Prostate cancer rates have been on the rise in recent years. In 2020, prostate cancer remains the most common malignancy among men worldwide. In China, prostate cancer has become an important factor in threatening the life safety of men [1, 2]. Global Cancer statistics and Chinese Cancer statistics [3-5] show that in recent years, prostate cancer rates continue to rise. Currently, most men with advanced prostate cancer develop castration-resistant prostate cancer(CRPC) [6]. How to further improve the efficacy of CRPC while reducing adverse reactions, has become a focus in this field. In the past decades, immunotherapy has been used to treat prostate cancer through anti-tumor effects driven by immune response. It has brought new immunotherapeutic opportunities. Sipuleucel-T is strongly supported by the U.S. Food and Drug Administration for the treatment of CRPC and has shown promising results. Pembrolizumab has become an important therapeutic tool for prostate cancer immunotherapy [7, 8]. Cancer vaccines use tumor cell-associated antigens to induce a specific anti-tumor immune response that is durable and robust. As an important part of immunotherapy, cancer vaccines have unique and significant advantages against prostate cancer, including monocyte vaccines and dendritic cells,accines, viral vaccines, peptide vaccines and DNA/mRNA vaccines [9]. Among them, Sipuleucel-T plays a great role in promoting prostate cancer immunotherapy. Therefore, this article reviews the latest progress on prostate cancer vaccine, especially Sipuleucel-T vaccine based on mononuclear cells.
Figure 1 shows that general view of vaccine for prostate cancer.

Sipuleucel-T

Sipuleucel-T (Provenge®, Dendreon, USA) is an active immune cell-based immunotherapy that induces an immune response against prostate acid phosphatase (PAP). Prostate acid phosphatase (PAP) is expressed in approximately 95% of prostate cancers and is mainly limited to prostate tissue, which is a target for prostate cancer tumor vaccine development. It is a type of autocellular immunotherapeutic vaccine, composed of peripheral mononuclear cells. Sipuleucel-T consists of autologous peripheral blood mononuclear cells including antigen presenting cells (APCs). Peripheral blood mononuclear cells from patients were obtained by a standard procedure of leukocyte separation approximately 3 days prior to infusion. To increase the immune response to PAP, it is activated by adding PAP and the recombinant fusion protein of immune activator GM-CSF (PAP-GM-CSF) at a specific stage of cell culture. The active components of Sipuleucel-T are autologous APCs and PAP-GM-CSF, in addition to T cells, B cells, natural killer cells, and other cells that specifically bind to PAP expressed in prostate cancer tissue to kill tumor cells. The technology causes patients' own immune system to respond to prostate cancer. In 2010, the US Food and Drug Administration (FDA) approved it into the clinic, and it is the only cell active immune product licensed to treat asymptomatic or mild CRPC [10, 11]. The patient's peripheral blood mononuclear cells (PBMC) rich in antigen-presenting cells (APC) were collected by leukapheresis. After incubating with PA2024 in vitro, the activated cells were injected a new APC, which elicits an antitumor immune response. Among them, PA2024 is the carboxyterminal terminus of PAP and the granulocyte-macrophage colony-stimulating factor (GM-CSF). The amino terminal of GM-CSF was linked to the recombinant protein (PAP-GMCSF). The whole procedure, including leukapheresis, cell activation and reinfusion, repeated every 2 weeks for a total of 3 times (weeks 0, 2 and 4) [12].
IMPACT(NCT00065442) phase III randomized, double-blind, placebo clinical trial [13], where 512 patients were randomly assigned to receive Sipuleucel-T or placebo (2꞉1). After a median follow-up of 34.1 months, the results showed that: Compared with placebo group (121 patients, 70.8%), Sipuleucel-T group (210 patients, 61.6%) had a 22% relative reduction in the risk of death, and the adjusted hazard ratio for death was 0.78 (95%CI: 0.61-0.98, P=0.03). The median overall survival (OS) was improved by 4.1 months (25.8 months vs 21.7 months). The estimated 36-month survival rate was 31.7% (vs. 23.0% with placebo); In another exploratory study, baseline PSA was found to be a predictor of Sipuleucel-T efficacy [14]. In this study, all patients were divided into four groups on average, with 128 patients in each group. Baseline PSA values (ng/ml) were ≤ 22.1, > 22.1-50.1, > 50.1-134.1, and > 134.1, respectively. The group with the best Sipuleucel-T efficacy was the group with the lowest PSA interval. The median OS in the treatment and control groups was 41.3 and 28.3 months, respectively, while the median OS in the treatment and control groups for the highest PSA interval was 18.4 and 15.6 months.. The study concluded that while Sipuleucel-T is effective in all patients, it is most effective in patients predicted to have a lower risk of progression, so the earlier Sipuleucel-T is used, the better is the treatment response. Sipuleucel-T can only be used by the patient. Before infusion, the patient's identity must be confirmed to match that marked on the infusion bag. When given 3 times, about 2 weeks apart from each treatment, OS of patients with advanced prostate cancer can be significantly improved and the average survival time can be extended by more than 4 months. The most common adverse events (incidence ≥15%) included chills, fatigue, fever, back pain, nausea, joint pain, and headache. Sipuleucel-T was well tolerated, and the most common adverse events were fever and influenza-like symptoms. However, it is worth noting that there was no significant difference in progression-free survival (PFS) or prostate specific antigen (PSA) decline between the two groups. Less than 3% of Sipuleucel-T patients had a PSA decline of 50% or more. Based on the IMPACT [13], D9901 (NCT00005947) [15], D9902A(NCT01133704) [16], double-blind, controlled, multicenter phase III randomized trials, in April 2010, the FDA officially approved Sipuleucel-T as the first prostate cancer vaccine for the treatment of asymptomatic or mildly symptomatic mCRPC [8]. The clinical use of this drug has greatly promoted the development of cancer vaccines, but unfortunately, prostate cancer vaccines other than Sipuleucel-T have not shown promising clinical benefit in large, randomized phase II and III trials.

