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Prostate cancer is currently one of the most common malignancies that endanger the lives and health of elderly men. In recent years, immunotherapy, which exploits the activation of anti-cancer host immune cells to accomplish tumor-killing effects, has emerged as a new study avenue in the treatment of prostate cancer. As an important component of immunotherapy, cancer vaccines have a unique position in the precision treatment of malignant tumors. Monocyte cell vaccines, dendritic cell vaccines, viral vaccines, peptide vaccines, and DNA/mRNA vaccines are the most often used prostate cancer vaccines. Among them, Sipuleucel-T, as a monocyte cell-based cancer vaccine, is the only FDA-approved therapeutic vaccine for prostate cancer, and has a unique position and role in advancing the development of immunotherapy for prostate cancer. However, due to its own limitations, Sipuleucel-T has not been widely adopted. Meanwhile, owing to the complexity of immunotherapy and the specificity of prostate cancer, the remaining prostate cancer vaccines have not shown good clinical benefit in large randomized phase II and phase III trials, and further in-depth studies are still needed.

Modeling the effect of immunotherapies on human castration-resistant prostate cancer.

In this paper we analyze the potential effect of immunotherapies on castration-resistant form of human Prostate Cancer (PCa). In particular, we examine the potential effect of the dendritic vaccine sipuleucel-T, the only currently available immunotherapy option for advanced PCa, and of ipilimumab, a drug targeting the Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), exposed on the CTLs membrane, currently under Phase II clinical trial. The model, building on the one by Rutter and Kuang, includes different types of immune cells and interactions and is parameterized on available data. Our results show that the vaccine has only a very limited effect on PCa, while repeated treatments with ipilimumab appear potentially capable of controlling and even eradicating an androgen-independent prostate cancer. From a mathematical analysis of a simplified model, it seems likely that, under continuous administration of ipilimumab, the system lies in a bistable situation where both the no-tumor equilibrium and the high-tumor equilibrium are attractive. The schedule of periodic treatments could then determine the outcome, and mathematical models could help determine an optimal schedule.

Dendritic cell vaccine therapy for colorectal cancer.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the United States despite an array of available treatment options. Current standard-of-care interventions for this malignancy include surgical resection, chemotherapy, and targeted therapies depending on the disease stage. Specifically, infusion of anti-vascular endothelial growth factor agents in combination with chemotherapy was an important development in improving the survival of patients with advanced colorectal cancer, while also helping give rise to other forms of anti-angiogenic therapies. Yet, one approach by which tumor angiogenesis may be further disrupted is through the administration of a dendritic cell (DC) vaccine targeting tumor-derived blood vessels, leading to cytotoxic immune responses that decrease tumor growth and synergize with other systemic therapies. Early generations of such vaccines exhibited protection against various forms of cancer in pre-clinical models, but clinical results have historically been disappointing. Sipuleucel-T (Provenge®) was the first, and to-date, only dendritic cell-based therapy to receive FDA approval after significantly increasing overall survival in prostate cancer patients. The unparalleled success of Sipuleucel-T has helped revitalize the clinical development of dendritic cell vaccines, which will be examined in this review. We also highlight the promise of these vaccines to instill anti-angiogenic immunity for individuals with advanced colorectal cancer.

Racial Disparity in Response to Prostate Cancer Systemic Therapies.

PURPOSE OF REVIEW: In this review, we aim to describe racial differences in response to treatment for metastatic castration-resistant prostate cancer (mCRPC). RECENT FINDINGS: Recent data suggests that, despite higher risk features, African Americans may respond better than Caucasians to systemic therapies for advanced prostate cancer. This improved response is not limited to one class of drugs but can be seen with androgen-pathway directed therapies, chemotherapy, bone-targeted therapy, and immunotherapy. The mechanisms for this are being further explored. African Americans may respond better to mCRPC treatments but validation in prospective clinical trials is needed.

Immunotherapy in Prostate Cancer: Teaching an Old Dog New Tricks.

Immunotherapy is rapidly transforming cancer care across a range of tumor types. Although Sipuleucel-T represented the first successful vaccine for the treatment of established cancer, other immunotherapeutic approaches for prostate cancer such as checkpoint inhibitors have been relatively disappointing to date. However, significant promise is on the horizon as there is a wide array trials evaluating immunotherapy in prostate cancer patients. These include both immune checkpoint inhibitors and antigen-specific approaches including vaccines, antibody-drug conjugates, and antitumor antibodies. Furthermore, a better understanding of the key mechanisms that promote the immunosuppressive microenvironment of prostate cancer is emerging. These insights may eventually make it possible to determine which patients will benefit from immunotherapy. This review will discuss the successes and failures of immunotherapy in prostate cancer. We will also present key lessons learned from completed trials and highlight important ongoing studies.

