Prostate Cancer Immunotherapy Research Articles

DNA Damage Response Inhibitor and Anti-PD-L1 Therapy for Prostate Cancer: Development of Predictive Biomarkers

Despite significant benefit for other cancer subtypes, immune checkpoint therapy (ICT) has not yet been shown to significantly improve outcomes for men with castrationresistant prostate cancer (CRPC). Previous studies have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICT response in prostate cancer and potentially oither solid tumors, in part due to the induction of innate immune activation and regulation of the tumor cell– and/or immune cell–expressed B7 immune checkpoint protein PD-L1, which can be targeted by anti-PD-L1 agents. With this information and orientation, development of PD-L1 expression as a potential predictive biomarker for clinical response to ICT therapy has received widespread attention. However, the complex heterogeneous expression patterns of tumor cell–expressed PD-L1 and its related posttranslational modification in tumors substantially complicate detection and interpretation of PD-L1 in clinical samples using IHC and currently available PD-L1 antibodies. We discuss the potential roles of PD-L1 in prostate cancer and potential approaches to more accurately detect its expression in clinical tumor samples. Additional understanding of PD-L1 functions and development of improved methods to detect PD-L1 as a predictive biomarker for prostate cancer immunotherapy will likely benefit patients with advanced prostate cancer.

Overcoming Immune Resistance With Radiation Therapy in Prostate Cancer.

Prostate cancer is the second most common cancer in men and represents a significant healthcare burden worldwide. Therapeutic options in the metastatic castration-resistant setting remain limited, despite advances in androgen deprivation therapy, precision medicine and targeted therapies. In this review, we summarize the role of immunotherapy in prostate cancer and offer perspectives on opportunities for future development, based on current knowledge of the immunosuppressive tumor microenvironment. Furthermore, we discuss the potential for synergistic therapeutic strategies with modern radiotherapy, through modulation of the tumor microenvironment. Emerging clinical and pre-clinical data suggest that radiation can convert immune desert tumors into an inflamed immunological hub, potentially sensitive to immunotherapy.

Anti-PD-L1 plus enzalutamide does not improve overall survival in prostate cancer

The addition of atezolizumab (anti-PD-L1) to enzalutamide (androgen receptor antagonist) did not prolong survival in metastatic prostate cancer.1 Efficacy with immunotherapies in prostate cancer will require additional studies to elucidate and target mechanisms of resistance within the prostate tumor microenvironment.

M2 macrophage increase in prostate adenocarcinoma after high-dose rate brachytherapy.

271 Background: Brachytherapy delivers high doses of hypofractionated radiation (RT) internally within the prostate tumor. While radiation has been shown to exhibit immunomodulatory effects, the success of combining radiation and immunotherapy in prostate cancer has been limited. M2 macrophages can contribute to an immunosuppressive tumor environment, and we therefore hypothesize that radiation may increase the abundance of M2 macrophage in the prostate tumor immune infiltrate. Methods: 10 Patients with intermediate risk prostate cancer (age 51-78; 7 GS 3+4, 3 GS 4+3) underwent high-dose rate brachytherapy (2 implants, 13.5Gy per implant, 1 week apart). Patients consented to biopsies before each fraction at the first and second implant. Bulk RNA-seq gene expression was performed on formalin-fixed, paraffin-embedded pre- vs. post-RT tumor samples, and then analyzed with a machine learning deconvolution model to resolve immune cell abundances. CD68+CD163+ M2 macrophages were analyzed with multiplex immunohistochemistry and quantified with tissue analysis software. Paired t-test was used to compare M2 macrophage abundance pre- versus post-RT. Results: Bulk RNA-seq deconvolution demonstrated that the most prevalent immune cell types in the pre-RT samples were resting CD4 memory T cells (39.7%), resting mast cells (38.5%), and M2 macrophages (30.4%), while those in the post-RT samples were M2 Macrophages (78.7%), resting mast cells (58.1%), and resting CD4 memory T cells (48%). M2 macrophages demonstrated the greatest increase, which was corroborated by multiplex IHC: average CD68+CD163+ cell counts were significantly elevated after RT (pre-RT 63.7 vs. post-RT 200.1 per mm2, p=0.015). Conclusions: Hypofractionated radiation increases the immunosuppressive M2 macrophage population in prostate cancer, which may present a therapeutic target to augment the efficacy of radiation and immunotherapy combinations.