Immunologic mechanism of action of Sipuleucel-T

The immune response induced by Sipuleucel-T is multifaceted, and APC-mediated immune response is the basis of its action, that is, it induces the body to produce PAP specific T cells and B cells, thereby activating the body's immune response to prostate cancer and generating an anticancer effect. The specific mechanisms of sipuleucel-T are as follows: 1) APC activation and immune enhancement. Increased cumulative APC activation, a measure of product potency and immune activation, was statistically significantly associated with improved OS. Sipuleucel-T infusions at weeks 2 and 4 resulted in increased APC activation. This indicates that the first infusion (week 0) primes the immune system and subsequent treatments enhance the immune response. Meanwhile, APC activation is more effective in patients with early prostate cancer [17]. 2) Generate specific immune responses against PAP and PA2024. 3) Antigen diffusion. After an initial immune response to a specific target antigen, Sipuleucel-T expands its response to other antigens expressed by the tumor, which is known as antigen diffusion. In this process, tumor cells lysed by antigen-specific T cells release additional tumor-associated antigens (TAA), which are eventually expressed by the tumor-associated antigens. APC processing and presentation to induce B cells and T cells to produce immune responses against secondary antigens (such as E-RAS, KLK2, K-RAS, LGALS3 and LGALS8, etc.), which are closely related to the improved survival benefits of Sipuleucel-T [18, 19]. 4) T cell reactive transfer and cytotoxic T lymphocyte (CTL) activity. Fong et al.[20] pointed out that neoadjuvant Sipuleucel-T could induce systemic antigen-specific T cell response and activation effect before radical prostatectomy.
T cells should be recruited to the prostate tumor microenvironment to enhance the immune effect. Antonarakis et al. [21] measured the expression of CD107a on CD8+ T cells specific for PAP or PA2024 and demonstrated that Sipuleucel-T could generate antigen-specific CTL responses in prostate cancer patients. The study found that this response was associated with improved OS after Sipuleucel-T treatment. Kibel et al. [22] documented the cytolytic activity of CTLS against target cells expressing PAP by video, demonstrating tumor induction by antigen-specific CD8+ cells, where tumor lysis is an important part of the mechanism of action of Sipuleucel-T. At the same time, Sipuleucel-T treatment alters the B cell receptor repertoire and induces the development of long-term immune memory in the organism, making it more useful for killing tumors [23].

