The Prostate Cancer Immune Microenvironment, Biomarkers and Therapeutic Intervention (original) (raw)
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Immunotherapy in Advanced Prostate Cancer: Current Knowledge and Future Directions
Biomedicines, 2022
The advent of immunotherapy has revolutionized cancer treatment. Unfortunately, this has not been the case for metastatic castration-resistant prostate cancer (mCRPC), likely due to the heterogeneous and immune-suppressive microenvironment present in prostate cancer. The identification of molecular biomarkers that could predict response to immunotherapy represents one of the current challenges in this clinical scenario. The management of advanced castration-resistant prostate cancer is rapidly evolving and immunotherapy treatments, mostly consisting of immune checkpoint inhibitors combinations, BiTE® (bispecific T-cell engager) immune therapies, and chimeric antigen receptors (CAR) are in development with promising results. This review analyses the current evidence of immunotherapy treatments for mCRPC, evaluating past failures and promising approaches and discussing the directions for future research.
Is There a Role for Immunotherapy in Prostate Cancer?
Cells, 2020
In the last decade, immunotherapy has revolutionized the treatment landscape of several hematological and solid malignancies, reporting unprecedented response rates. Unfortunately, this is not the case for metastatic castration-resistant prostate cancer (mCRPC), as several phase I and II trials assessing programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors have shown limited benefits. Moreover, despite sipuleucel-T representing the only cancer vaccine approved by the Food and Drug Administration (FDA) for mCRPC following the results of the IMPACT trial, the use of this agent is relatively limited in everyday clinical practice. The identification of specific histological and molecular biomarkers that could predict response to immunotherapy represents one of the current challenges, with an aim to detect subgroups of mCRPC patients who may benefit from immune checkpoint monoclonal antibodies as monotherapy or in combination with other anticancer a...
Immunotherapy in prostate cancer: current state and future perspectives
Therapeutic Advances in Urology, 2020
Metastatic castrate resistant prostate cancer (PCa) remains an incurable entity. In the era of immunotherapy, the complex PCa microenvironment poses a unique challenge to the successful application of this class of agents. However, in the last decade, a tremendous effort has been made to explore this field of therapeutics. In this review, the physiology of the cancer immunity cycle is highlighted in the context of the prostate tumor microenvironment, and the current evidence for use of various classes of immunotherapy agents including vaccines (dendritic cell based, viral vector based and DNA/mRNA based), immune checkpoint inhibitors, Chimeric antigen receptor T cell therapy, antibody-mediated radioimmunotherapy, antibody drug conjugates, and bispecific antibodies, is consolidated. Finally, the future directions for combinatorial approaches to combat PCa are discussed.
Immune Response Drives Outcomes in Prostate Cancer: Implications for Immunotherapy
2020
BackgroundThe heterogeneity of the immune microenvironment leads to the different response results of immune checkpoint blockade therapy. We aimed to propose a robust molecular classification of prostate cancer microenvironment to identify ideal patients for delivering effective immunotherapy.MethodsA total of 1,557 prostate cancer patients were enrolled in the current study, including 69 real-world samples from the AHMU-PC cohort. Non-negative matrix factorization algorithm was employed to virtually microdissect the patients to immune and non-immune subclasses. The patients in the immune class were dichotomized to immune activated and suppressed subtypes by the nearest template prediction of activated stroma signature. The curative effects of different immune subclasses in response to immunotherapy were also predicted.ResultsWe termed the newly identified molecular class of tumors as “immune class”, which was characterized by a high enrichment of T cell, B cell, NK cell, macrophage...
Cancers, 2012
Active immunotherapy is dependent on the ability of the immune system to recognize and respond to tumors. Despite overwhelming evidence to support a cell-mediated immune response to prostate cancer, it is insufficient to eradicate the disease. This is likely due to a high level of suppression at the tumor site from a variety of sources, including immunosuppressive cells. Immune cells entering the tumor microenvironment may be inhibited directly by the tumor, stromal cells or other immune cells that have been induced to adopt a suppressive phenotype. The resurgence of interest in immunotherapy following the approval of sipuleucel-T and ipilimumab by the Food and Drug Administration has brought about new strategies for overcoming tumor-mediated suppression and bolstering anti-tumor responses. Improved understanding of the immune response to prostate cancer can lead to new combination therapies, such as the use of vaccine with small molecule and checkpoint inhibitors or other immunotherapies.
