Cancer Treatment Vaccines for Treatment of Prostate Cancer: Comparison
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Prostate cancer (PCa) is the most commonly diagnosed cancer and the second most common cause of death due to cancer. About 30% of patients with PCa who have been castrated develop a castration-resistant form of the disease (CRPC), which is incurable. In the last decade, new treatments that control the disease have emerged, slowing progression and spread and prolonging survival while maintaining the quality of life. These include immunotherapies; however, we do not yet know the optimal combination and sequence of these therapies with the standard ones. All therapies are not always suitable for every patient due to co-morbidities or adverse effects of therapies or both, so there is an urgent need for further work on new therapeutic options. Advances in cancer immunotherapy with an immune checkpoint inhibition mechanism (e.g., ipilimumab, an anti-CTLA-4 inhibitor) have not shown a survival benefit in patients with CRPC. Other immunological approaches have also not given clear results, which has indirectly prevented breakthrough for this type of therapeutic strategy into clinical use. Currently, the only approved form of immunotherapy for patients with CRPC is a cell-based medicine, but it is only available to patients in some parts of the world. Based on what was gained from recently completed clinical research on immunotherapy with dendritic cell-based immunohybridomas, the aHyC dendritic cell vaccine for patients with CRPC, we highlight the current status and possible alternatives that should be considered in the future.

  • prostate cancer
  • immunotherapy
  • dendritic cell-based vaccines
  • castration-resistant prostate cancer
  • tumor microenvironment
  • biomarkers

 

1. Introduction

Most cancer treatment vaccines are based on the use of tumor antigens (TAs), which can be tumor-associated antigens (TAAs) or more rarely, tumor-specific antigens (TSA), to activate the patient’s immune system through cascade-regulating diverse immune cell activity, starting with the entry of the TAA into antigen-presenting cells (APCs), which then present the antigen together with the molecules of the major histocompatibility complex (MHC) to naive lymphocytes. Several types of lymphocytes are activated in this process, including CD4+ and CD8+ cells, which theoretically could lead to both specific cellular immunity and humoral immune responses against tumor cells, promoting their destruction and preventing tumor growth [1]. Thus, cancer treatment vaccines are generally composed of an adjuvant that functions to activate APCs and a target protein or peptide known to be associated with the cancer [2]. After intravenous, subcutaneous or intradermal injection, antigen-loaded APCs, usually dendritic cells (DCs), migrate to the draining lymph nodes where they present small peptide fragments of the target antigen on MHC molecules to prime T cell recognition.
Historically, the first cancer treatment vaccine based on tumor cells and tumor lysates was developed in 1980. Scientists used autologous tumor cells to treat colorectal cancer [3]. The first human TSA was identified in melanoma in the early 1990s [4]. This opened a new chapter in the use of TAs in cancer vaccines. In 2010, a cell-based treatment vaccine (sipuleucel-T) was successfully used to treat PCa [5]. In 2011, the Nobel Prize in physiology or medicine was awarded for discovering the role of DCs in the immune system. The scientific editors selected the published research of scientist Topalian and colleagues in the field of cancer immunotherapy as the breakthrough article of 2013 [6]. In 2018, the Nobel Prize was awarded to James Allison (University of Texas MD Anderson Cancer Center) and Tasuku Honjo (Kyoto University School of Medicine) for their discoveries leading to new approaches in harnessing the immune system to fight cancer, consisting of checkpoint inhibition mechanisms. The recent outbreak of the coronavirus pandemic has spurred the development of vaccine technology and put cancer vaccines back in the spotlight. Currently, many cancer vaccines are still in the preclinical and clinical research stages [7].
Cancer treatment vaccines can be broadly categorized into four different types based on the way TAs are introduced and presented to the immune system: nucleic acid-, peptide-, viral vector- and cell-based vaccines, as described in the following sections for the treatment of PCa.