Immunotherapy to prevent progression on active surveillance study (IPASS): A phase II, randomized, double-blind, controlled trial of PROSTVAC in prostate cancer patients who are candidates for active surveillance.

249 Background: Immunotherapy could potentially prevent disease progression for early-stage prostate cancer. In this randomized Phase 2 clinical trial, we evaluated the clinical effects of PROSTVAC, a vaccinia/fowlpox viral vector-based immunotherapy that contains PSA and three T-cell costimulatory molecules, in patients with localized prostate cancer. Methods:154 patients with clinically localized, low- or favorable intermediate-risk prostate cancer active surveillance were randomized (2:1) to receive 7 doses of subcutaneous PROSTVAC or placebo (empty fowlpox vector) over 140 days. Post-intervention prostate biopsy was performed 7-14 days after the last dose. Participants were followed for 6 months post-treatment. The primary outcome was change from baseline to post-vaccination in CD4 and CD8 T cell infiltration in biopsy tumor tissue. Secondary outcomes included changes in prostate biopsy Gleason grade (Grade Group) and serum PSA. Results: There were no differences in CD4 and CD8 densities (count of cells/mm2) in post-treatment biopsy tumor tissue between groups ( p = 0.63 and p = 0.75, respectively). Compared to placebo, patients who received PROSTVAC were less likely to demonstrate upgrading at follow-up biopsy, but this difference did not attain significance (22% vs. 40%, p= 0.08). There was no difference in the change of PSA from baseline to 6 months post-treatment between arms ( p= 0.30). Conclusions: In this first-of-kind trial of immunotherapy for localized prostate cancer, PROSTVAC was well tolerated but did not elicit significant prostate tissue T-cell responses compared to placebo. The favorable post-treatment biopsy grade findings in PROSTVAC patients merit further evaluation and longer-term clinical follow-up. Clinical trial information: NCT02326805.

A phase 1b clinical trial of cabozantinib (CABO) and abiraterone (ABI) with checkpoint inhibitor immunotherapy (CPI) in metastatic hormone-sensitive prostate cancer (mHSPC) (CABIOS Trial).

TPS214 Background: Multiple systemic therapies have resulted in improved overall survival (OS) for mHSPC, including several AR-targeted agents (ARTA) and docetaxel chemotherapy. However, patients (pts) with high volume de novo metastatic prostate cancer still only have an OS of approximately 50 months. Thus, more effective combination strategies for initial treatment of mHSPC are urgently needed. CABO, a multi-tyrosine kinase inhibitor (including MET, VEGFR-1, -2,-3, AXL) has shown synergy with ABI as well as with CPI in preclinical studies. CABO and ABI have demonstrated an acceptable safety profile in metastatic castration resistant prostate cancer (mCRPC) (Choudhury et al Prostate 2018), and CABO and atezolizumab (ATEZO) in combination have showed a promising efficacy signal and manageable safety profile in mCRPC (COSMIC-021, NCT03170960; Agarwal ESMO 2021). The phase 3 CONTACT-02 trial (NCT04446117) is randomizing mCRPC pts to either CABO and ATEZO or a second generation ARTA. Given the robust preclinical and emerging clinical data for the use of both CABO and CPI therapy in advanced prostate cancer and the need to optimize therapy earlier in the course of disease, in the present trial we intend to evaluate the safety and tolerability of ABI, CABO, and CPI in mHSPC. Methods: CABIOS (NCT04477512) is a phase Ib, single center, open label trial of ABI, CABO and the CPI nivolumab (NIVO), an anti-PD-1 monoclonal antibody, in pts with mHSPC. Key inclusion criteria include histologically or cytologically confirmed metastatic prostate adenocarcinoma without neuroendocrine/small cell differentiation and radiographic evidence of metastatic disease. Ongoing androgen deprivation (ADT) within 12 weeks of study start is allowed. Key exclusion criteria include evidence of castration resistance, prior treatment with second-generation androgen receptor inhibitors, CYP17 inhibitors, CABO, or checkpoint inhibitor immunotherapy (anti-PD-1/PD-L1, CTLA-4), active autoimmune disease, and ongoing treatment with systemic corticosteroids daily. The primary objective of the trial is evaluation of the safety and tolerability of this combination therapy in the trial population; the primary endpoint is the frequency of dose-limiting toxicities (DLTs) as measured by CTCAE v5.0. The study will employ a 3 + 3 design evaluating ABI 1,000 mg once daily with prednisone 5 mg daily, NIVO 480 mg IV every 4 weeks, and a CABO starting dose of 20 mg once daily at dose level 1 (DL1). If 0 of 3 pts at DL1 experience a DLT, 3 pts will be enrolled at DL2 with CABO 40 mg once daily. If 1 of 3 pts at DL1 experience a DLT, 3 additional pts will be enrolled at DL1. If 0 of 3 pts experience a DLT at DL2, the study will move to a recommended phase 2 dose (RP2D) expansion cohort. Total sample size of approximately 20 pts is expected depending on DLT frequencies. Enrollment is ongoing. Clinical trial information: NCT04477512.