Immunotherapy for Prostate Cancer: Recent Advances, Lessons Learned, and Areas for Further Research
Clinical Cancer Research, 2011
A surge of interest in therapeutic cancer vaccines has arisen in the wake of recent clinical trials suggesting statistically significant and clinically meaningful improvements in overall survivalwith substantially limited side effects compared with chemotherapy-in patients with metastatic castration-resistant prostate cancer. One of these trials led to the registration of sipuleucel-T, the first approved therapeutic vaccine for cancer patients. This review highlights emerging patterns from clinical trials suggesting more appropriate patient populations (i.e., lower tumor volume, less aggressive disease) and endpoints (i.e., overall survival) for studies of immunotherapy alone, as well as biologically plausible explanations for these findings. We also explore the rationale for ongoing and planned studies combining therapeutic vaccines with other modalities. Finally, we attempt to put these findings into a practical clinical context and suggest fertile areas for future study. While our discussion focuses on prostate cancer, the concepts we address most likely have broad applicability to immunotherapy for other cancers as well.
Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer
Cancers
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 t...
Challenges in Manipulating Immune System to Treat Prostate Cancer
PubMed, 2019
First cancer vaccine that was approved for routine therapy was sipuleucel-T for treatment of patients with metastatic castration resistant prostate cancer. However, other immunotherapy drugs evaluated in prostate cancer, particularly immune checkpoint inhibitors, have failed to show therapeutic effect. There are several potential explanations for lack of response of prostate cancer to these drugs. These explanations, which are related to specific genetic (e.g. low mutational burden) and immunological (e.g. immunosuppressive tumor immune microenvironment) background of prostate cancer are discussed in this review. Also, new therapeutic strategies to overcome prostate cancer immunotherapy resistance and to select subgroups of patients that could benefit from immunotherapy are outlined.
From Bench to Bedside: Immunotherapy for Prostate Cancer
BioMed Research International, 2014
The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided.
Immunotherapy for Castration-Resistant Prostate Cancer
Urologic Clinics of North America, 2012
Background: The approval of sipuleucel-T in conjunction with data from other immunotherapeutic trials for prostate cancer and other solid tumors demonstrates the potential of harnessing the patient's immune system for long-term survival. Thus, a range of therapeutic approaches are under evaluation. This review describes the rationale for immunotherapy for prostate cancer, summarizes the approaches under evaluation, and discusses sequencing options for immunotherapy in the current treatment paradigm. Design: References for this review were identified through searches of PubMed with the search terms "prostate cancer," "immune system," "vaccine," "immunotherapy," and "T cells." Articles were also identified through searches of the authors' own files. The final reference list was generated based on originality and relevance. Results: The immune system can recognize and respond to prostate tumor antigens, effected through tumor-associated antigens and tumor infiltration of immune effector cells. However, evidence also suggests that prostate tumors are adept at escaping immunological recognition, thus hypothesizing multiple therapeutic strategies. Therapeutic approaches could include vaccination and modulation of T-cell function via the blockade of checkpoint receptors such as cytotoxic T-lymphocyte antigen-4 and programmed death 1. In phase III trials, sipuleucel-T improved overall survival for an M1 patient population with castration-resistant prostate cancer and ipilimumab also did so when given after radiotherapy in a subset of better risk patients. In randomized phase II trials, prostate-specific antigen-TRICOM improved overall survival and tasquinimod improved progression-free survival. Conclusion: Although immunotherapy has the potential to affect advanced prostate cancer, additional research is needed to (1) identify predictive or surrogate markers of activity, (2) understand which agents are clinically effective alone or in combination with other therapies, and (3) define the optimal timing for an immunotherapy to achieve maximal benefit.