Clinical application of Sipuleucel-T

Efficacy evaluation. The IMPACT study [13] showed that Sipuleucel-T could prolong the median OS of mCRPC patients. Schellhammer et al. [14] pointed out that PSA was a strong predictor of Sipuleucel-T treatment response (P<0.0001), and with the decrease of baseline PSA, Sipuleucel-T treatment response would be greater. The hazard ratio for OS was 0.51(95% CI: 0.31-0.85) in patients with baseline PSA ≤ 22.1 ng/mL and 0.84 (95%CI: 0.31-0.85) in patients with PSA >134 ng/mL. (0.55 to 1.29), indicating a benefit of Sipuleucel-T at an earlier stage of cancer. Early use of Sipuleucel-T has less tumor immunosuppression and more APC activation, which is more conducive to the long-term stimulation of immune response and long-term clinical benefit. Another notable clinical feature of Sipuleucel-T is the delayed effect, in which proximal end points such as PSA levels, objective disease progression, and the occurrence of disease-related pain are not altered. In contrast, there was an improvement in the distal end points [24]. Small et al. [25] found that Sipuleucel-T treatment was not associated with time to disease-related pain (TDRP) (HR=0.819, 95% CI: 0.616-1.089, P=0.170), which was associated with delayed time to first use of opioid analgesics (TFOA) (HR=0.755, 95%CI: 0.579-0.985, P=0.038). These changes in late outcomes may be related to the time required to exert the immune antitumor effect after Sipuleucel-T treatment. Sipuleucel-T results were also variable in different ethnic groups.
The PROCEED study [26] showed that compared with whites, African Americans had a higher median OS after Sipuleucel-T treatment (HR= 0.81, 95%CI: 0.68-0.97, P=0.03). This may be related to the differences in the immune system between different ethical backgrounds [27].
The value of drug combinations. Prostate cancer has a low mutation burden and a small number of tumor infiltrating CD8+ T cells, which makes prostate cancer a "cold tumor" of immune response, resulting in a far worse effect of immunotherapy than other solid tumors [28]. Therefore, combination therapy is commonly used in prostate cancer immunotherapy. Theoretically, combination of Sipuleucel-T with the activation and spread of the immune response, combined with the durable efficacy and safety profile, offers the promise of prolonged anticancer activity and is of great value. A randomized phase II open-label trial evaluated Sipuleucel-T versus androgen deprivation therapy (ADT) in the treatment of patients with biochemical recurrence. The results showed that the safety of different administration sequences was good. The PA2024-specific T cell response of Sipuleucel-T first was higher than that of ADT first (P= 0.001), which could induce greater anti-tumor immune response [29]. The results of a mathematical model for Sipuleucel-T and ADT response in prostate cancer developed by Jain et al. [30] showed that 2 doses of vaccine administered before ADT was optimal, reducing cancer mortality by approximately 45% and maximizing median OS. Small et al. [31] randomized phase II trial evaluating Sipuleucel-T combined with abiraterone in the treatment of mCRPC showed that simultaneous administration did not attenuate or change the immune effect of Sipuleucel-T, and the combination was well tolerated. Radiotherapy (hereafter referred to as radiotherapy) and chemotherapy (hereafter referred to as chemotherapy) may synergize with immunotherapy to enhance and expand antitumor immune responses. However, in a randomized phase II trial of Sipuleucel-T combined with radiotherapy, irradiation of up to 30 Gy to a single metastatic site in asymptomatic or minimally symptomatic mCRPC patients did not enhance the immune response associated with Sipuleucel-T treatment [32]. With respect to combination chemotherapy, few studies have been conducted, and two clinical trials evaluating the sequencing of Sipuleucel-T plus docetaxel (NCT02793219 and NCT02793765) were withdrawn with reduction in demand. In addition, a randomized phase II trial of Sipuleucel-T combined with radium 223 in the treatment of bone metastatic mCRPC showed that the combination therapy could improve clinical efficacy, but the immune response was low [33]. Due to the lack of effector T cell infiltration in the tumor microenvironment (TME), the efficacy of immune checkpoint inhibitors (ICI) monotherapy in the treatment of prostate cancer is not good. More recently, Sinha et al. [34] combined Sipuleucel-T and ipilimumab, showing that combination therapy produced modest clinical responses without changing antigen-specific responses. The phase Ib study by Dorff et al. [35] on mCRPC patients who received different sequential regimens of atezolizumab, and Sipuleucel-T showed that the combination therapy was safe and may be more beneficial regardless of the order of administration. At the same time, other emerging therapies, such as the combination of cytokine IL-7, have also achieved encouraging results in phase II trials [36]. Currently, compared with other immunotherapies, Sipuleucel-T is not widely used, in part because its clinical success rate is limited, and the cost associated with its treatment is not acceptable to most patients. However, the immunologic benefit of Sipuleucel-T in combination therapy still sets the stage for additional large trials.
Clinical limitations "A survey of factors associated with the use of Sipuleucel-T in mCRPC patients in the United States [37] showed that only 730 of 7272 patients treated received Sipuleucel-T, and ethnicity, region of residence, income, and professional recommendation were associated with its use." From a cost perspective, Sipuleucel-T requires three infusions over a period of 1 month. However, the cost-effectiveness analysis for the treatment of mCRPC patients found that the treatment strategy without sipuleucel-T could show the most favorable incremental cost-effectiveness ratios (ICER) [38]. At the same time, the delayed effect of Sipuleucel-T, resulting in the lack of PSA or objective response in clinical trials, affects the assessment of disease progression. Currently, Sipuleucel-T is not widely adopted outside the United States. This drug has been discontinued in Europe because of its complex management, low survival benefit, and high price [39]. Its owner, Dendreon, went bankrupt due to production capacity and financial problems, and was completely acquired by China's Sanpower Group. 

