immunotherapy for prostate cance

An Overview of Immunotherapy: The Potential Treatment for Prostate Cancer
Prostate cancer (PC) is the world’s second most prevalent malignant condition in men after lung cancer, with 1,276,106 new diagnoses and 358,989 deaths (3.8 % of all men’s cancer deaths) in 2018 [1,2]. The prevalence and death of prostate cancer globally correspond with the average age of 66 years when diagnosed. Notably, for African-American men, prevalence rates are higher relative to white men, with 158.3 new cases diagnosed per 100,000 men, and their mortality is almost twice as white men [3]. Reasons for this imbalance is speculated for social, environmental and genetic differences. Even though 2,293,818 new cases are expected before 2040, the mortality rate will be expected to rise up to 1.05% [4]. Optimal prostate cancer treatment appears to be challenging. Current treatment methods include surgery, radiotherapy, cryosurgery, hormonal therapy, chemotherapy, immunotherapy etc for the prevention of prostate cancer, which can help monitor and avoid the life-threatening condition (17).
Surgery is not considered as the monotherapy but it is one of the multimodality approaches for men with prostate cancer. Surgery is primarily prescribed for locally advanced prostate carcinoma which are at high risk. The two popular forms of surgery in prostate cancer are pelvic lymphadenectomy (PLDN) and radical prostatectomy (RP). PLND is the most reliable method for diagnosis of lymph node metastases in prostate cancer, however its clinical advantages are debatable in the treatment. PLND is usually recommended for high-risk prostate cancer during RP as 15% to 40% of nodes would get positive result [18]. High risk RP for prostate cancer is usually avoided due to the side impacts, such as high rates of positive surgical margins, high rates of prostate specific antigen (PSA) recurrence and risk of metastasis of the lymph node [19].
The second major treatment technique for localised high-risk prostate cancer is radiation therapy. Brachytherapy and External beam radiation therapy (EBRT) are commonly used prostate cancer treatment techniques with substantial scientific and clinical advancement in recent decades. EBRT uses high energy beams during the treatment which can cause secondary cancers in the region of the radiation [20]. Cryosurgery is a treatment technique that uses intense cold temperature to kill prostate tumour cells. It is recommended for localised low risk prostate cancer [21]. Chemotherapy is known to be the least effective way to treat the cancer, it only helps to slow down the cancer’s growth but does not cure the prostate cancer completely [17].
Immunotherapy includes several immune mechanisms such as promoting the identification and removal of non-self antigens, priming T cells, increasing or propagating antigen appearance, enhancing T cell mediated lysis, activating B lymphocytes, and inducing humoral responses. The prostate cancer can be immunogenic as the microenvironment of the tumour generates various specific tumour associated antigens (TAAs) such as prostate acid phosphatase [PAP], prostate specific antigen [PSA] and prostate-specific membrane antigen [PSMA] which are used as targets during immunotherapy [22] including tumour infiltrating lymphocytes (TILs) known as natural killer (NK) cells, CD4 and CD8 T cell, macrophages and dendritic cells (DCs) within the tumour [23]. Although highly immunosuppressive micro-environment is likely to obstruct prostate cancer immunogenicity due to the existence of regulatory T Cells (Tregs) or the improper functionality of TILs [24]. High risk prostate cancer with weaker prognosis shows lower T-cell and DC infiltration and high prevalence of tumour associated macrophages and Tregs. However, increased NK cell infiltration within tumours is linked to low risk of prostate cancer development [25]. The immunosuppressive microenvironment can be defeated by generating immune response against tumour cells using immunotherapy.
Charles Huggins discovered in the 1940s that prostate cancer can decline in response to androgen ablation, and ever since then targeting the androgen receptor (AR) signalling axis remains the hallmark of advanced prostate cancer treatment [5,6]. Despite the initially high success rates of androgen depletion therapies and medications are far from curative and eventually, the condition can advance to a pathological state known as castration-resistant prostate cancer (CRPC) [7].
Immunotherapy can be categorised into four types: cancer vaccine, T cell therapy, cytokines and checkpoint inhibitors. In 2004, docetaxel was the first agent to prolong the survival for men with CRPC [8,9]. It received Food and Drug Administration (FDA) clearance in 2005, followed by sipuleucel-T in 2010 [10, 11]. A cell-based autologous antigen (APC), sipuleucel-T was the only cancer vaccine approved to treat metastatic prostate cancer. Cabazitaxel, abiraterone, enzalutamide and radium-223 all have been shown to extend life for men with advanced prostate cancer, eventually receiving approval for the treatment of men with CRPC [12-16]. There are different types of immune checkpoint blockers such as cytotoxic T lymphocyte antigen 4 (CTLA-4) which is maintained in immunotherapy by downregulating T cell activation and in the aspects of checkpoint inhibition for prostate cancer after that which looks into the conventional cytotoxic agents and also the therapies of receptor target. Another undergoing clinical trial, FDA-approved checkpoint is anti-CTLA-4 blocking antibody ipilimumab which is able to treat advanced melanoma. Till date there are around 6 antibodies targeting Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), these checkpoints regulate immunosuppression and treat solid tumour and melanoma. 28
An essential cytokine for cancer immunotherapy is interleukin 2 (IL-2) which mediates T-cell activation and recruitment. Interleukin-15 (IL-15) is also one of the effective cytokines for cancer immunotherapy which has many biological roles similar to IL-2. Activation-induced cell death (AICD) of CD8 effector T cells causes IL-2 to prevent T cell responses by removing self-reactive T cells, it is also involved in the preservation and retention of Tregs. In comparison, IL-15 plays an important role in the survival of CD8 memory T cells, activation of T and NK cells, in the inhibition of AICD although it does not affect Tregs. IL-15’s distinct functions allow it more suitable for cancer immunotherapy. 29
The purpose of this review is to critically compare clinical trials of several immunotherapies such as vaccine, checkpoints and cytokines and analyse the best type of immunotherapy to treat the prostate cancer.

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