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Minerva Urologica E Nefrologica = the... Feb 2018To evaluate the available evidence on the standard diagnosis and management of men with metastatic castration resistant prostate cancer (mCRPC), and providing the timely... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
To evaluate the available evidence on the standard diagnosis and management of men with metastatic castration resistant prostate cancer (mCRPC), and providing the timely update on new pharmacological treatments.
EVIDENCE ACQUISITION
A systematic literature search from from January 2000 until March 2017 was performed by combining the following MESH terms: castrate resistant prostate cancer, abiraterone, enzalutamide, 223radium, sipuleucel-T, docetaxel, cabazitaxel, resistance mechanisms, resistance to androgen deprivation, androgen receptor (AR) mutations, amplifications, splice variants, and AR alterations. We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).
EVIDENCE SYNTHESIS
In the few last years the introduction of new treatment modalities as abiraterone or enzalutamide have significantly change our prospective in mCRPC management increasing patients survival and quality of life. The standard imaging modalities to define the presence of regional or distant metastasis or the different resistant mechanisms to the available treatments are still an issue of debate, however several studies are ongoing to define the standard of care and to reduce treatments' resistance. Data from ongoing phase III trials are awaited to introduce in clinical new effective treatments that can be used in patients resistant to abiraterone/enzalutamide or more probably in a different phase of the disease.
CONCLUSIONS
Castration resistant prostate cancer is now the key issue in prostate cancer management and research. Our challenge in the near future will be to identify the right treatment or better the right combination and sequencing of treatments that should be used in patients with mCRPC or even with advanced prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Quality of Life
PubMed: 28707844
DOI: 10.23736/S0393-2249.17.02976-9 -
Current Opinion in Supportive and... Sep 2017To provide an overview of current strategies being investigated in the development of immunotherapy in prostate cancer. (Review)
Review
PURPOSE OF REVIEW
To provide an overview of current strategies being investigated in the development of immunotherapy in prostate cancer.
RECENT FINDINGS
Development of immunotherapy in prostate cancer actually began in 2010 with FDA approval of sipuleucel-T. Given that immune checkpoint inhibitor trials have either been negative at the phase III level or underwhelming in smaller studies, it is likely that combination strategies will be required to further maximize the impact immune-based therapies on the clinical course of the disease. Emerging data suggests the presence of multiple checkpoint inhibitors in the prostate cancer tumor microenvironment highlighting the need for combination immunotherapy platforms that would potentially include androgen deprivation, chemotherapy, or radiation.
SUMMARY
Preclinical and clinical data support immune-based combinations in prostate cancer and several trials are underway to better define the future of immunotherapy in prostate cancer.
Topics: B7-H1 Antigen; Cancer Vaccines; Drug Therapy, Combination; Humans; Immunotherapy; Male; Neoplasm Metastasis; Programmed Cell Death 1 Receptor; Prostatic Neoplasms; Tissue Extracts
PubMed: 28644303
DOI: 10.1097/SPC.0000000000000278 -
Journal For Immunotherapy of Cancer Jun 2021Prostate cancer is the second leading cause of cancer-related death in men in the USA; death occurs when patients progress to metastatic castration-resistant prostate...
BACKGROUND
Prostate cancer is the second leading cause of cancer-related death in men in the USA; death occurs when patients progress to metastatic castration-resistant prostate cancer (CRPC). Although immunotherapy with the Food and Drug Administration-approved vaccine sipuleucel-T, which targets prostatic acid phosphatase (PAP), extends survival for 2-4 months, the identification of new immunogenic tumor-associated antigens (TAAs) continues to be an unmet need.
METHODS
We evaluated the differential expression profile of castration-resistant prostate epithelial cells that give rise to CRPC from mice following an androgen deprivation/repletion cycle. The expression levels of a set of androgen-responsive genes were further evaluated in prostate, brain, colon, liver, lung, skin, kidney, and salivary gland from murine and human databases. The expression of a novel prostate-restricted TAA was then validated by immunostaining of mouse tissues and analyzed in primary tumors across all human cancer types in The Cancer Genome Atlas. Finally, the immunogenicity of this TAA was evaluated in vitro and in vivo using autologous coculture assays with cells from healthy donors as well as by measuring antigen-specific antibodies in sera from patients with prostate cancer (PCa) from a neoadjuvant clinical trial.
RESULTS
We identified a set of androgen-responsive genes that could serve as potential TAAs for PCa. In particular, we found transglutaminase 4 (Tgm4) to be highly expressed in prostate tumors that originate from luminal epithelial cells and only expressed at low levels in most extraprostatic tissues evaluated. Furthermore, elevated levels of expression in primary PCa tumors correlated with unfavorable prognosis in patients. In vitro and in vivo assays confirmed the immunogenicity of TGM4. We found that activated proinflammatory effector memory CD8 and CD4 T cells were expanded by monocyte-derived dendritic cell (moDCs) pulsed with TGM4 to a greater extent than moDCs pulsed with either PAP or prostate-specific antigen (PSA), and T cells primed with TGM4-pulsed moDCs produce functional cytokines following a prime/boost regiment or in vitro stimulation. An IgG antibody response to TGM4 was detected in 30% of vaccinated patients, while fewer than 8% of vaccinated patients developed antibody responses to PSA or prostate-specific membrane antigen (PSMA).