2.1. Nucleic Acid-Based Vaccines

2. Nucleic Acid-Based Vaccines

Nucleic acid vaccines contain DNA or RNA encoding TA. RNA-based vaccines consist of TA-encoding mRNA. The use of mRNA as a cancer treatment vaccine has several advantages: a high level of safety due to the impossibility of incorporation into the genome, i.e., without insertional mutagenesis and the absence of the introduction of an infectious virus; enables the simultaneous delivery of several antigens for different TAs; the RNA only needs to be internalized into the cytoplasm, which is immediately followed by antigen(s) expression; can elicit humoral and cell-mediated immune responses, thereby increasing the likelihood of overcoming vaccine resistance; and efficient manufacturing. On the other hand, there are also challenges in using mRNA, such as a short half-life and only transient protein expression. Currently, several mRNA cancer vaccines are in clinical trials for various types of cancer [8] (melanoma, lymphoma, colorectal cancer); however, only one RNA-based vaccine has been tested for the treatment of prostate cancer, which failed to show a survival benefit despite increased immunogenicity [9][10]. Nevertheless, combination therapy with an mRNA vaccine and immune checkpoint inhibitors shows better prospects for cancer treatment [11], and a similar combination therapy for prostate cancer may prove beneficial in the future.
DNA-based vaccines consist of genetically modified DNA, usually in the form of plasmids that contain the coding sequence of the target antigen. They can be delivered by a variety of routes as well as by different strategies (e.g., electroporation, sonoporation, gene gun). The antigen encoded by the DNA vaccine is then expressed and presented on the MHC molecules for T cell activation. An advantage of DNA vaccines is the activation of both innate and adaptive immunity [12][13][14]. Another important advantage is that they promote a systemic immune response and immunological memory [15]. However, DNA vaccines typically exhibit relatively poor immunogenicity, especially in clinical trials, mostly due to poor DNA uptake into cells and due to the various mechanisms of resistance during tumor development [16][17].
DNA-based vaccines containing information on various TAAs, such as the prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), prostatic acid phosphatase (PAP), androgen receptor (AR) and testicular cancer antigen, have not demonstrated increased clinical efficacy but most trials have shown an immunological response [18]. In addition to shared TAAs, such as AR and PAP, the DNA vaccine platform can generate personalized cancer vaccines for patients with PCa [19]. An ongoing phase 1 clinical trial (NCT03532217) utilizes a combination of a neoantigen DNA vaccination, nivolumab, ipilimumab and PROSTVAC for patients with metastatic hormone-sensitive prostate cancer (mHSPC), which takes advantage of both shared and personalized antigen approaches.

2.2. Peptide-Based Vaccines

3. Peptide-Based Vaccines

Peptide-based vaccines are built of subunits containing the specific epitope of the tumor antigen [20]. After intradermal injection, professional APCs in the skin are exposed to the synthetic vaccine peptides, corresponding products and antigens associated with cancer. In a phase 1/2 clinical trial (NCT01784913) for patients with metastatic hormone-sensitive prostate cancer (mHSPC), UV1, a synthetic long-peptide vaccine containing fragments of human telomerase reverse transcriptase (hTERT) was administered in combination with granulocyte–macrophage colony-stimulating factor (GM-CSF). hTERT is normally repressed in healthy cells, but is usually overexpressed in cancer cells, and is responsible for the immortality of tumor cells [21]. Another rapidly evolving approach is the development of personalized peptide vaccines that involve identifying peptide candidates for individual patients for their ability to induce an immune response in vitro and of subsequent administration to the patient [22].

