrate-Resistant Prostate Cancer (mCRPC).

INTRODUCTION: Despite the introduction of various novel therapies for management of metastatic castrate resistant prostate cancer (mCRPC) in recent decades, available treatment options are finite and remain limited. Multiple historical studies have demonstrated activity and a favorable toxicity profile of oral metronomic cyclophosphamide (mCyc) in prostate cancer (PCa). Unlike the cytotoxic immunosuppressive effects of high-dose intravenously-administered cyclophosphamide, continuous low doses of oral mCyc have a unique immune-stimulatory mechanism of action. MATERIALS AND METHODS: This is a retrospective, multi-institution study of men with 43 patients with mCRPC treated mCyc. Patient demographic information as well as clinical, pathologic, and genomic characteristics of their PCa were extracted. The primary endpoint was the rate of PSA decline by ≥ 50% (ie, PSA50). Additional efficacy and toxicity data as well as cost analysis compared to other commonly used agents in mCRPC was obtained. RESULTS: PSA50 was noted in 20.9% of patients, while an additional 25.6% patients achieved < PSA50 and 6.9% reported improvement in prostate cancer-related symptoms without any PSA reduction. Meanwhile, 9.3% of patients required mCyc dose reduction, 11.6% needed dose interruption due to toxicity, and no treatment discontinuations due to toxicity were observed. mCyc was also cost effective compared to other agents commonly used in mCRPC. CONCLUSIONS: Despite the small sample size and retrospective nature of this dataset, mCyc demonstrated promising rapid activity and a tolerable toxicity profile in a heavily pretreated mCRPC population with aggressive clinical, pathologic, and genomic disease features.

Bispecific PSMA antibodies and CAR-T in metastatic castration-resistant prostate cancer.

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related deaths in men in the United States. The treatment paradigm for prostate cancer has evolved with the emergence of a variety of novel therapies which have improved survival; however, treatment-related toxicities are abundant and durable responses remain rare. Immune checkpoint inhibitors have shown modest activity in a small subset of patients with prostate cancer and have not had an impact on most men with advanced disease. The discovery of prostate-specific membrane antigen (PSMA) and the understanding of its specificity to prostate cancer has identified it as an ideal tumor-associated antigen and has revived the enthusiasm for immunotherapeutics in prostate cancer. T-cell immunotherapy in the form of bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapy have shown exceptional success in treating various hematologic malignancies, and are now being tested in patients with prostate cancer with drug design centered on various target ligands including not just PSMA, but others as well including six-transmembrane epithelial antigen of the prostate 1 (STEAP1) and prostate stem cell antigen (PSCA). This summative review will focus on the data surrounding PSMA-targeting T-cell therapies. Early clinical studies with both classes of T-cell redirecting therapies have demonstrated antitumor activity; however, there are multiple challenges with this class of agents, including dose-limiting toxicity, 'on-target, off-tumor' immune-related toxicity, and difficulty in maintaining sustained immune responses within a complex and overtly immunosuppressive tumor microenvironment. Reflecting on experiences from recent trials has been key toward understanding mechanisms of immune escape and limitations in developing these drugs in prostate cancer. Newer generation BiTE and CAR T-cell constructs, either alone or as part of combination therapy, are currently under investigation with modifications in drug design to overcome these barriers. Ongoing innovation in drug development will likely foster successful implementation of T-cell immunotherapy bringing transformational change to the treatment of prostate cancer.

New therapies utilizing T-cell immunotherapy for patients with metastatic prostate cancer There are ongoing developments in therapeutic strategies for the treatment of patients with metastatic castrate-resistant prostate cancer. Many of these developments involve the activation of the immune system to target neoplastic prostate cells and tumors. Conventional immunotherapy modalities such as checkpoint inhibitors did not provide robust response in clinical study to warrant a change to the prostate cancer treatment paradigm. However, we are now seeing various agents in the form of bispecific antibodies and chimeric antigen receptor's which influence T-cell activity and are leading to interesting and promising pre-clinical and clinical results. This review article highlights the biologic rationale for employment of T-cell redirecting therapies for the treatment of prostate cancer, and reviews much of the exciting data emerging within the field.

Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer.

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors' immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. Considering that immunotherapy has shown modest results in advanced prostate cancer to date, we review the biologic rationale and promising results of BiTE therapy in this clinical setting and discuss potential tumor-associated antigens that may be integrated into BiTE construct designs. Our review also aims to evaluate the advances of BiTE therapies in prostate cancer, illustrate the major obstacles and underlying limitations, and discuss directions for future research.