CONCLUSIONS
These results suggest that TGM4 is an immunogenic, prostate-restricted antigen with the potential for further development as an immunotherapy target.
Topics: Animals; Humans; Immunotherapy; Male; Mice; Prostate; Transglutaminases
PubMed: 34193566
DOI: 10.1136/jitc-2020-001649 -
Clinical Cancer Research : An Official... Nov 2017In the last few years, immunotherapy has become an important cancer treatment modality, and although the principles of immunotherapy have evolved over many decades, the... (Review)
Review
In the last few years, immunotherapy has become an important cancer treatment modality, and although the principles of immunotherapy have evolved over many decades, the FDA approvals of sipuleucel-T and ipilimumab began a new wave in immuno-oncology. Despite the current enthusiasm, it is unlikely that any of the immunotherapeutics alone can dramatically change prostate cancer outcomes, but combination strategies are more promising and provide a reason for optimism. Several completed and ongoing studies have shown that the combination of cancer vaccines or checkpoint inhibitors with different immunotherapeutic agents, hormonal therapy (enzalutamide), radiotherapy (radium 223), DNA-damaging agents (olaparib), or chemotherapy (docetaxel) can enhance immune responses and induce more dramatic, long-lasting clinical responses without significant toxicity. The goal of prostate cancer immunotherapy does not have to be complete eradication of advanced disease but rather the return to an immunologic equilibrium with an indolent disease state. In addition to determining the optimal combination of treatment regimens, efforts are also ongoing to discover biomarkers of immune response. With such concerted efforts, the future of immunotherapy in prostate cancer looks brighter than ever. .
Topics: Cancer Vaccines; Combined Modality Therapy; Humans; Immunologic Factors; Immunomodulation; Immunotherapy; Immunotherapy, Adoptive; Male; Molecular Targeted Therapy; Prostatic Neoplasms
PubMed: 28663235
DOI: 10.1158/1078-0432.CCR-17-0019 -
Therapeutic Advances in Urology Aug 2016Prostate cancer is the most common cancer in men and the second most deadly. About one-third of patients with prostate cancer will develop metastatic disease. We discuss... (Review)
Review
Prostate cancer is the most common cancer in men and the second most deadly. About one-third of patients with prostate cancer will develop metastatic disease. We discuss the six United States Food and Drug Administration (FDA) approved treatments for metastatic castrate-resistant prostate cancer (mCRPC) with a strong focus on sipuleucel-T. Sipuleucel-T is the first immunotherapy shown to improve survival in asymptomatic or minimally-symptomatic mCRPC. Herein, we discuss the proposed mechanism of sipuleucel-T and its synthesis. We describe in detail the three randomized controlled trials (RTCs) that led to its approval. We also compiled the newest research regarding use of sipuleucel-T with other agents and in different patient populations. Finally, we discuss the current ongoing trials.
PubMed: 27928429
DOI: 10.1177/1756287216645314 -
Chinese Clinical Oncology Apr 2017Adoptive cell therapy (ACT) has been developed in cancer treatment by transferring/infusing immune cells into cancer patients, which are able to recognize, target, and... (Review)
Review
Adoptive cell therapy (ACT) has been developed in cancer treatment by transferring/infusing immune cells into cancer patients, which are able to recognize, target, and destroy tumor cells. Recently, sipuleucel-T and genetically-modified T cells expressing chimeric antigen receptors (CAR) show a great potential to control metastatic castration-resistant prostate cancer and hematologic malignancies in clinic. This review summarized some of the major evidence-based ACT and the challenges to improve cell quality and reduce the side effects in the field. This review also provided future research directions to make sure ACT widely available in clinic.
Topics: Cancer Vaccines; Humans; Immunotherapy, Adoptive; Male; Neoplasms; Prostatic Neoplasms, Castration-Resistant; T-Lymphocytes; Tissue Extracts
PubMed: 28482671
DOI: 10.21037/cco.2017.02.07 -
Journal of Stem Cells & Regenerative... 2014To prove clinical benefits of cancer vaccine is currently difficult, except for one phase III trial has documented improved overall survival with the vaccine,... (Review)
Review
To prove clinical benefits of cancer vaccine is currently difficult, except for one phase III trial has documented improved overall survival with the vaccine, Sipuleucel-T, although induction of anti-tumor immune responses through cancer vaccine is theoretically promising and would be straightforward. In contrast, immune checkpoint blockade with anti-CTLA4 mAb and anti-PD-1 mAb has demonstrated clear evidence of objective responses including improved overall survival and tumor shrinkage, driving renewed enthusiasm for cancer immunotherapy in multiple cancer types. In addition, there is a promising novel cancer immunotherapy, CAR therapy-a personalized treatment that involves genetically modifying a patient's T-cells to make them target tumor cells. We are now facing new era of cancer immunotherapy.
PubMed: 25075156
DOI: 10.46582/jsrm.1001003 -
Prostate Cancer and Prostatic Diseases Dec 2019Sipuleucel-T is an autologous cellular immunotherapy that is FDA approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant...
