Submit to Cancers Review for Cancers Propose a Special Issue

Journal Browser

► Journal Browser

The Use of Combination Therapies to Treat Castration-Resistant Prostate Cancer

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 16989

Share This Special Issue

Special Issue Editors

Prof. Hardev Pandha

E-Mail Website
Guest Editor

Professor of Medical Oncology, Consultant Physician in Medical Oncology Director, Surrey Cancer Research Institute Faculty of Health and Medical Sciences University of Surrey, Guildford, Surrey, United Kingdom GU2 7WG, UK
Interests: tumour immunology; urological cancer; malignant melanoma; gene therapy

Dr. Stephanie McArdle

E-Mail Website
Guest Editor

The John van Gets Cancer Research Centre, Nottingham Trent University, Nottingham NG1 8NS, UK
Interests: peptide vaccines for the treatment of aggressive prostate cancer; TNBC and GBM
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The majority of prostate cancer cases are diagnosed while the cancer is still confined to the prostate and nearby organs, and the 5 years survival for these men is 100% which is, however, reduced by a third if, at the time of diagnosis, the cancer has already spread to other parts of the body. Standard therapy for organ confined prostate cancer include active surveillance, external beam radiotherapy, brachytherapy and radical prostatectomy. The treatment of metastatic disease involves androgen deprivation therapy (ADT), and either possibly up-front docetaxel chemotherapy or abiraterone or, upon progression, the subsequent addition of anti-androgens (abiraterone or enzalutamide) to ADT. Prolonged ADT and sequential therapies promote the development of a neuroendocrine prostate cancer phenotype (NEPC). NEPC is characterized by loss of AR expression, and resistance to hormonal therapies. NEPC is a poorly defined clinical phenotype of aggressive disease and causes approximately 10–25% of prostate cancer-related deaths.

Although the emergence of immunotherapeutic approaches has delivered significant benefits across a range of immunogenic tumors, the same impact has yet to be seen for prostate cancer, for which there are a number of potential reasons, including the establishment of an immunosuppressive TME which can be driven, at least in part, by the presence of MDSCs, depression and chronic cellular stress. Notwithstanding this, evidence supports the concept that inducing immunity to prostate-related proteins such as prostatic acid phosphatase (PAP) can be of therapeutic benefit.

Therefore, improving the efficacy of immunotherapies requires approaches to attenuate the immunosuppressive nature of the TME, to take into account the different immunological challenge of NEPC and the impact of depression or chronic stress.

This Special Issue will take a closer look at the latest immunotherapy treatments being assessed to treat hormone resistant prostate cancer with a focus on NEPC.

Prof. Hardev Pandha
Dr. Stephanie McArdle
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Hormone resistant prostate cancer
NEPC
immunotherapy
combination therapy

Published Papers (4 papers)

Download All Papers

Research

Jump to: Review

27 pages, 2589 KiB

Open AccessArticle

A Mutated Prostatic Acid Phosphatase (PAP) Peptide-Based Vaccine Induces PAP-Specific CD8⁺ T Cells with Ex Vivo Cytotoxic Capacities in HHDII/DR1 Transgenic Mice

by Pauline Le Vu, Jayakumar Vadakekolathu, Sarra Idri, Holly Nicholls, Manon Cavaignac, Stephen Reeder, Masood A. Khan, Dennis Christensen, Alan Graham Pockley and Stéphanie E. McArdle

Cancers 2022, 14(8), 1970; https://doi.org/10.3390/cancers14081970 - 13 Apr 2022

Cited by 2 | Viewed by 2160

Abstract

Background: Current treatments for castrate (hormone)-resistant prostate cancer (CRPC) remain limited and are not curative, with a median survival from diagnosis of 23 months. The PAP-specific Sipuleucel-T vaccine, which was approved by the FDA in 2010, increases the Overall Survival (OS) by 4 months, but is extremely expensive. We have previously shown that a 15 amino accid (AA) PAP sequence-derived peptide could induce strong immune responses and delay the growth of murine TRAMP-C1 prostate tumors. We have now substituted one amino acid and elongated the sequence to include epitopes predicted to bind to several additional HLA haplotypes. Herein, we present the immunological properties of this 42mer-mutated PAP-derived sequence (MutPAP42mer). Methods: The presence of PAP-135-143 epitope-specific CD8⁺ T cells in the blood of patients with prostate cancer (PCa) was assessed by flow cytometry using Dextramer™ technology. HHDII/DR1 transgenic mice were immunized with mutated and non-mutated PAP-derived 42mer peptides in the presence of CAF^®09 or CpG ODN1826 (TLR-9 agonist) adjuvants. Vaccine-induced immune responses were measured by assessing the proportion and functionality of splenic PAP-specific T cells in vitro. Results: PAP-135-143 epitope-specific CD8⁺ T cells were detected in the blood of patients with PCa and stimulation of PBMCs from patients with PCa with mutPAP42mer enhanced their capacity to kill human LNCaP PCa target cells expressing PAP. The MutPAP42mer peptide was significantly more immunogenic in HHDII/DR1 mice than the wild type sequence, and immunogenicity was further enhanced when combined with the CAF^®09 adjuvant. The vaccine induced secretory (IFNγ and TNFα) and cytotoxic CD8⁺ T cells and effector memory splenic T cells. Conclusions: The periphery of patients with PCa exhibits immune responsiveness to the MutPAP42mer peptide and immunization of mice induces/expands T cell-driven, wild-type PAP immunity, and therefore, has the potential to drive protective anti-tumor immunity in patients with PCa. Full article

