Immunotherapy for Prostate Cancer – turning the immunological desert into an oasis of hope

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Background

The development of effective immunotherapies for cancer has been one of the major developments in oncology within the last 10 years, stimulated by breakthroughs in the knowledge of both the function of immune effector cells and the barriers and defences exerted by the tumour microenvironment. One of the greatest advances was the discovery of molecules on T cells, known as immune checkpoints, that could stop the activity of these cells. This discovery has propelled remarkable advances in the survival of patients with certain cancers such as melanoma, renal cell carcinoma, and lung cancer. For example, patients with advanced metastatic melanoma now achieve over 50% survival over 5 years with combined treatment with anti-CTLA-4 and anti-PD1 antibodies (Ipilimumab (Yervoy™) and nivolumab (Opdivo™) whereas before the advent of these drugs, average survival was from 6 to 9 months.

There are advantages of immunotherapy versus other types of cancer treatment. First, there is the possibility of a long, durable response, where memory T cells are involved, which could stop recurrence. Second, the potential to clear metastases promises to be more significant than any other form of treatment.

The treatment of prostate cancer using immunotherapy has long been considered a desirable goal, due to the lack of therapies that can target metastatic disease and the side effects of current treatments from early to late stage disease, including incontinence and impotence arising from surgery, resistance developing to hormone treatment, and recurrence after radiotherapy or chemotherapy. Prostate cancer is the most common and the second most mortal cancer in men. Therefore, despite the larger percentage of men surviving late-stage prostate cancer after 5 years (20-30%) compared with cancers such as melanoma, the number of men dying is still considerably high, overtaking deaths from breast cancer in 2019.

Over fifteen years ago, the knowledge that prostatic antigens such as prostate-specific acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), and NKX3.1 are present on cancer cells in higher amounts than on normal cells led to the advent of prostate cancer vaccines, such as Provenge™, that created new interest in the use of immunotherapies against prostate cancer. However, in more recent years, it has been shown that the prostate cancer microenvironment exerts considerable immunosuppressive effects as shown by the presence of anergic NK and T cells, and regulatory T cell populations with the milieu and the conversion of active CD8 T cells into regulatory cells once reaching this environment. Moreover, prostate cancer has been described as an immunological desert, or “immunologically cold”, where few T cells infiltrate tumours, compared with tumours such as melanoma. This has been demonstrated by the relative lack of success observed with immune checkpoint inhibitors, where, in all but a small minority of patients, no significant clinical responses have been observed with well-known checkpoint immunotherapies such as Ipilimumab, anti-PDL1 or anti-PD-1.

The purpose of this Research Topic is to put forward the evidence that immunotherapy can be a new hope for prostate cancer. In this issue, a range of therapeutic solutions will be demonstrated to illustrate the potential and actual success of immunotherapies in prostate cancer. We will focus on the following topics:

1. Vaccines beyond Provenge: the potential of oncolytic viruses and new vaccine approaches
2. Making checkpoint inhibitors work in prostate cancer: turning on neoantigens by increasing mutational burden to drive the creation of T cells and thus switch on the efficacy of checkpoint inhibitors
3. Using immunostimulatory agents such as cytokines and STING agonists to drive the activation and expansion of NK cells, dendritic cells and CD8 T cells
4. Changing the microenvironment of prostate cancer: the use of inhibitors to target suppressor macrophages and address the role of the stroma in the tumour microenvironment
5. The use of combination therapies, with combination of immunotherapies, or immunotherapies plus radiotherapy, chemotherapies or hormonal therapies.
We believe that this Research Topic issue will inform and create a forum for the development of novel immunotherapeutic approaches for prostate cancer.

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