Single-Cell Analysis Reveals EP4 as a Target for Restoring T-Cell Infiltration and Sensitizing Prostate Cancer to Immunotherapy.

Immunotherapies targeting immune checkpoint molecules have shown promising treatment for a subset of cancers; however, many "cold" tumors, such as prostate cancer, remain unresponsive. We aimed to identify a potential targetable marker relevant to prostate cancer and develop novel immunotherapy. Analysis of transcriptomic profiles at single-cell resolution was performed in clinical patients' samples, along with integrated analysis of multiple RNA-sequencing datasets. The antitumor activity of YY001, a novel EP4 antagonist, combined with anti-programmed cell death protein 1 (PD-1) antibody was evaluated both in vitro and in vivo. We identified EP4 (PTGER4) as expressed in epithelial cells and various immune cells and involved in modulating the prostate cancer immune microenvironment. YY001, a novel EP4 antagonist, inhibited the differentiation, maturation, and immunosuppressive function of myeloid-derived suppressor cells (MDSC) while enhancing the proliferation and anticancer functions of T cells. Furthermore, it reversed the infiltration levels of MDSCs and T cells in the tumor microenvironment by overturning the chemokine profile of tumor cells in vitro and in vivo. The combined immunotherapy demonstrated a robust antitumor immune response as indicated by the robust accumulation and activation of CD8+ cytotoxic T cells, with a significantly decreased MDSC ratio and reduced MDSC immunosuppression function. Our study identified EP4 as a specific target for prostate cancer immunotherapy and demonstrated that YY001 inhibited the growth of prostate tumors by regulating the immune microenvironment and strongly synergized with anti-PD-1 antibodies to convert completely unresponsive prostate cancers into responsive cancers, resulting in marked tumor regression, long-term survival, and lasting immunologic memory.

Docetaxel remodels prostate cancer immune microenvironment and enhances checkpoint inhibitor-based immunotherapy.

Background: Prostate cancer is usually considered as immune “cold” tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to explore clinically actionable strategies to sensitize prostate cancer to immunotherapy. In this study, we investigated whether docetaxel-based chemohormonal therapy induces immunologic changes and potentiates checkpoint blockade immunotherapy in prostate cancer.Methods: We performed transcriptome and histopathology analysis to characterize the changes of prostate cancer immune microenvironment before and after docetaxel-based chemohormonal therapy. Furthermore, we investigated the therapeutic benefits and underlying mechanisms of chemohormonal therapy combined with anti-PD1 blockade using cellular experiments and xenograft prostate cancer models. Finally, we performed a retrospective cohort analysis to evaluate the antitumor efficacy of anti-PD1 blockade alone or in combination with docetaxel-based chemotherapy.Results: Histopathology assessments on patient samples confirmed the enrichment of tumor-infiltrating T cells after chemohormonal therapy. Moreover, we found that docetaxel activated the cGAS/STING pathway in prostate cancer, subsequently induced IFN signaling, resulting in lymphocytes infiltration. In a xenograft mouse model, docetaxel-based chemohormonal therapy prompted the intratumoral infiltration of T cells and upregulated the abundance of PD1 and PD-L1, thereby sensitizing mouse tumors to the anti-PD1 blockade. To determine the clinical significance of these results, we retrospectively analyzed a cohort of 30 metastatic castration-resistant prostate cancer patients and found that docetaxel combined with anti-PD1 blockade resulted in better prostate-specific antigen progression-free survival when compared with anti-PD1 blockade alone.Conclusions: Our study demonstrates that docetaxel activates the antitumoral immune response and facilitates T cell infiltration in a cGAS/STING-dependent manner, providing a combination immunotherapy strategy that would improve the clinical benefits of immunotherapy.

