Seminar Article
Utilizing precision medicine to modulate the prostate tumor microenvironment and enhance immunotherapy

https://doi.org/10.1016/j.urolonc.2018.11.009Get rights and content

Abstract

The last two decades of cancer research have seen two major advancements in our ability to treat cancer: precision medicine and immunotherapy. While these approaches have shown striking anticancer efficacy in numerous malignancies, they have not shown similar success and applicability in advanced prostate cancer patients. The fields of precision medicine and immunotherapy have come to realize that targeted therapies are capable of not only inhibiting tumor cell growth, but also promoting antitumor immunity by modulating the tumor microenvironment. Here we examine how personalized medicine can be used to target the tumor immune microenvironment in prostate cancer, with the goal of enhancing clinical responses to immunotherapy.

Introduction

As technological advances have expanded our ability to identify, isolate, and interrogate unique genetic changes within an individual patient's tumor, so has the effort to develop therapeutic agents that can be used to target these specific alterations. This precision medicine revolution–characterizing the genomics of individual patient tumor samples to develop a personalized treatment regimen targeting aberrations critical to the growth and progression of that unique cancer–has led to a fundamental reconsideration of how we can most effectively treat cancer. In several malignancies with well-defined genomic alterations, utilizing personalized targeted therapies has led to dramatic clinical successes. For example, the use of monoclonal antibodies such as trastuzumab to target human EGF receptor 2 (HER-2) positive breast cancer [1], or small molecule tyrosine kinase inhibitors such as imatinib to target the breakpoint cluster region (BCR)- Abelson (ABL) fusion protein in chronic myelogenous leukemia [2], have elicited clinical responses that have significantly changed the clinical management of these diseases. However, similar advances in personalized medicine have not been seen in the treatment of prostate cancer (CaP), despite continued research into the genomic alterations that occur throughout the development and progression of this disease.

CaP remains one of the most significant health concerns for men, being the most commonly diagnosed and second leading cause of cancer related death in American men [3]. While organ-confined disease can be treated with localized therapies, about a third of patients relapse and develop biochemically-recurrent disease, and are treated with androgen deprivation, which targets the aberrant and critical activity of the androgen receptor (AR) [4]. While most patients experience a period of disease regression, tumors invariably recur as castrate-resistant disease, which often metastasize to the lymph node, bone, and other tissue sites. Metastatic, castrate-resistant CaP (mCRPC) is lethal, despite several new therapeutic options having been approved for patients with this late stage of disease, including second-generation agents targeting the activity of the AR such as abiraterone [5] and enzalutamide [6], taxane-based chemotherapies such as docetaxel [7], bone-targeting radiation therapy radium-223 [8], and the immunotherapy sipuleucel-T [9]. However, these agents provide a relatively small median benefit in overall survival, highlighting the urgent need for more effective therapies for patients with advanced disease.

Section snippets

CaP immunotherapy and the tumor immune microenvironment

Like most cancers, the development and progression of CaP occurs within a complex tumor microenvironment composed of tumor cells as well as fibroblasts, endothelial cells, extracellular matrix components, and various immune populations. While this includes immune cells with potential antitumor activity (including T cells [10], [11], [12], [13] and NK cells [14]), there are also several suppressive immune populations that are elevated in CaP patients, including regulatory T cells [13],

Using personalized targeted therapies to modulate the prostate tumor immune microenvironment

The advancement of precision medicine has led to an increased understanding of the genomic factors that contribute to the development and progression of CaP. Given the ease of access to primary prostate tumor samples, several studies have provided an in-depth characterization of alterations that occur during the development of localized CaP [40], [41], [42], [43], [44], [45], [46], [47]. While these studies have identified the range of alterations that occur throughout the development and

Future directions

One of the central challenges in evaluating how targeted therapies and immunotherapies modulate the mCRPC tumor microenvironment is the difficulty in obtaining series biopsies of metastatic lesions. As CaP most commonly metastasizes to the bone, obtaining viable tumor material from pre- and post-treatment biopsy samples presents logistical, economic, and technical hurdles that have hindered their widespread incorporation into mCRPC clinical trials. Additionally, when tissue can be procured,

Conflicts of interest

The authors declare no relevant potential conflicts of interest.

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    Funding: This work was supported by the American Cancer Society (131569-IRG-17-181-04-IRG; BMO).

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