Immune-checkpoint inhibitors and metastatic prostate cancer therapy: Learning by making mistakes

Claps, Mélanie; Mennitto, Alessia; Guadalupi, Valentina; Sepe, Pierangela; Stellato, Marco; Zattarin, Emma; Gillessen, Silke; Sternberg, Cora N.; Berruti, Alfredo; Braud, F.G.M. De; Verzoni, Elena; Procopio, Giuseppe

doi:10.1016/j.ctrv.2020.102057

Cited by 29 publications

(20 citation statements)

References 82 publications

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Section: Recent Immunotherapy Clinical Trials In Prostate Cancermentioning

confidence: 99%

“…The clinical trials phase I and II with programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors have shown limited benefits [124][125][126]. The most promising strategies for mCRPC treatment combining of two different checkpoint inhibitors or combining one checkpoint inhibitor with enzalutamide, an anti-androgen approved for use in mCRPC [124][125][126]. Recent studies investigating the combination of anti-PD-1 and anti-CTLA4 had promising results in phase I/II and III [127][128][129] with the autologous cellular immunotherapy sipuleucel-T [130].…”

Section: Recent Immunotherapy Clinical Trials In Prostate Cancermentioning

confidence: 99%

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The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

Melo

Vidotto

Chaves

et al. 2021

IJMS

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Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.

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Section: Recent Immunotherapy Clinical Trials In Prostate Cancermentioning

confidence: 99%

Section: Recent Immunotherapy Clinical Trials In Prostate Cancermentioning

confidence: 99%

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

Melo

Vidotto

Chaves

et al. 2021

IJMS

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“…Abnormal activating inhibitory immune checkpoint pathways have been regarded as the vital method of immune escape ( Modena et al, 2016 ). However, it is unlikely that there were long-lasting responses from immunotherapy (including various immune checkpoint inhibitor) in the whole PCa patients ( Claps et al, 2020 ). How to identify those suitable to receive immunotherapy is hot topic of discussion for urologist ( Wong and Yu, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Ferroptosis-Based Molecular Signature Associated with Biochemical Recurrence-Free Survival and Tumor Immune Microenvironment of Prostate Cancer

You

Sun

et al. 2022

Front. Cell Dev. Biol.

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Objective: To identify ferroptosis-related molecular clusters, and to develop and validate a ferroptosis-based molecular signature for predicting biochemical recurrence-free survival (BCRFS) and tumor immune microenvironment of prostate cancer (PCa).Materials and Methods: The clinical data and transcriptome data of PCa were downloaded from TCGA and GEO database. Ferroptosis-related genes (FRGs) were obtained from FerrDb database. We performed consensus clustering analysis to identify ferroptosis-related molecular subtypes for PCa. Univariate and multivariate Cox regression analysis were used to establish a ferroptosis-based signature for predicting BCRFS. Internal verification, external verification and subgroup survival analysis were then successfully performed.Results: There was a total of 40 differentially expressed FRGs in PCa. We then identified three ferroptosis-related molecular clusters of PCa, which have significantly different immune infiltrating cells, tumor immune microenvironment and PD-L1 expression level. More importantly, a novel ferroptosis-based signature for predicting BCRFS of PCa based on four FRGs (including ASNS, GPT2, NFE2L2, RRM2) was developed. Internal and external verifications were then successfully performed. Patients with high-risk score were associated with significant poor BCRFS compared with those with low-risk score in training cohort, testing cohort and validating cohort, respectively. The area under time-dependent Receiver Operating Characteristic (ROC) curve were 0.755, 0.705 and 0.726 in training cohort, testing cohort and validating cohort, respectively, indicating the great performance of this signature. Independent prognostic analysis indicated that this signature was an independent predictor for BCRFS of PCa. Subgroup analysis revealed that this signature was particularly suitable for younger or stage T III-IV or stage N0 or cluster 1-2 PCa patients. Patients with high-risk score have significantly different tumor immune microenvironment in comparison with those with low-risk score. The results of qRT-PCR successfully verified the mRNA expression levels of ASNS, GPT2, RRM2 and NFE2L2 in DU-145 and RWPE-1 cells while the results of IHC staining exactly verified the relative protein expression levels of ASNS, GPT2, RRM2 and NFE2L2 between PCa and BPH tissues.Conclusions: This study successfully identified three ferroptosis-related molecular clusters. Besides, we developed and validated a novel ferroptosis-based molecular signature, which performed well in predicting BCRFS and tumor immune microenvironment of PCa.

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“…30 In particular, as prior studies have shown that DDR defects may sensitize to ICT, we examined the subset of patients who had undergone germline (n=13) and/or somatic (n=16) tumor mutational testing. 31 Among the six patients with Open access rPFS >6 months, four underwent germline or somatic mutational testing, and DDR alterations were identified in three patients: #23, somatic PALB2 and germline BRCA2; #21, somatic ATM; and #7, germline ATM (online supplemental table 5). Notably, two patients who carried somatic CDK12 alterations (#3 and #16) had rPFS less than 6 months, although our method did not permit identification of the biallelic CDK12 loss that has previously been reported as a distinct subset of patients that may benefit from ICT (online supplemental table 5).…”

Section: Immunogeneticsmentioning

confidence: 99%

Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment

Subudhi

Siddiqui

Aparicio

et al. 2021

J Immunother Cancer

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BackgroundImmune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone.HypothesisCombined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone.Patients and methodsIn this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline.ResultsTwenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints.ConclusionsTremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment.Trial registration numberNCT03204812.

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Immune-checkpoint inhibitors and metastatic prostate cancer therapy: Learning by making mistakes

Cited by 29 publications

References 82 publications

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

A Novel Ferroptosis-Based Molecular Signature Associated with Biochemical Recurrence-Free Survival and Tumor Immune Microenvironment of Prostate Cancer

Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment

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