Downregulation of SEPTIN5 inhibits prostate cancer progression by increasing CD8+ T cell infiltration.

Background: Prostate cancer (PCa) is one of the most common carcinomas in men, and aberrant expression of SEPTIN5 (SEPT5) has been detected in PCa tissues. However, the role of SEPT5 in PCa is still unclear. In this study, we attempted to explore the expression changes, clinical relevance and immunomodulatory function of SEPT5 in PCa. Methods: The expression and clinical significance of SEPT5 were evaluated based on bioinformatic analysis and were verified by western blotting, real time PCR and IHC. Allograft mouse models were used to assess the role of SEPT5 on PCa tumour formation and immunomodulatory function. Mass cytometry and IHC were used to determine the effects of SEPT5 on immune cell infiltration, especially CD8+ T cell infiltration. Correlations between SEPT5 expression and cytokine gene expression were analyzed based on TCGA and DKFZ datasets. RNA-seq and chemokine array were performed to confirm the effects of SEPT5 on cytokine production. Results: High SEPT5 expression was found in PCa and was associated with PCa prognosis. Importantly, downregulation of SEPT5 inhibited PCa progression in vivo. In addition, SEPT5 expression was negatively correlated with immune infiltrating cell levels, chemokine and cytokine gene expression associated with CD8+ T cell infiltration and activation. Downregulation of SEPT5 increased the proportion of immune cells, especially CD8+ T cells, in tumour tissue. Both the expression of CCL5, CXCL5, CXCL9, CXCL10 and INFGR1 were elevated in mRNA and protein levels after SEPT5 knockdown. Conclusions: In summary, downregulation of SEPT5 inhibited PCa progression, which may be mediated by increasing immune cell infiltration levels, especially CD8+ T cells, by promoting the production of IFNG-inducible chemokines and cytokines expression associated with immune cell infiltration. Our findings suggest that SEPT5 may serve as a prognostic biomarker of PCa and may be a target molecule to enhance the efficacy of immunotherapy for PCa in the future.

Immunotherapy for prostate cancer: Requirements for a successful regime transfer.

Despite the revolutionary progress in cancer treatment using immune checkpoint inhibitors (ICIs), remarkable responses in prostate cancer treatment have not yet been achieved. The disappointing previous results of ICIs have required further studies towards combined treatment targeting other pathways and restricted the eligibility criteria for patients with high mutation burdens, especially those with mismatch repair deficiency. Cancer immunotherapies activate adaptive immune systems, rather than directly attack tumor cells with their own cytotoxicity. Therefore, refractoriness to ICIs can not only be derived from the intractable nature of tumor cells per se , but also from their hostile milieu. Here, we reviewed the prostate cancer immunotherapies exploring clinical trials to date, along with the molecular characteristics of prostate cancer and its microenvironment.

A Model-Based Framework to Identify Optimal Administration Protocols for Immunotherapies in Castration-Resistance Prostate Cancer.