Comparative Effectiveness of Front-Line Ipilimumab and Nivolumab or Axitinib and Pembrolizumab in Metastatic Clear Cell Renal Cell Carcinoma.

BACKGROUND: Treatment of metastatic renal cell carcinoma (mRCC) is rapidly evolving with new combination therapies demonstrating improved response rates and survival. There are no head-to-head prospective trials comparing an immunotherapy doublet with an immunotherapy/tyrosine-kinase inhibitor-based combination. We compare real-world outcomes in patients treated with axitinib/pembrolizumab (axi/pembro) or ipilimumab/nivolumab (ipi/nivo). The primary endpoints were overall-survival (OS) and real-world progression-free survival (rwPFS). PATIENTS AND METHODS: We used a de-identified database to select patients diagnosed with clear cell mRCC and treated with front-line axi/pembro or ipi/nivo from 2018 to 2022. Analyses are adjusted using propensity score-based inverse probability of treatment weighting, balancing age, gender, insurance, race, IMDC risk, and nephrectomy status. We compared survival by treatment groups using weighted and unweighted Kaplan-Meier curves with log-rank tests and weighted Cox proportional hazards regressions. RESULTS: We included a total of 1506 patients with mRCC who received frontline axi/pembro (n = 547) or ipi/nivo (n = 959). Median follow-up time was 20.0 months (range: 0.2-47.6). Baseline demographics were similar between the 2 cohorts. Adjusted median OS for the full population was 28.9 months for axi/pembro and was 24.3 months for ipi/nivo (P = .09). Twenty-four-month survival was 53.8% for axi/pembro treated patients and 50.2% for ipi/nivo treated patients. rwPFS was 10.6 months for axi/pembro treated patients and 6.9 months for ipi/nivo treated patients. Treatment with axi/pembro conferred improved survival in the IMDC favorable risk strata, with no significant difference in survival observed within the full cohort. CONCLUSIONS: In this retrospective, real-world study of patients treated with front-line combination therapy, patients with IMDC favorable risk disease had better survival when treated with axi/pembro compared to ipi/nivo. However, survival for the entire population and the 24-month median overall survival were not statistically different between treatment groups. Longer follow-up is necessary to discern any emerging significant differences.

Determining Front-Line Therapeutic Strategy for Metastatic Clear Cell Renal Cell Carcinoma.

The therapeutic landscape for metastatic renal cell carcinoma has rapidly evolved over the years, and we are now in an era of combination therapy strategies employing immune checkpoint blockade and anti-angiogenesis targeted therapy. Since 2018, we have gained regulatory approval for four distinct combination therapies, all with survival benefits, and with guideline recommendation for use in the front-line setting. As such, treatment selection has become increasingly complex with a myriad of treatment choices but little high-level head-to-head data to guide treatment selection. Heterogeneity in tumor biology further complicates treatment selection as tumors vary in behavior and treatment responsiveness. Ongoing development of biomarkers will certainly assist in this setting, and validation of predictive markers represents an unmet need. In their absence, we highlight features of disease and nuances to datasets from landmark prospective clinical trials to help inform treatment selection. There is growing evidence to support deferring upfront systemic therapy in some patients, with opportunities for active surveillance or metastasis-directed therapy. In others, upfront systemic therapy is warranted and necessitates thoughtful consideration of multiple clinicopathologic parameters to inform optimal patient-centered decision making.

Assessing plasma circulating tumor human papillomavirus (HPV) DNA in determining treatment response in HPV-associated oropharyngeal cancer.

BACKGROUND: Human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma is a subset of head and neck cancer with a unique mechanism of carcinogenesis. Local disease is treated definitively with a multimodal approach. Navigating recurrences can be challenging, as they are sometimes indiscernible from de novo primary malignancies. Identification of dynamic biomarkers that are specific to HPV-mediated disease may assist in disease monitoring. We present a 78-year-old man who developed a squamous cell carcinoma in the lung 7 years after completing definitive chemoradiation for his p16+ head and neck squamous cell carcinoma. METHODS: A novel assay for plasma circulating tumor HPV DNA was employed and provided a tool for longitudinal disease monitoring during therapy. CONCLUSION: We bring attention to a novel assay and highlight its potential for use in the treatment paradigm of HPV-mediated oropharyngeal carcinoma.