Boosting the Immune Response—Combining Local and Immune Therapy for Prostate Cancer Treatment

Abstract

Due to its slow progression and susceptibility to radical forms of treatment, low-grade PC is associated with high overall survival (OS). With the clinical progression of PC, the therapy is becoming more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by e.g., immune evasion through Treg cells, synthesis of immunosuppressive mediators, and the defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of tumors and eliminate the immunosuppressive properties of the TME. In the settings of PC treatment, this can be commonly achieved with radiation therapy (RT). In addition, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), and irreversible electroporation (IRE) were shown to boost the anti-cancer response. Nevertheless, the present guidelines restrict their application to the context of a clinical trial or a prospective cohort study. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.

Cell Membrane Perforation: Patterns, Mechanisms and Functions

“…[211] Studies also indicated that irreversible electroporation has immunomodulatory activity and increases the level of tumor-infiltrating cells, decreases the level of regulatory T (T reg ) cells, and improves the therapeutic effect of immune checkpoint blockade. [212][213][214][215][216]…”

A Mathematical Model for Predicting Patient Responses to Combined Radiotherapy with CTLA-4 Immune Checkpoint Inhibitors

“…Despite the growing number of trials combining RT and ICI, whether the RT regimen in combination with ICI is the appropriate choice remains an open question, especially considering factors such as the timing of the radiation [5], sequencing [6], and patient selection [7]. Numerous studies [8][9][10][11][12] have investigated the integration of these treatments based on preclinical evidence demonstrating a synergistic interaction between them. However, it remains unclear how to optimally integrate these therapeutic modalities in the treatment of cancer patients.…”

Androgen receptor signaling blockade enhances NK cell-mediated killing of prostate cancer cells and sensitivity to NK cell checkpoint blockade

“…Although the first therapeutic cancer vaccine approved more than a decade ago targeted prostate tumors (sipuleucel-T), the clinical efficacy of immunotherapy for treating PCa remains limited, with poor responses to checkpoint inhibitors as monotherapy [3]. PCa tumors display an immunosuppressive tumor microenvironment mediated by reduced expression of human leucocyte antigen (HLA) surface expression, decreased neoantigen expression, phosphatase and tensin homolog (PTEN) protein loss, and dysfunction of interferon (IFN) type I signaling [4-5]. These factors contribute to low response rates to checkpoint inhibitors in most cases of mCRPC, except for MSI-H tumors and those with CDK12 mutations [6-7].…”