Simple SummaryAlthough ipilimumab has been approved for the treatment of many types of cancer, most prostate cancer patients seem to not respond well to the therapy. Here, we mathematically investigate the clinical relevance of ipilimumab, as mono-therapy and in combination with the dendritic cell vaccine sipuleucel-T, for the treatment of castration-resistant prostate cancer patients. The employed optimization problem, which incorporates a function of toxicity depending on the drug concentration, establishes precise protocols of administration of ipilimumab to control or eradicate prostate tumor, and defines how changing of key parameters affects the outcome. Overall, this mathematical study can help in optimizing the clinical use of ipilimumab for the effective treatment of castration-resistant prostate cancer patients.Prostate cancer (PCa) is one of the most frequent cancer in male population. Androgen deprivation therapy is the first-line strategy for the metastatic stage of the disease, but, inevitably, PCa develops resistance to castration (CRPC), becoming incurable. In recent years, clinical trials are testing the efficacy of anti-CTLA4 on CRPC. However, this tumor seems to be resistant to immunotherapies that are very effective in other types of cancers, and, so far, only the dendritic cell vaccine sipuleucel-T has been approved. In this work, we employ a mathematical model of CRPC to determine the optimal administration protocol of ipilimumab, a particular anti-CTLA4, as single treatment or in combination with the sipuleucel-T, by considering both the effect on tumor population and the drug toxicity. To this end, we first introduce a dose-depending function of toxicity, estimated from experimental data, then we define two different optimization problems. We show the results obtained by imposing different constraints, and how these change by varying drug efficacy. Our results suggest administration of high-doses for a brief period, which is predicted to be more efficient than solutions with prolonged low-doses. The model also highlights a synergy between ipilimumab and sipuleucel-T, which leads to a better tumor control with lower doses of ipilimumab. Finally, tumor eradication is also conceivable, but it depends on patient-specific parameters.

Metabolic response to immunotherapy in prostate cancer.

Metabolic response to immunotherapy in prostate cancer.

Biomarker-driven immunotherapy for precision medicine in prostate cancer.

Although immunotherapy has recently revolutionized standard of care in different cancer types, prostate cancer has generally failed to show dramatic responses to immune checkpoint inhibitors. As in other tumors, the goal in prostate cancer is now to target treatments more precisely on patient's individual characteristics through precision medicine. Defects in mismatch repair, mutations in the exonuclease domain of the DNA polymerase epsilon (POLE), high tumor mutational burden and the presence of biallelic loss of CDK12 among others, are predictive biomarkers of response to immunotherapy. In the present review, we summarize the evolving landscape of immunotherapy in prostate cancer, including precision approaches and strategies to define classes of responsive patients and scale up resistance to immune checkpoint inhibitors.

A Double-Edged Sword Role of Cytokines in Prostate Cancer Immunotherapy.

Prostate cancer (PC) is one of the most common malignancies among men and is the second leading cause of cancer death. PC immunotherapy has taken relatively successful steps in recent years, and these treatments are still being developed and tested. Evidence suggests that immunotherapy using cytokines as essential mediators in the immune system may help treat cancer. It has been shown that cytokines play an important role in anti-tumor defense. On the other hand, other cytokines can also favor the tumor and suppress anti-tumor responses. Moreover, the dose of cytokine in cancer cytokine-based immunotherapy, as well as the side effects of high doses, can also affect the outcomes of treatment. Cytokines can also be determinative in the outcome of other immunotherapy methods used in PC. In this review, the role of cytokines in the pathogenesis of cancer and their impacts on the main types of immunotherapies in the treatment of PC are discussed.

421 A first-in-human (FIH) phase I/IIa clinical trial assessing a ribonucleic acid lipoplex (RNA-LPX) encoding shared tumor antigens for immunotherapy of prostate cancer; preliminary analysis of PRO-MERIT