Sipuleucel-T for the treatment of prostate cancer: novel insights and future directions.

Sipuleucel-T, an autologous cellular immunotherapy manufactured from antigen-presenting cells primed to recognize prostatic acid phosphatase, was the first immunotherapy product approved by the US FDA. It was approved for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer after it was shown to provide a survival advantage. Additional studies have examined its use in other clinical settings and in combination with other approved and investigational immunotherapy agents. This review will discuss the pivotal trials leading to approval, will outline some of the biomarkers associated with its efficacy and will review some of the ongoing combination strategies. Maximizing the efficacy of sipuleucel-T through better patient selection or through combination approaches remains the challenge of the future.

Immunotherapy in metastatic prostate cancer.

INTRODUCTION: Prostate cancer remains a challenge as a target for immunological approaches. The approval of the first cell-based immune therapy, Sipuleucel-T for prostate cancer introduced prostate cancer as a solid tumor with the potential to be influenced by the immune system. METHODS: We reviewed articles on immunological management of prostate cancer and challenges that lie ahead for such strategies. RESULTS: Treatments have focused on the identification of novel cell surface antigens thought to be unique to prostate cancer. These include vaccines against carbohydrate and blood group antigens, xenogeneic and naked DNA vaccines, and pox viruses used as prime-boost or checkpoint inhibitors. No single vaccine construct to date has resulted in a dramatic antitumor effect. The checkpoint inhibitor, anti-CTLA-4 has resulted in several long-term remissions, but phase III trials have not demonstrated an antitumor effect or survival benefit. CONCLUSIONS: Multiple clinical trials suggest that prostate cancer may not be optimally treated by single agent immune therapies and that combination with biologic agents, chemotherapies, or radiation may offer some enhancement of benefit.

Recent advancement in targeted therapy and role of emerging technologies to treat cancer.

Cancer is a complex disease that causes abnormal cell growth and spread. DNA mutations, chemical or environmental exposure, viral infections, chronic inflammation, hormone abnormalities, etc., are underlying factors that can cause cancer. Drug resistance and toxicity complicate cancer treatment. Additionally, the variability of cancer makes it difficult to establish universal treatment guidelines. Next-generation sequencing has made genetic testing inexpensive. This uncovers genetic mutations that can be treated with specialty drugs. AI (artificial intelligence), machine learning, biopsy, next-generation sequencing, and digital pathology provide personalized cancer treatment. This allows for patient-specific biological targets and cancer treatment. Monoclonal antibodies, CAR-T, and cancer vaccines are promising cancer treatments. Recent trial data incorporating these therapies have shown superiority in clinical outcomes and drug tolerability over conventional chemotherapies. Combinations of these therapies with new technology can change cancer treatment and help many. This review discusses the development and challenges of targeted therapies like monoclonal antibodies (mAbs), bispecific antibodies (BsAbs), bispecific T cell engagers (BiTEs), dual variable domain (DVD) antibodies, CAR-T therapy, cancer vaccines, oncolytic viruses, lipid nanoparticle-based mRNA cancer vaccines, and their clinical outcomes in various cancers. We will also study how artificial intelligence and machine learning help find new cancer treatment targets.

Knowledge mapping and current trends of immunotherapy for prostate cancer: A bibliometric study.

Background: Prostate cancer (PCa) is the second most common malignancy in men worldwide. Growing evidence substantiates the important role of immunotherapy in human tumors. Given that immunotherapy is often unsatisfactory on PCa, many studies have been conducted on PCa immunotherapy to improve treatment efficacy. However, no relevant bibliometric study of PCa immunotherapy has hitherto been reported. A bibliometric analysis was performed to evaluate the global scientific production of PCa immunotherapy research and characterize the development trends for future studies in this article. Methods: The publications related to PCa immunotherapy were extracted from the Web of Science Core Collection. The contribution and co-occurrence relationships of countries/regions, institutions, journals, references, authors, and keywords were assessed and visualized by VOSviewer and CiteSpace to identify research hotspots and potential future trends. Results: A total of 3,583 publications related to PCa immunotherapy from 1999 to 2021 were collected. The results of annual publications and citations exhibited a steady increase over the past 22 years. The National Cancer Institute in the USA published far more papers during the study than any institute. Accordingly, the USA had the most publications (n = 1,954, 54.54%). Gulley, James L. had the most number of published papers, and Small, Eric J. was the most co-cited authors in this field. Cancer Immunology Immunotherapy was the most productive journal, with 145 publications on PCa immunotherapy. Keyword cluster and keyword burst analyses showed that research in PCa immunotherapy shifted from "t cell infiltration" and "sipuleucel t" to "immune checkpoint inhibitor", "CTLA-4", and "PD-L1 expression". Conclusion: PCa immunotherapy has attracted much attention, reflected by the increasing number of annual publications and citations. Much emphasis has been placed on exploring the complex immunogenicity and tumor microenvironment for PCa and identifying the patient population who can benefit from immunotherapy. Combining immune checkpoint inhibitors with other therapeutic options and cancer vaccines represents the future development trends in PCa immunotherapy.

Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body Radiation for Patients with Metastatic Castrate-Resistant Prostate Cancer.

(1) We hypothesized that adding concurrent stereotactic ablative radiotherapy (SAbR) would increase the time to progression in patients with metastatic castrate-resistant prostate cancer (mCRPCA) treated with sipuleucel-T. (2) Patients with a history of prostate cancer (PC), radiographic evidence of metastatic disease, and rising prostate-specific antigen (PSA) > 0.2 ng/dL on castrate testosterone levels were enrolled in this single-arm phase II clinical trial and treated with sipuleucel-T and SAbR. The primary endpoint was time to progression (TTP). Cellular and humoral responses were measured using ELISpot and Luminex multiplex assays, respectively. (3) Twenty patients with mCRPC were enrolled and treated with SAbR to 1−3 sites. Treatment was well tolerated with 51, 8, and 4 treatment-related grade 1, 2, and 3 toxicities, respectively, and no grade 4 or 5 adverse events. At a median follow-up of 15.5 months, the median TTP was 11.2 weeks (95% CI; 6.8−14.0 weeks). Median OS was 76.8 weeks (95% CI; 41.6−130.8 weeks). This regimen induced both humoral and cellular immune responses. Baseline M-MDSC levels were elevated in mCRPC patients compared to healthy donors (p = 0.004) and a decline in M-MDSC was associated with biochemical response (p = 0.044). Responders had lower baseline uric acid levels (p = 0.05). No clear correlation with radiographic response was observed. (4) While the regimen was safe, the PC-antigen-specific immune response induced by SAbR did not yield a synergistic clinical benefit for patients treated with sipuleucel-T compared to the historically reported outcomes.

Castration-resistant prostate cancer with bone metastases: toward the best therapeutic choice.

The treatment landscape for metastatic castration-resistant prostate cancer has evolved extremely in recent years and several drug classes are now available. Nonetheless, the lack of validated predictive biomarkers makes therapeutic choice and the best sequential approach difficult. The location of the metastatic site could be a valid criterion for choosing among the treatment options available. Although bone remains the most frequent metastatic site and a possible target for many drugs, recent data suggest a profound shift in the disease spectrum with visceral metastases increasing incidence. This review describes the presently available and ongoing therapies for patients with CRPC and bone metastases, focusing on the role of bone metastases as a possible driver for selecting therapies in these patients.

Therapeutic metastatic prostate cancer vaccines: lessons learnt from urologic oncology.

INTRODUCTION: Therapeutic cancer vaccines have been recognized as a promising treatment option in clinical oncology for nearly three decades. However, despite many efforts, only one cancer vaccine - sipuleucel-T, activating the anti-PAP (prostatic acid phosphatase) immune response, has obtained Food and Drug Administration (FDA) approval. MATERIAL AND METHODS: This review describes the most advanced research on the use of therapeutic cancer vaccines in the treatment of prostate cancer. RESULTS: In addition to sipuleucel-T, which was approved in urologic oncology in 2010, four cancer vaccines were and have been tested in phase III clinical trials in patients with metastatic castration resistant prostate cancer (mCRPC): GVAX (prostate cancer variant) containing irradiated prostate cancer cell, PPV peptide vaccine, PCVAC/PCa dendritic cell-based vaccine and PROSTVAC anti PSA (prostate-specific antigen) vaccine. This review compares the most promising and best-studied cancer vaccines: sipuleucel-T and PROSTVAC. Currently, both vaccines have been tested in combination with other therapeutic approaches, including check point inhibitors. CONCLUSIONS: It seems possible that the efficacy of sipuleucel-T and PROSTVAC could be increased in combination therapy with other medications.

Recurrent Bilateral Strokes in a Patient Treated With Sipuleucel-T for Prostate Cancer.