DCVAC/PCa vaccine is a PBMC-derived autologous dendritic cell vaccine that can be generated by pulsing PBMC obtained by apheresis with killed prostate cancer cells (LNCaP) followed by subcutaneous injection of mature dendritic cells [40]. Two phase I/II small sample clinical trials [41, 42] have shown that DCVAC/PCa has a good safety profile in the treatment of prostate cancer and can improve the prostate-specific antigen doubling time (PSA). PSADT was significantly prolonged (P<0.001 8). At present, there are few basic and clinical studies on the vaccine. One trial evaluated DCVAC/ PCa combined with first-line chemotherapy (docetaxel plus prednisone) in patients with mCRPC. The results of a randomized, double-blind, phase III trial of the safety and efficacy of DCVAC/PCa in combination with a single-line chemotherapy agent [43] showed that DCVAC/ PCA [maintain consistency and define] in combination with a single-line chemotherapy agent did not prolong OS in mCRPC patients (23.9 months vs 24.3 months, HR: Hr: 1.04, 95% CI: 0.90-1.21, P=0.60).

Individualized peptide vaccines

Personalized peptide vaccines (PPV) are tumor vaccines that are produced by selecting individual peptides for vaccination based on individual genetic structure and functional differences. The mechanism of PPV is that the specific tumor antigen peptide is delivered to the major histocompatibility complex (MHC) on the surface of APC, which is degraded into short peptides in APC and forms peptide-MHC-TCR complex, which is recognized by T cells. The corresponding CTL response is stimulated, thereby carrying out anti-tumor immunity [55]. A randomized, double-blind, placebo-controlled phase III trial of PPV in patients with CRPC who progressed after docetaxel chemotherapy [56] showed that PPV did not prolong OS (P=0.77). Subgroup analysis showed that patients with lower percentage of neutrophils or higher percentage of lymphocytes at baseline could benefit from PPV treatment.