BackgroundPRO-MERIT is a FIH, open-label, multicenter, Phase I/IIa trial investigating a liposomal RNA vaccine (BNT112) targeting the prostate cancer tumor-associated antigens (TAAs) kallikrein-2, kallikrein-3, acid phosphatase prostate, homeobox B13 (HOXB13), and NK3 homeobox 1. BNT112 is being investigated as monotherapy and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer (mCRPC) and newly diagnosed high risk localized prostate cancer (LPC).MethodsThe trial involves dose titration in mCRPC patients (who have progressed after at least 2 but no more than 3 lines of systemic therapy) with BNT112 monotherapy (Part 1, fully recruited), followed by expansion cohorts (Part 2, recruiting) in both mCPRC and LPC with either BNT112 as monotherapy or in combination with cemiplimab. Primary trial endpoints investigate safety, tolerability, and preliminary anti-tumor activity (by Prostate Cancer Working Group 3 criteria). Secondary endpoints include determination of systemic induction or expansion of vaccine antigen-specific T cells. Vaccine-induced immune responses are analyzed ex vivo using an interferon-γ enzyme-linked immune absorbent spot (ELISpot) assay and following short-term in vitro stimulation.ResultsAs of 17 May 2021, 11 patients have received BNT112 monotherapy (9 Part 1; 2 in Part 2) and 3 patients have received BNT112 in combination with cemiplimab (at least one cycle completed). In Part 1, all 9 patients were stage IV at diagnosis and were receiving androgen deprivation therapy. Median age was 68 years. Two out of 9 patients experienced Grade 3 hypertension, leading to one dose reduction, that was initially reported as dose-limiting toxicity (DLT). All recovered within 24 h with no sequelae and the Safety Review Committee eventually concluded the events did not meet the DLT definition. Most common related adverse events (AEs) were pyrexia and hypertension. Eight serious AEs were reported in 5 patients, all unrelated to BNT112. In the 5 patients in Part 2, no additional safety signals or concerns were identified to date, either with BNT112 as monotherapy or in combination with cemiplimab. ELISpot data showed vaccine-induced immune responses were present in 7/7 ELISpot-evaluable patients. All 5 BNT112 TAAs were found to be immunogenic. Responses to each antigen were observed in at least 2 subjects. Initial responses with decreased prostate-specific antigen (PSA) levels have been observed in 2 patients in the BNT112 monotherapy arm.ConclusionsThese data suggest that BNT112 has an acceptable safety profile. Additionally, BNT112 induces robust immune and PSA responses in patients with advanced prostate cancer.AcknowledgementsThe authors would like to acknowledge Camilla West (BioNTech SE) for medical writing support.Trial RegistrationClinicaltrials.gov: NCT04382898.Ethics ApprovalEthics & Institutional Review Board approvals were obtained from the respective participating countries prior to initiation of the trial.

Cytotopic (Cyto-) IL-15 as a New Immunotherapy for Prostate Cancer: Recombinant Production in Escherichia coli and Purification.

Interleukin-15 (IL-15) is a cytokine previously suggested as a potential immunotherapy for cancer treatment. IL-15 can effectively reduce tumor growth in many preclinical tumor models including prostate cancer. This is due to its ability to expand and activate immune cells, such as CD8+ T cells and natural killer cells. To increase the potency of IL-15, we have engineered a protein variant that can be modified to localize and be retained in tissues where it is administered. However, the production of recombinant IL-15, the purity, and correct refolding of the final protein is not always ideal. In the current study, we aimed to optimize the methodology for production and purification of a modified recombinant human IL-15 and investigate the efficacy of the produced protein in the treatment of prostate tumors. Human IL-15 with its polypeptide sequence modified at the C-terminus to enable thiol conjugation with membrane localizing peptides, was produced in E. coli and purified using mild denaturing conditions (2M urea) from a washing step or from solubilization of inclusion bodies. The purified protein from the wash fraction was conjugated to a myristoylated peptide to form a membrane-localizing IL-15 (cyto-IL-15). The efficacy of cyto-IL-15 was investigated in subcutaneous TRAMP-C2 prostate tumors in mice and compared with cyto-IL-15 derived from protein purified from inclusion bodies (cyto-IL-15 Gen). When mild denaturing conditions were used for purification, the largest amount of IL-15 was collected from the wash fraction and a smaller amount from inclusion bodies. The protein from the wash fraction was mainly present as a monomer, whereas the one from inclusion bodies formed homodimers and higher complexes. After cytotopic modification, the purified IL-showed great efficacy in delaying prostate tumor growth (∼50%) and increased mice survival by ∼1.8-fold compared with vehicle. This study demonstrates an alternative, inexpensive and efficient method to produce and purify a modified version of IL-15 using mild denaturing conditions. This IL-15, when cytotopically modified, showed great efficacy as a monotherapy in prostate tumors in mice further highlighting the potential of IL-15 as a cancer immunotherapy.