2.3. Viral Vector-Based Vaccines

4. Viral Vector-Based Vaccines

These vaccines consist of viruses as a vector to transfer the gene-encoding TA(s) into patients, resulting in stimulation of the host’s immune response against the antigen [23][24]. In 2003, a phase 2 clinical study for patients with minimally symptomatic castration-resistant form of the disease (CRPC) was conducted with PSA-TRICOM (PROSTVAC-VF), a virus-based vaccine using a combination of two viral vectors. Each vector encodes for PSA and three immune costimulatory molecules [25][26]. The virus infects APCs and this triggers cell surface protein expression and subsequent interaction with T cells, which in turn enhances the targeted immune response and cell-mediated destruction of tumor cells [27][28]. The PROSTVAC-VF vaccine was well tolerated. Overall survival was prolonged compared with the control group (25.1 months versus 16.6 months). However, the primary objective, which was to increase the time to progression, was not achieved. Patients with a higher disease burden had less benefit [27][29]. PSA-TRICOM did not receive US Food and Drug Administration (FDA) approval based on the findings of these trials.

2.4. Cell-Based Vaccines

5. Cell-Based Vaccines

The source of TAs to be introduced to the immune system can also be whole cells, autologous or allogeneic [30]. These are usually utilized in combination with GM-CSF to induce the growth and differentiation of DCs involved in antigen presentation [31].

2.4.1. Tumor Cell-Based Vaccines

5.1. Tumor Cell-Based Vaccines

In this approach, the whole tumor cell is used as an antigen, which in turn facilitates both humoral and cellular immune responses. Tumor cells can be autologous or allogeneic and are usually genetically modified to express the immune stimulatory cytokine GM-CSF. GM-CSF induces the recruitment of APCs, which initiates a cascade of immune responses [32]. GVAX is a whole tumor cell-based vaccine against PCa and is genetically modified to secrete GM-CSF and irradiated to prevent further cell division. Although phase 1 and 2 studies confirmed clinical efficacy and safety, two phase 3 trials, VITAL-1 and VITAL-2, failed to show a clinical benefit [32][33][34]. There are attempts to improve the efficacy of GVAX-PCa by combining it with ICIs [35].

