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Prostate cancer immunotherapy: Improving clinical outcomes with a multi-pronged approach.

ABSTRACT: Cancer immunotherapy has gained traction in recent years owing to remarkable tumor clearance in some patients. Despite the notable success of immune checkpoint blockade (ICB) in multiple malignancies, engagement of the immune system for targeted prostate cancer (PCa) therapy is still in its infancy. Multiple factors contribute to limited response, including the heterogeneity of PCa, the cold tumor microenvironment, and a low number of neoantigens. Significant effort is being invested in improving immune-based PCa therapies. This review is a summary of the status of immunotherapy in treating PCa, with a discussion of multiple immune modalities, including vaccines, adoptively transferred T cells, and bispecific T cell engagers, some of which are undergoing clinical trials. In addition, this review also focuses on emerging mechanism-based small-molecule tyrosine kinase inhibitors with immune modulatory properties that, either as single agents or in combination with other immunotherapies, have the potential to improve clinical outcomes.

SUBMITTER: Sridaran D

PROVIDER: S-EPMC10591038 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Prostate cancer immunotherapy: Improving clinical outcomes with a multi-pronged approach.

Sridaran Dhivya D Bradshaw Elliot E DeSelm Carl C Pachynski Russell R Mahajan Kiran K Mahajan Nupam P NP

Cell reports. Medicine 20230921 10

Cancer immunotherapy has gained traction in recent years owing to remarkable tumor clearance in some patients. Despite the notable success of immune checkpoint blockade (ICB) in multiple malignancies, engagement of the immune system for targeted prostate cancer (PCa) therapy is still in its infancy. Multiple factors contribute to limited response, including the heterogeneity of PCa, the cold tumor microenvironment, and a low number of neoantigens. Significant effort is being invested in improvin ...[more]

PMID: 37738978

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Project description:BackgroundProstate cancer (PCa), a globally prevalent malignancy, displays intricate heterogeneity within its epithelial cells, closely linked with disease progression and immune modulation. However, the clinical significance of genes and biomarkers associated with these cells remains inadequately explored. To address this gap, this study aimed to comprehensively investigate the roles and clinical value of epithelial cell-related genes in PCa.MethodsLeveraging single-cell sequencing data from GSE176031, we conducted an extensive analysis to identify epithelial cell marker genes (ECMGs). Employing consensus clustering analysis, we evaluated the correlations between ECMGs, prognosis, and immune responses in PCa. Subsequently, we developed and validated an optimal prognostic signature, termed the epithelial cell marker gene prognostic signature (ECMGPS), through synergistic analysis from 101 models employing 10 machine learning algorithms across five independent cohorts. Additionally, we collected clinical features and previously published signatures from the literature for comparative analysis. Furthermore, we explored the clinical utility of ECMGPS in immunotherapy and drug selection using multi-omics analysis and the IMvigor cohort. Finally, we investigated the biological functions of the hub gene, transmembrane p24 trafficking protein 3 (TMED3), in PCa using public databases and experiments.ResultsWe identified a comprehensive set of 543 ECMGs and established a strong correlation between ECMGs and both the prognostic evaluation and immune classification in PCa. Notably, ECMGPS exhibited robust predictive capability, surpassing traditional clinical features and 80 published signatures in terms of both independence and accuracy across five cohorts. Significantly, ECMGPS demonstrated significant promise in identifying potential PCa patients who might benefit from immunotherapy and personalized medicine, thereby moving us nearer to tailored therapeutic approaches for individuals. Moreover, the role of TMED3 in promoting malignant proliferation of PCa cells was validated.ConclusionsOur findings highlight ECMGPS as a powerful tool for improving PCa patient outcomes and supply a robust conceptual framework for in-depth examination of PCa complexities. Simultaneously, our study has the potential to develop a novel alternative for PCa diagnosis and prognostication.

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Project description:BackgroundTherapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients. We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simple mathematical models.Methodology/principal findingsWe developed a general mathematical model encompassing the basic interactions of a vaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cell vaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes in prostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were divided into each patient's training set and his validation set. The training set, used for model personalization, contained the patient's initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized models were simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set. The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients (the coefficient of determination between the predicted and observed PSA values was R(2) = 0.972). The model could not account for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validated personalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccination regimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Conclusions/significanceUsing a few initial measurements, we constructed robust patient-specific models of PCa immunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value and feasibility of individualized model-suggested immunotherapy protocols.

Dataset Information

Prostate cancer immunotherapy: Improving clinical outcomes with a multi-pronged approach.

Publications

Prostate cancer immunotherapy: Improving clinical outcomes with a multi-pronged approach.

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