Overcoming Immune Resistance in Prostate Cancer: Challenges and Advances.

Simple SummaryImmunotherapy has changed the landscape of treatment modalities available for many different types of malignancies. However, the factors that influence the success of immunotherapeutics have not been as clearly seen in advanced prostate cancer, likely due to immunosuppressive factors that exist within the prostate cancer tumor microenvironment. While there have been many immunotherapeutics used for prostate cancer, the majority have targeted a single immunosuppressive mechanism resulting in limited clinical efficacy. More recent research centered on elucidating the key mechanisms of immune resistance in the prostate tumor microenvironment has led to the discovery of a range of new treatment targets. With that in mind, many clinical trials have now set out to evaluate combination immunotherapeutic strategies in patients with advanced prostate cancer, in the hopes of circumventing the immunosuppressive mechanisms.The use of immunotherapy has become a critical treatment modality in many advanced cancers. However, immunotherapy in prostate cancer has not been met with similar success. Multiple interrelated mechanisms, such as low tumor mutational burden, immunosuppressive cells, and impaired cellular immunity, appear to subvert the immune system, creating an immunosuppressive tumor microenvironment and leading to lower treatment efficacy in advanced prostate cancer. The lethality of metastatic castrate-resistant prostate cancer is driven by the lack of therapeutic regimens capable of generating durable responses. Multiple strategies are currently being tested to overcome immune resistance including combining various classes of treatment modalities. Several completed and ongoing trials have shown that combining vaccines or checkpoint inhibitors with hormonal therapy, radiotherapy, antibody–drug conjugates, chimeric antigen receptor T cell therapy, or chemotherapy may enhance immune responses and induce long-lasting clinical responses without significant toxicity. Here, we review the current state of immunotherapy for prostate cancer, as well as tumor-specific mechanisms underlying therapeutic resistance, with a comprehensive look at the current preclinical and clinical immunotherapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and impaired cellular immunity that have largely limited the utility of immunotherapy in advanced prostate cancer.

EIF5B regulates the expression of PD-L1 in prostate cancer cells by interacting with Wig1

BackgroundEukaryotic translation initiation factors (eIFs) are the key factors to synthesize translation initiation complexes during the synthesis of eukaryotic proteins. Besides, eIFs are especially important in regulating the immune function of tumor cells. However, the effect mechanism of eIFs in prostate cancer remains to be studied, which is precisely the purpose of this study.MethodsIn this study, three groups of prostate cancer cells were investigated. One group had its eIF5B gene knocked down; another group had its Programmed death 1 (PD-L1) overexpressed; the final group had its Wild-type p53-induced gene 1 (Wig1) overexpressed. Genetic alterations of the cancer cells were performed by plasmid transfection. The expression of PD-L1 mRNA was detected by quantitative real-time PCR (qRT-PCR), and the expressions of PD-L1 and eIF5B proteins were observed by western blot assays. Cell Counting Kit-8 (CCK-8), flow cytometry, Transwell and Transwell martrigel were used to investigated cell proliferation, apoptosis, migration and invasion, respectively. The effect of peripheral blood mononuclear cells (PBMCs) on tumor cells was observed, and the interaction between eIF5B and Wig1 was revealed by co-immunoprecipitation (CoIP) assay. Finally, the effects of interference with eIF5B expression on the growth, morphology, and immunity of the tumor, as well as PD-L1 expression in the tumor, were verified by tumor xenograft assays in vivo.ResultsCompared with normal prostate epithelial cells, prostate cancer cells revealed higher expressions of eIF5B and PD-L1 interference with eIF-5B expression can inhibit the proliferation, migration, invasion and PD-L1 expression of prostate cancer cells. Meanwhile, the cancer cell group with interference with eIF5B expression also demonstrated greater, apoptosis and higher vulnerability to PBMCs. CoIP assays showed that Wig1 could bind to eIF5B in prostate cancer cells, and its overexpression can inhibit the proliferation, migration, invasion and PD-L1 expression of cancer cells while promoting apoptosis. Moreover, interference with eIF5B expression can inhibit tumor growth, destroy tumor morphology, and suppress the proliferation of tumor cells.ConclusioneIF5B can promote the expression of PD-L1 by interacting with Wig1. Besides, interference with eIF5B expression can inhibit the proliferation, migration, invasion and immunosuppressive response of prostate cancer cells. This study proposes a new target, eIF5B, for immunotherapy of prostate cancer.