2.4.2. Dendritic Cell-Based Vaccines

5.2. Dendritic Cell-Based Vaccines

Today, the only approved modality of immunotherapy for patients with CRPC is cell-based medicine using the power of DCs. In the United States, it is available as sipuleucel-T [5] and in Slovenia (EU) as the recent next-generation medicine, aHyC (autologous hybridoma cells), which consists of DCs electrofused with autologous tumor cells [36]. Although both medicines are based on autologous cells, they differ significantly in terms of administration and other properties.
The most efficient, often designated “professional” APCs in the body are DCs. They play a key role in the activation and regulation of the acquired immune response; thus, they have been used extensively for the preparation of antitumor vaccines. After recognizing and binding, generally foreign antigens, they present them to other effector immune cells and thereby initiate a cellular immune response cascade. DCs are able to activate both naive and memory T lymphocytes and are thus the most suitable cell entity for amplifying the antitumor immune response [37]. Antigenic tumor material can also be provided to the patient’s immune system by equipping DCs with TAs. This is achieved by incubating DCs with tumor apoptotic bodies, with tumor necrotic lysates or with proteins, peptides or even mRNA alone. Such vaccines are prepared from the patient’s own immune cells, which can be exposed ex vivo to TAs and then introduced back into the patient, where they are supposed to boost the immune response to cancer cells in the body [38][39]. DCs have been used in clinical trials as a form of therapeutic treatment in cancer patients, including PCa for more than three decades, demonstrating that such an approach is safe (usually with only a few non-serious side effects), can trigger antitumor immunity and, in some cases, can prolong survival. However, the clinical efficacy (e.g., time to disease progression, symptoms) has been shown to be modest, although an immune response has been demonstrated in many cases (reviewed by Sutherland et al. [40]). One such example is sipuleucel-T, an autologous cell vaccine generated from a patient’s white blood cells, containing around 20% of DC markers, activated with a recombinant fusion protein (PA2024) to which a TSA (PAP) has been added. PAP is a glycoprotein enzyme synthesized by prostate epithelial cells, and its expression significantly increases in the progression of PCa [41][42]. The patient’s white blood cells are incubated ex vivo with the recombinant protein PA2024 consisting of PAP fused to GM-CSF, allowing the APCs to present the antigen on their surface [43]. The cell suspension is then re-infused intravenously into the patient (50 × 106 CD54+ cells/250 mL suspension). Based on the results of the multicenter IMPACT study, the FDA approved sipuleucel-T in 2010 for the treatment of patients with CRPC with minimal or no symptoms. They reported a 4.1-month increase in survival compared with the placebo (25.8 versus 21.7 months [5]).
DCVAC is another known example of a DC-based vaccine. It is composed of activated DCs and dead cells of the prostate cancer cell line, LNCaP. Phase 1 and 2 studies showed improved survival in patients who received docetaxel and the DCVAC vaccine in combination [44]. However, no improvement in survival was found in a phase 3 study [45].
The DC immunotherapy strategy can be improved by a completely personalized approach. One effective way to achieve exposure of TAs is fusion of the plasma membranes of DCs and tumor cells of the same patient; the resulting hybrid cells, so-called immunohybridomas, mediate functions of original cells. They have the properties of APCs and contain both known and unknown TAs, derived from tumor cells. Recently, one such completely autologous DC-based cell vaccine has been tested in a phase 1/2 randomized, placebo-controlled trial by preparing DCs from the patient’s monocytes and using the electrofusion method to merge their plasma membranes with the patient’s own (autologous) cancer cells into immunohybridomas, termed aHyC, that were administered subcutaneously to the patients enrolled in the study [36][46]. The results revealed that the median overall survival was 58.5 months (95% confidence interval [CI], 38.8–78.2 months), and was inversely correlated to the subpopulation of NK cells in the peripheral blood, which were attenuated with the aHyC application, demonstrating modulation of the patient’s immune response [36]. Median cancer-specific survival was prolonged by 33 months compared with controls, almost 7 years after the diagnosis of CRPC [46].
Electrofusion of tumor cells and DCs to form hybridomas has been previously developed and evaluated with confocal microscopy and flow cytometry [47][48]. Antigen presentation also involves late endocytotic compartments (lysosomes) containing MHC II molecules, so heterologous fusion of vesicles (from different cell types, heterologous) is required to deliver antigens to MHC II molecules in hybridomas. It has been shown that fusion of late endocytotic compartments also occurs in aHyC hybridomas and that the efficacy of this approach, measured as an increased in vitro cytotoxic T cell response, is stronger when the proportion of fused late endocytic compartments is greater in electrofused hybridoma cells [49][50]. Furthermore, the advantage of the fusion of autologous tumor cells and DCs over other forms of vaccines is that such immunotherapy is not limited to only those types of tumors in which the potentially immunogenic antigenic determinants are currently well known. They are also effective against unidentified TAs, which arise from fused tumor cells and are bound to MHC class I and II molecules by specialized antigen presentation mechanisms of DCs, and presented to T lymphocytes for recognition [51].
In addition, in all forms of DC-based vaccines, DCs also express essential costimulatory molecules for effective activation of T lymphocytes and produce pro-inflammatory cytokines (e.g., interleukin-12). Thus, they can activate antigen-specific antitumor CD4+ and CD8+ clones of T lymphocytes in a balanced manner [49][52]. The activation of CD4+ T cells is necessary for long-term stimulation of the formation and functioning of antitumor effector CD8+ T lymphocytes, which ultimately destroy cancer cells and reduce the tumor burden. Research into the production and use of cell hybridomas has progressed all the way to clinical trials. It has been shown that patients with various diffuse forms of cancer tolerate this type of treatment well, with effector immune antitumor mechanisms proven to be reactivated, but objective tumor regression was confirmed only in a small number of patients [38][53]. Nevertheless, in vitro studies unequivocally demonstrate a significantly stronger activation of T lymphocytes with aHyC than with any other DC-based vaccines [54][55]. Therefore, the future of treatment with hybridomas obtained from tumor cells and DCs, such as aHyC, is very promising among cell-based vaccines.