(This article belongs to the Special Issue The Use of Combination Therapies to Treat Castration-Resistant Prostate Cancer)

► Show Figures

Figure 1

Review

Jump to: Research

39 pages, 4085 KiB

Open AccessReview

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

by Erin G. Shackleton, Haleema Yoosuf Ali, Masood Khan, Graham A. Pockley and Stephanie E. McArdle

Cancers 2021, 13(5), 1145; https://doi.org/10.3390/cancers13051145 - 8 Mar 2021

Cited by 13 | Viewed by 5074

Abstract

Prostate cancer (PCa) is the second-most common cancer in men worldwide and treatment options for patients with advanced or aggressive prostate cancer or recurrent disease continue to be of limited success and are rarely curative. Despite immune checkpoint blockade (ICB) efficacy in some melanoma, lung, kidney and breast cancers, immunotherapy efforts have been remarkably unsuccessful in PCa. One hypothesis behind this lack of efficacy is the generation of a distinctly immunosuppressive prostate tumor microenvironment (TME) by regulatory T cells, MDSCs, and type 2 macrophages which have been implicated in a variety of pathological conditions including solid cancers. In PCa, Tregs and MDSCs are attracted to TME by low-grade chronic inflammatory signals, while tissue-resident type 2 macrophages are induced by cytokines such as IL4, IL10, IL13, transforming growth factor beta (TGFβ) or prostaglandin E2 (PGE2) produced by Th2 cells. These then drive tumor progression, therapy resistance and the generation of castration resistance, ultimately conferring a poor prognosis. The biology of MDSC and Treg is highly complex and the development, proliferation, maturation or function can each be pharmacologically mediated to counteract the immunosuppressive effects of these cells. Herein, we present a critical review of Treg, MDSC and M2 involvement in PCa progression but also investigate a newly recognized type of immune suppression induced by the chronic stimulation of the sympathetic adrenergic signaling pathway and propose targeted strategies to be used in a combinatorial modality with immunotherapy interventions such as ICB, Sipuleucel-T or antitumor vaccines for an enhanced anti-PCa tumor immune response. We conclude that a strategic sequence of therapeutic interventions in combination with additional holistic measures will be necessary to achieve maximum benefit for PCa patients. Full article

(This article belongs to the Special Issue The Use of Combination Therapies to Treat Castration-Resistant Prostate Cancer)

► Show Figures

Figure 1

22 pages, 2037 KiB

Open AccessEditor’s ChoiceReview

Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer

by Dhruv Bansal, Melissa A. Reimers, Eric M. Knoche and Russell K. Pachynski

Cancers 2021, 13(2), 334; https://doi.org/10.3390/cancers13020334 - 18 Jan 2021

Cited by 42 | Viewed by 5692

Abstract

Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents’ combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC. Full article

(This article belongs to the Special Issue The Use of Combination Therapies to Treat Castration-Resistant Prostate Cancer)

► Show Figures

Figure 1

23 pages, 678 KiB

Open AccessReview

Treatment Combinations with DNA Vaccines for the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC)

by Melissa Gamat-Huber, Donghwan Jeon, Laura E. Johnson, Jena E. Moseman, Anusha Muralidhar, Hemanth K. Potluri, Ichwaku Rastogi, Ellen Wargowski, Christopher D. Zahm and Douglas G. McNeel

Cancers 2020, 12(10), 2831; https://doi.org/10.3390/cancers12102831 - 30 Sep 2020

Cited by 13 | Viewed by 3348

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a challenging disease to treat, with poor outcomes for patients. One antitumor vaccine, sipuleucel-T, has been approved as a treatment for mCRPC. DNA vaccines are another form of immunotherapy under investigation. DNA immunizations elicit antigen-specific T cells that cause tumor cell lysis, which should translate to meaningful clinical responses. They are easily amenable to design alterations, scalable for large-scale manufacturing, and thermo-stable for easy transport and distribution. Hence, they offer advantages over other vaccine formulations. However, clinical trials with DNA vaccines as a monotherapy have shown only modest clinical effects against tumors. Standard therapies for CRPC including androgen-targeted therapies, radiation therapy and chemotherapy all have immunomodulatory effects, which combined with immunotherapies such as DNA vaccines, could potentially improve treatment. In addition, many investigational drugs are being developed which can augment antitumor immunity, and together with DNA vaccines can further enhance antitumor responses in preclinical models. We reviewed the literature available prior to July 2020 exploring the use of DNA vaccines in the treatment of prostate cancer. We also examined various approved and experimental therapies that could be combined with DNA vaccines to potentially improve their antitumor efficacy as treatments for mCRPC. Full article

(This article belongs to the Special Issue The Use of Combination Therapies to Treat Castration-Resistant Prostate Cancer)

► Show Figures