The Current Role of Immunotherapy in mCRPC: A Systematic Review

Research Article

Austin J Clin Case Rep. 2021; 8(7): 1222.

The Current Role of Immunotherapy in mCRPC: A Systematic Review

Dalibey H1,2,3, Hansen TF1,2 and Zedan AH1,2*

¹Department of Oncology, Vejle Hospital, Vejle, Denmark

²Institute of Regional Health Research, University of Southern Denmark, Denmark

³University of Southern Denmark, Odense, Denmark

*Corresponding author: Zedan AH, Department of Oncology, Vejle Hospital, Beriderbakken 4, 7100 Vejle, Denmark

Received: May 31, 2021; Accepted: June 29, 2021; Published: July 06, 2021


Background: The development of immunotherapy has shown promising results in several malignant diseases, including prostate cancer, calling for a systematic review of the current literature. This review aims to evaluate the present data and prospects of immune checkpoint inhibitors in metastatic Castration Resistant Prostate Cancer (mCRPC).

Methods: Articles were identified via a systematic search of the electronic database Pubmed, in accordance with the PICO process and following the PRISMA guidelines. Articles in English studying immune checkpoint inhibitors in patients with mCRPC published between March 2010 and March 2020 were eligible for inclusion. Endpoints of interest were Overall Survival (OS), Progression-Free Survival (PFS), clinical Overall Response Rate (ORR), and Prostate-Specific Antigen (PSA) response rate.

Results: Ten articles were identified as eligible for inclusion. The studies primarily explored the use of Ipilimumab, a CTLA-4 inhibitor, and Pembrolizumab, a PD-1 inhibitor. These drugs were both used either as monotherapy or in combination with other treatment modalities. The largest trial included in the review demonstrated no significant difference in overall survival between the intervention and placebo. However, two studies presented promising data combing immunotherapy and immune vaccines. Grade 3 and 4 adverse events ranging from 10.1% to 82.3%, whit diarrhea, rash, and fatigue were the most frequently reported. Forty relevant ongoing trials were identified exploring immunotherapy with or without a parallel treatment modality.

Conclusion: Overall, the current data shows that the effect of immune checkpoint inhibitors as monotherapy may have limited impact on mCRPC, and the results from ongoing combinational trials are eagerly awaited.

Keywords: Cancer-immunotherapy; Immune-checkpoint; Prostaticneoplasms; Castration-resistant


Prostate Cancer (PCa), the fourth most common cause of cancerrelated deaths in men worldwide, is a high mortality disease calling for improvements [1]. Treatment options for early and localized stages of PCa are promising and the disease generally develops slowly. Symptoms, however, are typically interpreted as age-related, resulting in PCa often being detected in its advanced stages. Treatment with Androgen-Deprivation Therapies (ADT) can initiate antitumor activity in the initial phase of PCa, however, the tumor cells eventually stop responding to ADT and progress to a state referred to as Castration-Resistant Prostate Cancer (CRPC).

Despite the many therapeutic choices introduced in the past two decades, CRPC is still considered terminal, with a median survival of only 16-21 months [2]. The poor prognosis may partly be explained by both the aggressiveness of the disease and the limitations of the available treatments.

Many alternative therapies have been investigated over the past years. However, one treatment modality in particular has dominated the past century; immunotherapy. In contrast to chemotherapy, which causes immunosuppression, immunotherapy cooperates with the immune system to fight cancer. Treatment with immunotherapy is able to target a wide variety of regulatory pathways, with individual drugs aiming for different targets.

In general, the immune system’s activity must be carefully regulated to ensure that activation only occurs when required. The immune system has several “off switches” responsible for its inactivation. Two of them; Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) and programmed cell death protein 1 (PD- 1), are currently targeted by immunotherapy. These off switches, or pathways, Called Immune Checkpoints (ICP) have been well documented. ICP’s comprise a variety of regulatory pathways that are crucial for the initiation, duration, and regulation of the immune response. The immune system also uses the ICP’s to distinguish between normal and apoptosis-demanding cells.

In cancer diseases, tumor cells evade the immune system by overexpressing ICP receptors, resulting in the inhibition of T-cells. The understanding of these pathways has led to the discovery of a new treatment option; ICP Inhibitors (ICPIs). The ICPIs work by inhibiting the ICP receptors on cancer cells, thereby making tumor cells visible for the immune system [3]. The ICPIs have become a cornerstone in the treatment of cancers such as lung cancer and metastatic melanoma [4]. A phase-3 clinical trial in metastatic melanoma patients showed a significant improvement in survival with the drug Ipilimumab [5]. The subsequent FDA approval of this fully human CTLA-4 inhibiting monoclonal antibody paved the way for a number of clinical trials in many cancer types, including PCa.