Sipuleucel-T is approved by the US Food and Drug Administration (FDA) for the treatment of castration-resistant prostate cancer (CRPC). Herein, we present a patient with recurrent bilateral embolic stroke who was on sipuleucel-T therapy for CRPC. Laboratory and imaging data didn't reveal any source of embolic stroke. A focused history disclosed that the patient received two doses of sipuleucel-T before the first stroke and was advised not to receive his third dose. He reported no other episode of stroke at the six-month follow-up. This case highlights the importance of identifying sipuleucel-T as a potential cause of embolic stroke if the source is not detectable, as discontinuing the therapy can be beneficial. Physicians should evaluate patients for risk of stroke before starting the therapy to prevent future strokes.

Sipuleucel-T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database.

AIMS: The major cardiovascular (CV) adverse effects observed with sipuleucel-T from large multi-institutional clinical trials included thromboembolic events, myocardial infarction, and congestive heart failure in up to 0.3% of patients with CV risk factors. The incidence, outcomes, and mechanisms in real-world clinical settings of these CV adverse effects to date have not been fully elucidated. Our study identified a patient with sipuleucel-T-induced inflammatory cardiomyopathy, which led to the identification of CV adverse effects associated with sipuleucel-T from a large pharmacovigilance database and elucidation of its potential mechanisms. METHODS AND RESULTS: Using the MedDRA term 'cardiac disorders' (System Organ Class level), CV adverse events associated with sipuleucel-T versus all other drugs were reviewed from VigiBase, a large pharmacovigilance database. Disproportionality analysis was calculated by the information component (IC), a Bayesian disproportionality indicator. A positive IC025 (IC 95% lower end credibility interval) value (>0) is the traditional threshold used in statistical signal detection at the Uppsala Monitoring Centre. From VigiBase, the total number of CV adverse drug reaction reported with sipuleucel-T was 306 out of a total of 22 980 104 adverse drug reactions in VigiBase on 10/25/2020. MedDRA preferred terms levels were grouped into major CV adverse drug reaction categories where we observed significant reports of myocardial ischaemia, supraventricular tachycardia (particularly atrial fibrillation/atrial flutter), congestive heart failure, and valvular disorders. Myocardial ischemia included acute myocardial infarction (IC025 2.3) with n = 4/26 (15%) of these individual case safety reports considered fatal. Among patients with 'cardiac failure congestive' (IC025 1.5), 11 of these 43 cases (26%) were fatal with 42 (98%) of these cases considered to be solely due to sipuleucel-T. CONCLUSIONS: Patients with CV risk factors who are receiving sipuleucel-T may be at higher risk for congestive heart failure, myocardial ischemia, and supraventricular tachycardia. Electrocardiograms during weekly sipuleucel-T infusions and left ventricular function monitoring with echocardiogram should be considered in these patients. Our findings are suggestive of another rare presentation of T-cell-mediated CV toxicity with cancer immunotherapy.

A Model-Based Framework to Identify Optimal Administration Protocols for Immunotherapies in Castration-Resistance Prostate Cancer.

Prostate cancer (PCa) is one of the most frequent cancer in male population. Androgen deprivation therapy is the first-line strategy for the metastatic stage of the disease, but, inevitably, PCa develops resistance to castration (CRPC), becoming incurable. In recent years, clinical trials are testing the efficacy of anti-CTLA4 on CRPC. However, this tumor seems to be resistant to immunotherapies that are very effective in other types of cancers, and, so far, only the dendritic cell vaccine sipuleucel-T has been approved. In this work, we employ a mathematical model of CRPC to determine the optimal administration protocol of ipilimumab, a particular anti-CTLA4, as single treatment or in combination with the sipuleucel-T, by considering both the effect on tumor population and the drug toxicity. To this end, we first introduce a dose-depending function of toxicity, estimated from experimental data, then we define two different optimization problems. We show the results obtained by imposing different constraints, and how these change by varying drug efficacy. Our results suggest administration of high-doses for a brief period, which is predicted to be more efficient than solutions with prolonged low-doses. The model also highlights a synergy between ipilimumab and sipuleucel-T, which leads to a better tumor control with lower doses of ipilimumab. Finally, tumor eradication is also conceivable, but it depends on patient-specific parameters.

Immunotherapy for Localized Prostate Cancer: The Next Frontier?