GX301

GX301 is a vaccine consisting of four telomerase peptides and two immune adjuvants (Montanide ISA-51 and imiquimod). It was found to be safe and immunogenic in phase I trials [57]. The results of a multicenter, randomized, parallel-group, open-label phase II trial showed that GX301 vaccine was safe and immunogenic in patients with mCRPC, and the immune response rate was related to the number of immunizations, which provided a reference for treatment options in future studies [58].

DNA vaccines are closed circular DNA plasmids designed using target antigens, encoding antigens under the action of a strong mammalian promoter, and improving immunogenicity through targeted antigen presentation to kill tumor cells. Currently, DNA-based prostate cancer vaccines mainly include vaccines encoding PAP, PSMA, PSA, etc.[59]. A phase I/IIa trial of encoded PAP [60] showed that the vaccine had a good safety profile, with 14% (3/22) of patients producing PAP-specific IFN-γ-secreting CD8+ T cells immediately after treatment. PAP specific CD4+ and/or CD8+ T cell proliferation was observed in 41% (9/22) patients, and the difference in PSADT was statistically significant (P<0.05). Similarly, the safety and efficacy of DNA vaccine encoding PSMA were also confirmed in phase I/II trials, and its PSADT was significantly increased (P=0.0417) [61]. A recent study [62] showed that PSMA or T-cell receptor γ alternate reading frame protein, peptides of TARP, incorporated into spherical nucleic acid (SNA) vaccines with optimized structures, can significantly affect adaptive immune responses to clinically used prostate cancer targets.

This may become a new research direction in the future. The mRNA vaccine is a synthetic protein antigen encoded by the mRNA sequence delivered to the body to cause the body to express the corresponding protein and induce the body to produce an immune response against the protein to achieve the purpose of disease prevention and treatment [63-65]. Among them, safe and efficient delivery system is the core key technology of mRNA vaccine development [66]. Currently, mRNA vaccines for prostate cancer are under development. To address the bottleneck of tumor antigen screening and vaccine candidates, Zheng et al. [67] showed that KLHL17, CPT1B, IQGAP3, LIME1, YJEFN3, KIAA1529, MSH5, and CELSR3 are important markers of prostate adenocarcinoma. Patients with PRAD immune subtype (PIS) 2 and 3 are more suitable for vaccination. The mechanisms of action and study results of these different types of vaccines are shown in Table 1.

In recent years, remarkable progress has been made in prostate cancer immunotherapy, and a variety of new therapies have emerged. As the only prostate cancer vaccine that has been used in clinical practice so far, Sipuleucel-T plays a crucial role in promoting the progress of prostate cancer immunotherapy. However, cancer vaccines are limited to their own characteristics and have not shown greater clinical benefits compared with other therapies. Therefore, there is a need to further improve the cancer vaccination strategy, improve the design of Sipuleucel-T, and find evaluation indicators. It is anticipated that with the continuous optimization of Sipuleucel-T, its advantages in the targeted therapy of prostate cancer will become more significant, and more reasonable combination therapy in the future will continue to improve the tumor killing effect of immunotherapy.

Acknowledgements
We thank Dr. Sanjay Gupta (Case Western Reserve University & UH Cleveland Medical Center) for his proofreading for the review.

Ethical policy
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Approval from institutional ethical committee was taken.

Availability of data and materials
All data generated or analysed during this study are included in this publication.

Author contributions
ZW designed the study and was responsible for the writing of the original draft. ZY edited and approved the final manuscript.

Competing interests
All authors declare no competing interests.

Funding
None.

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