Safety of Dendritic Cell-Based Vaccines

CRPC mainly affects older men who are compromised because of other accompanying diseases. They are usually receiving a range of other therapies and are consequently more prone to various treatment complications [56]. In individual cases, the therapy must be changed due to adverse effects (AEs) of drugs, known interactions with other drugs, accompanying diseases or patient wishes.
The safety of DC immunotherapy has been documented in several phase 1 clinical trials [57]. Local injection site reactions (e.g., pain, erythema and pruritus) were common but generally mild. Systemic AEs with fever, malaise and other flu-like symptoms were observed; however, grade 3–4 systemic AEs according to Common Terminology Criteria for Adverse Events (CTCAE) were extremely rare [58]. It is possible to trigger autoimmune reactions with all types of immunotherapy. DC-based cancer treatment vaccines have been shown to rarely cause severe AEs, in contrast to other immunotherapeutic approaches such as monoclonal antibodies and cytokines [59]. In one study, up to 60% of patients treated with ipilimumab had AEs due to immune reactions (of which 15% were CTCAE grade 3–4) [60]. In contrast, patients treated with DC maintained their quality of life because of the low incidence of AEs [61]. Quality of life is an important indicator that wresearchers use for evaluating new cancer drugs. Reports on the impact of DC immunotherapy on quality of life are rare. One study evaluating 55 patients with renal cell carcinoma treated with DCs showed no negative effect of immunotherapy on quality of life [61].
Accordingly, the results of a recently completed clinical trial, in which the cell vaccine was prepared from DC and tumor cells, show a relatively high level of safety of treatment with aHyC [36]. The results also showed that the patients maintained a high level of functionality, remained active and self-caring and had quality free time, which contributed to psychological relief and a reduction in mental distress due to the disease. It should be noted here that the small sample (n = 16) dictates caution in interpreting the results.
aHyC therapy exhibits a favorable safety profile that can be attributed to several factors. First, the aHyC cell vaccine is completely autologous; tumor cells and DCs as the starting material for the production of immunohybridomas are obtained from the patient’s tissue and no other starting materials and raw materials are present in the final product. Second, wresearchers did not administer aHyC intravenously, but subcutaneously. Intravenous administration is generally not used for vaccination because it elicits a relatively small immune response compared with other injection routes [62], and may also cause allergic reactions. WResearchers believe that due to the completely personalized preparation of aHyC, there were no allergic or autoimmune reactions. Moreover, the lower incidence and lower intensity of AEs with aHyC compared with sipuleucel-T (administered intravenously) could be due to the fully autologous nature of the vaccine, quality of preparation and subcutaneous administration. No patient required hospitalization, no autoimmune reactions were detected and laboratory indicators of liver and kidney functions remained stable during the clinical investigation, which indicates that immunotherapy with aHyC does not affect the functioning of important organs in the body.

6. Conclusions and further directions

PCa has immunogenic potential, but the immunosuppressive TME prevents the immune system from responding appropriately to destroy tumor cells. Populations of inhibitory immune cells, fibroblasts and tumor cells produce cytokines that indirectly and directly inhibit the immune system, which should fight against tumor cells. In recent years, immunotherapy has had a profound impact on the treatment of metastatic cancer and has changed the standard of care for many types of tumors. WResearchers believe that immunotherapy in PCa is just the beginning of a long story. With further scientific work, weresearchers will be able to answer many questions, including the following. How can weresearchers make PCa more “hot”—prone to attacks by the immune system or immunotherapy? What is the exact mechanism by which an effective immune response is blocked? Are there different cancer cell-killing T cells that are activated by CTLA-4 inhibition versus those that are activated by PD-L1 inhibition? It is still difficult to predict what role aHyC immunotherapy will play in the future. In the coming years, weresearchers will obtain a clear answer about the role of new forms of systemic treatment, which may be used in combination and at earlier stages of the disease [63].

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