Interaction Between Modern Radiotherapy and Immunotherapy for Metastatic Prostate Cancer

Prostate cancer is the most frequently diagnosed cancer in men and a leading cause of cancer-related death. In recent decades, the development of immunotherapies has resulted in great promise to cure metastatic disease. However, prostate cancer has failed to show any significant response, presumably due to its immunosuppressive microenvironment. There is therefore growing interest in combining immunotherapy with other therapies able to relieve the immunosuppressive microenvironment. Radiation therapy remains the mainstay treatment for prostate cancer patients, is known to exhibit immunomodulatory effects, depending on the dose, and is a potent inducer of immunogenic tumor cell death. Optimal doses of radiotherapy are thus expected to unleash the full potential of immunotherapy, improving primary target destruction with further hope of inducing immune-cell-mediated elimination of metastases at distance from the irradiated site. In this review, we summarize the current knowledge on both the tumor immune microenvironment in prostate cancer and the effects of radiotherapy on it, as well as on the use of immunotherapy. In addition, we discuss the utility to combine immunotherapy and radiotherapy to treat oligometastatic metastatic prostate cancer.

Avelumab Combined with Stereotactic Ablative Body Radiotherapy in Metastatic Castration-resistant Prostate Cancer: The Phase 2 ICE-PAC Clinical Trial

BackgroundImmune checkpoint inhibitor monotherapy in metastatic castration-resistant prostate cancer (mCRPC) has produced modest results. High-dose radiotherapy may be synergistic with checkpoint inhibitors. ObjectiveTo evaluate the efficacy and safety of the PD-L1 inhibitor avelumab with stereotactic ablative body radiotherapy (SABR) in mCRPC. Design, setting, and participantsFrom November 2017 to July 2019, this prospective phase 2 study enrolled 31 men with progressive mCRPC after at least one prior androgen receptor–directed therapy. Median follow-up was 18.0 mo. InterventionAvelumab 10 mg/kg intravenously every 2 wk for 24 wk (12 cycles). A single fraction of SABR (20 Gy) was administered to one or two disease sites within 5 d before the first and second avelumab treatments. Outcomes measurements and statistical analysisThe primary endpoint was the disease control rate (DCR), defined as a confirmed complete or partial response of any duration, or stable disease/non–complete response/non–progressive disease for ≥6 mo (Prostate Cancer Clinical Trials Working Group 3–modified Response Evaluation Criteria in Solid Tumours version 1.1). Secondary endpoints were the objective response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS), and safety. DCR and ORR were calculated using the Clopper-Pearson exact binomial method. Results and limitationsThirty-one evaluable men were enrolled (median age 71 yr, 71% with ≥2 prior mCRPC therapy lines, 81% with >5 total metastases). The DCR was 48% (15/31; 95% confidence interval [CI] 30–67%) and ORR was 31% (five of 16; 95% CI 11–59%). The ORR in nonirradiated lesions was 33% (four of 12; 95% CI 10–65%). Median rPFS was 8.4 mo (95% CI 4.5–not reached [NR]) and median OS was 14.1 mo (95% CI 8.9–NR). Grade 3–4 treatment-related adverse events occurred in six patients (16%), with three (10%) requiring high-dose corticosteroid therapy. Plasma androgen receptor alterations were associated with lower DCR (22% vs 71%, p = 0.13; Fisher’s exact test). Limitations include the small sample size and the absence of a control arm. ConclusionsAvelumab with SABR demonstrated encouraging activity and acceptable toxicity in treatment-refractory mCRPC. This combination warrants further investigation. Patient summaryIn this study of men with advanced and heavily pretreated prostate cancer, combining stereotactic radiotherapy with avelumab immunotherapy was safe and resulted in nearly half of patients experiencing cancer control for 6 months or longer. Stereotactic radiotherapy may potentially improve the effectiveness of immunotherapy in prostate cancer.