Cancer vaccines, cytokines, and checkpoint inhibitors are immunotherapeutic agents that act within the cancer immunity cycle. Prostate cancer has provided unique opportunities for, and challenges to, immunotherapy drug development, including low tumor mutational burdens, limited expression of PD-L1, and minimal T-cell intratumoral infiltrates. Nevertheless, efforts are ongoing to help prime prostate tumors by turning a "cold" prostate cancer "hot" and thus rendering them more susceptible to immunotherapy. Combination treatments, use of molecular biomarkers, and use of new immunotherapeutic agents provide opportunities to enhance the immune response to prostate tumors.

Pharmacotherapeutic strategies for castrate-resistant prostate cancer.

INTRODUCTION: Metastatic castration-resistant prostate cancer (CRPC) is a potentially symptomatic disease with an eventual lethal outcome. Novel pharmaceutical agents are continuously studied with encouraging results in CRPC. AREAS COVERED: In this perspective, the authors present established and promising pharmacotherapeutic strategies for the management of CRPC; both with and without metastases. Apart from the different treatment strategies, the authors present the relevant sequence of treatment through disease progression. EXPERT OPINION: Usually, docetaxel should be considered the first line treatment in mCRPC. Abiraterone acetate (AA) plus prednisone or enzalutamide (ENZ) could be alternative treatments in chemotherapy naïve patients. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic mCRPC. Ra-223 has been approved for patients with mCRPC with symptomatic bone metastases (not visceral metastases). Cabazitaxel has been approved as the second line treatment to docetaxel in mCRPC. No differences in the overall survival has been observed between sequences starting with docetaxel versus AA/ENZ. Between AA-to-ENZ and ENZ-to-AA sequence, the AA-to-ENZ sequence appeared to be more favorable than the ENZ-to-AA regarding progression-free survival but not overall survival. Carbazitaxel seemed to retain its activity regardless of the treatment sequence. Of note, ENZ and apalutamide have been approved in non-metastatic CRPC.

A Retrospective Observational Analysis of Overall Survival with Sipuleucel-T in Medicare Beneficiaries Treated for Advanced Prostate Cancer.

INTRODUCTION: Since sipuleucel-T approval in 2010, the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) now includes the androgen-receptor signaling pathway inhibitors (ASPIs) abiraterone acetate or enzalutamide. In 2013 and 2014, these oral agents were approved for use in men with metastatic prostate cancer who had minimal to no symptoms. We compared overall survival (OS) in men who received their first mCRPC treatment using the Medicare Fee-for-Service 100% administrative claims research dataset with patient-level linkage to the National Death Index. METHODS: This retrospective cohort analysis (January 2013 to December 2017) included men who were chemo-naïve at treatment start in 2014 and who had continuous Medicare Parts A, B, and D eligibility during the 3-year observation period. We compared: first-line sipuleucel-T vs. first-line ASPIs and any-line sipuleucel-T vs. any-line ASPIs (without sipuleucel-T). We used a multivariable regression model to help control for potentially confounding factors while assessing survival outcomes. RESULTS: The model included 6044 eligible men (average age 75-78 years) with similar disease severity; > 80% were white. Median OS, presented as sipuleucel-T vs. ASPI, was 35.2 vs. 20.7 months (n, 906 vs. 5092; any-line cohort) and 34.9 vs. 21.0 months (n, 647 vs. 4810; first-line cohort). Model outcomes indicated sipuleucel-T was associated with significantly prolonged OS compared with ASPIs: adjusted hazard ratio, 0.59 (95% CI 0.527-0.651) and 0.56 (0.494-0.627) for the any-line and first-line cohorts, respectively. CONCLUSION: This analysis suggests use of sipuleucel-T at any time was associated with improved OS compared with ASPI use alone. Of note, these analyses are intended as descriptive rather than definitive as this dataset contains limited data on key clinical factors. While selection bias is a risk in secondary claims data, this research provides important insight into real-world treatment outcomes.

Immunotherapy in prostate cancer: current state and future perspectives.

Metastatic castrate resistant prostate cancer (PCa) remains an incurable entity. In the era of immunotherapy, the complex PCa microenvironment poses a unique challenge to the successful application of this class of agents. However, in the last decade, a tremendous effort has been made to explore this field of therapeutics. In this review, the physiology of the cancer immunity cycle is highlighted in the context of the prostate tumor microenvironment, and the current evidence for use of various classes of immunotherapy agents including vaccines (dendritic cell based, viral vector based and DNA/mRNA based), immune checkpoint inhibitors, Chimeric antigen receptor T cell therapy, antibody-mediated radioimmunotherapy, antibody drug conjugates, and bispecific antibodies, is consolidated. Finally, the future directions for combinatorial approaches to combat PCa are discussed.