BACKGROUND
Sipuleucel-T is an autologous cellular immunotherapy that is FDA approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). The IMPACT registry trial demonstrated a 4.1 month survival benefit, but not a consistent PSA response or improvement in progression-free survival. Based upon several factors, including this lack of objective treatment response, sipuleucel-T has been under-utilized in this patient population, despite current NCCN recommendations.
METHODS
In order to explore if delayed treatment response occurs in a subset of patients, we performed a single institutional retrospective analysis of mCRPC patients treated with sipuleucel-T and ongoing ADT alone. Within that group, we then identified a subset of sipuleucel-T-treated men with long-term disease control and no additional interventions. To independently confirm this finding, we evaluated a total of 336 patients from 4 large urology group practices treated with sipuleucel-T between 2010 and 2014 and identified 44 patients who met the same criteria and demonstrated evidence of PSA stabilization post sipuleucel-T treatment.
RESULTS
For this subgroup of patients, 79% (95% CI: 64.5%, 88.1%) survived 36 months with a median time to subsequent therapy of 17.8 months (95% CI 10.3, 25.3).
CONCLUSIONS
Although patient selection could account for some or all of these results, these data support the utilization of sipuleucel-T alone in select mCRPC patients that is associated with a delay in disease progression and a good overall prognosis.
Topics: Aged; Aged, 80 and over; Cancer Vaccines; Disease Progression; Humans; Immunotherapy; Kallikreins; Male; Middle Aged; Prognosis; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Time Factors; Tissue Extracts
PubMed: 30980027
DOI: 10.1038/s41391-019-0144-3 -
Cancer Science Sep 2015Cancer immunotherapies such as sipuleucel-T and ipilimumab are promising new treatments that harness the power of the immune system to fight cancer and achieve... (Review)
Review
Cancer immunotherapies such as sipuleucel-T and ipilimumab are promising new treatments that harness the power of the immune system to fight cancer and achieve long-lasting remission. Interleukin (IL)-27, a member of the IL-12 heterodimeric cytokine family, has pleiotropic functions in the regulation of immune responses with both pro-inflammatory and anti-inflammatory properties. Evidence obtained using a variety of preclinical mouse models indicates that IL-27 possesses potent antitumor activity against various types of tumors through multiple mechanisms without apparent adverse effects. These mechanisms include those mediated not only by CD8(+) T cells, natural killer cells and macrophages, but also by antibody-dependent cell-mediated cytotoxicity, antiangiogenesis, direct antiproliferative effects, inhibition of expression of cyclooxygenase-2 and prostaglandin E2 , and suppression of epithelial-mesenchymal transition, depending on the characteristics of individual tumors. However, the endogenous role of IL-27 subunits and one of its receptor subunits, WSX-1, in the susceptibility to tumor development after transplantation of tumor cell lines or endogenously arising tumors seems to be more complicated. IL-27 functions as a double-edged sword: IL-27 increases IL-10 production and the expression of programmed death ligand 1 and T-cell immunoglobulin and mucin domain-3, and promotes the generation of regulatory T cells, and IL-27 receptor α singling enhances transformation; IL-27 may augment protumor effects as well. Here, we review both facets of IL-27, antitumor effects and protumor effects, and discuss the potential clinical application of IL-27 as an antitumor agent.
Topics: Animals; Antineoplastic Agents; Humans; Immunotherapy; Interleukin-27; Neoplasms
PubMed: 26132605
DOI: 10.1111/cas.12731 -
Expert Review of Clinical Pharmacology Oct 2021: The proven efficacy of the cellular vaccine sipuleucel-T in 2010 led to optimism about immunotherapeutic approaches for the treatment of prostate cancer. Some surmised... (Review)
Review
: The proven efficacy of the cellular vaccine sipuleucel-T in 2010 led to optimism about immunotherapeutic approaches for the treatment of prostate cancer. Some surmised that prostate cancer might be an ideal target for immune-mediated killing given that the prostate is not an essential organ and expresses unique proteins including prostate-specific antigen, prostate-specific membrane antigen, and prostatic acid phosphatase that could be targeted without side effects. Subsequently, antibodies that inhibit the T cell checkpoints PD1 and CTLA4 were shown to stimulate antitumor immune responses, leading to tumor regression in several cancer types. These therapies have since been tested in several studies as treatments for prostate cancer, but appear to have limited efficacy in molecularly unselected patients.: In this review, we discuss these studies and evaluate features of prostate cancer and its host environment that may render it generally resistant to CTLA4 and PD1 blockade. We provide an overview of alternate immune checkpoints that may hold greater significance in this disease.: Combination therapies to target multiple layers of alternate immune checkpoints may be required for an effective immune response to prostate cancer. We discuss combination therapies currently being investigated.
Topics: Cancer Vaccines; Drug Resistance, Neoplasm; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Male; Molecular Targeted Therapy; Patient Selection; Prostate-Specific Antigen; Prostatic Neoplasms; Tissue Extracts
PubMed: 34263692
DOI: 10.1080/17512433.2021.1949287