Tumor cells in PCa exploit a broad range of mechanisms to evade activation of the immune system. A study has shown that activation and infiltration of T-cells and inflammatory cells in PCa tissue may mediate antitumor responses [6].

The first ever immunotherapy approved for the cancer treatment was the Sipuleucel-T injection, popularly known as “immune vaccine” [7], and for metastatic CRPC (mCRPC). Since its release in 2009, the therapy has been heavily elucidated through clinical research. However, the treatment has been poorly adopted due to it being effective only in a narrow group of patients and its high cost.

Recent promising results from immunotherapy have raised hopes for potential benefits from ICPIs in mCRPC. This has resulted in the initiation and publication of several mCRPC studies, yet with no recent review summarizing these results.

The aim of this review is to systematically identify and summarize the literature on the current status and future perspectives of ICPI treatment of mCRPC.

Checkpoint inhibitors

Research and understanding of the immune system are far from fully elucidated, and the current field of ICP-research is primarily focused on CTLA-4 and PD-1.


CTLA-4 is an ICP receptor present on the cell membrane of activated T-cells. With CTLA-4’s ability to downregulate effector T-cells’ activity and increase the activity of regulatory T-cells, CTLA- 4 plays an important role in the modulation of immune response [8,9].

The activation of T-cells requires signaling from two independent origins. Firstly, the T-cells are introduced with an antigen from the Antigen Presenting Cell (APC). Secondly, the binding of costimulatory receptor CD28 on T-cells to CD80/CD86 on the APC, resulting in an increase in the proliferation of T-cells and differentiation of T-cells into T-memory cells [10,11]. CTLA-4, a CD80 homologue, then binds to CD80/CD86 with greater affinity than its competitor CD28. This leads to the inhibition of T-cells, and subsequently avoiding hyperactivation of the immune system. The binding of CD28:CD80/86 initiates a positive response in which CTLA-4 is upregulated on the cell membrane [12]. Cancer cells disturb this pathway to their advantage, resulting in an immunosuppressive environment that prevents antitumor activity [13].

By inhibiting the CLTA-4 pathway with immunotherapy, it may be possible to hinder the immune-inactivated environment created by the cancer cells. This treatment may furthermore lead to activation and proliferation of effector T-cells and thereby increasing antitumor activity [14,15].


The PD-1/ Programmed Death Ligand 1 (PD-L1) pathway is another crucial pathway for the regulation of T-cell activity. Although similar to the CTLA-4 pathway, PD-L1 are expressed on numerous cells types and act in the peripheral tissue, whereas CTLA-4 are solely found on T-cells [16,17].

PD-1 is a transmembrane glycoprotein receptor expressed on CD4+ and CD8+ activated T-cells, B-lymphocytes, natural killer cells, and monocytes. The PD-1 receptor is a part of the CD28 superfamily and functions as an ICP and thereby decreases T-cell activity [18]. PD-1 has two primary ligands: programmed death-1 ligand 1(PDL1) and Programmed Death-Ligand 2 (PD-L2). When comparing the receptor affinity of PD-L1 and PD-L2, studies have shown that PD-L1 has a three times greater affinity to PD-1 than PD-L2 [19]. The PD-1/ PD-L1 checkpoint primarily functions as a regulator, preventing unwanted autoimmune-responses [20]. The expression of PD-L1 is initiated by interleukins that are produced when an interaction occurs between a T-cell and an antigen from an APC. The sudden expression of PD-L1 allows for the binding of PD-L1 to PD-1 and this binding initiates T-cell inhibition [21,22]. By overexpressing PD-L1, tumor cells hereby evade immune system activation and create an immunosuppressive microenvironment, favorable for their uncontrollable growth [23].

Inhibiting the PD-1/PD-L1 checkpoint with monoclonal antibodies may potentially reintroduce the T-cell antitumor activity and diminish the immunosuppressive microenvironment [24-26].

By creating a specific monoclonal antibody to inhibit the PD-1 immune checkpoint, the immune system’s awareness of cancer cells increases, and cytotoxic T-cells can once again react to the malignant tumor cells [27].


This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [28,29]. The PRISMA flow chart was used to map out the records identified, included, and excluded, and the reasons for exclusion, Figure 1.