Now the dust has settled over immune checkpoint blockade in metastatic prostate cancer

Mehra, Niven; Gerritsen, Winald R.

doi:10.1093/annonc/mdy239

Cited by 5 publications

(4 citation statements)

References 21 publications

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“…However, the PD-1 inhibitor pembrolizumab shows antitumor activity in patients with evidence of progression on enzalutamide [58] and in the docetaxelrefractory setting (Keynote-199 trial; NCT02787005). Several trials with immune checkpoint inhibitors as a single agent treatment or as combination therapy are currently ongoing in both unselected as in immunogenic subtypes, such as those harboring microsatellite instability, high tumor mutational load or biallelic inactivation of CDK12 or BRCA2 [59].…”

Section: Discussionmentioning

confidence: 99%

Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer

Westdorp

Creemers

Oort

et al. 2019

j. immunotherapy cancer

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Background: Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c + myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs). Methods: In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced 68 Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. Results: Both tetramer/dextramer-positive (dm +) and IFN-γ-producing (IFN-γ +) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm + and IFN-γ + antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1-2 toxicity.

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Section: Discussionmentioning

confidence: 99%

Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer

Westdorp

Creemers

Oort

et al. 2019

j. immunotherapy cancer

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“…An important feature of prostate cancer is the low tumor mutation burden and thus diminished neoantigen expression compared with many other cancers 104 . Only 10–30% of unselected patients respond to PD-1/PD-L1 blockade 105 . However, a recent study investigated 1551 prostate tumors and found that 32 (3.1%) prostate cancer specimens were associated with MSI-H molecular phenotype and high tumor mutation burden.…”

Section: Introductionmentioning

confidence: 99%

Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance

Wang

Cheng

2022

npj Precis. Onc.

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Prostate cancer is characterized by a high degree of heterogeneity, which poses a major challenge to precision therapy and drug development. In this review, we discuss how nongenetic factors contribute to heterogeneity of prostate cancer. We also discuss tumor heterogeneity and phenotypic switching related to anticancer therapies. Lastly, we summarize the challenges targeting the tumor environments, and emphasize that continued exploration of tumor heterogeneity is needed in order to offer a personalized therapy for advanced prostate cancer patients.

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“…Above all, the mCRPC state of prostate cancer is considered an immunologically cold malignancy, , rendering the body’s immune system ineffective in suppressing tumor growth. Clinical trials evaluating FDA approved cancer immunotherapies have been undertaken to address this escape mechanism. , Pembrolizumab ( anti -PD-1) provided a median survival of 7.9–14.1 months depending on patient cohort selection criteria . Other immune checkpoint inhibitors such as ipilimumab ( anti -CTLA-4) fail to increase overall survival in mCRPC patients .…”

Section: Introductionmentioning

confidence: 99%

“…Clinical trials evaluating FDA approved cancer immunotherapies have been undertaken to address this escape mechanism. 3,4 Pembrolizumab (anti-PD-1) provided a median survival of 7.9−14.1 months depending on patient cohort selection criteria. 5 Other immune checkpoint overall survival in mCRPC patients.…”

Section: ■ Introductionmentioning

confidence: 99%

Evaluation of a Radio-IMmunoStimulant (RIMS) in a Syngeneic Model of Murine Prostate Cancer and ImmunoPET Analysis of T-cell Distribution

et al. 2022

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An immunosuppressive tumor microenvironment and tumor heterogeneity have led to the resilience of metastatic castrate resistant prostate cancer (mCRPC) to current treatments. To address these challenges, we developed and evaluated a new drug paradigm, Radio-IMmunostimulant (RIMS), in a syngeneic model of murine prostate cancer. RIMS-1 was generated using a convergent synthesis employing solid phase peptide and solution chemistries. The prostate-specific membrane antigen (PSMA) inhibitory constant for natLu-RIMS-1 was determined, and radiolabeling with 177Lu generated 177Lu-RIMS-1. The TLR 7/8 agonist payload release from natLu-RIMS-1 was determined using a cathepsin B assay. The biodistribution of 177Lu-RIMS-1 was evaluated in a bilateral xenograft model in NCru nude mice bearing PSMA(+) (PC3-PiP) and PSMA(−) (PC3-Flu) tumors at 2, 24, and 72 h. The therapeutic effect of 177Lu-RIMS-1 was evaluated in C57BL/6J mice bearing RM1-PGLS (PSMA-positive, green fluorescent protein-positive, and luciferase-positive) tumors and compared to that of 177Lu-PSMA-617 at the same total administered radioactivity of 57 MBq and molar activity of 5.18 MBq/nmol. natLu-RIMS-1 and vehicle were evaluated as the controls. Immuno-positron emission tomography (PET) using 89Zr-DFO-anti-CD3 was used to visualize T-cell distribution during treatment. 177Lu-RIMS-1 was quantitatively radiolabeled at >99% radiochemical purity and maintained a high affinity toward PSMA (K i = 3.77 ± 0.5 nM). Cathepsin B efficiently released the entire immunostimulant payload in 17.6 h. 177Lu-RIMS-1 displayed a sustained uptake in PSMA(+) tumor tissue up to 72 h (2.65 ± 1.03% ID/g) and was not statistically different (P = 0.1936) compared to 177Lu-PSMA-617 (3.65 ± 0.59% ID/g). All animals treated with 177Lu-RIMS-1 displayed tumor growth suppression and provided a median survival of 30 days (P = 0.0007) while 177Lu-PSMA-617 provided a median survival of 15 days, which was not statistically significant (P = 0.3548) compared to the vehicle group (14 days). ImmunoPET analysis revealed 2-fold more tumor infiltrating T-cells in 177Lu-RIMS-1-treated animals compared to 177Lu-PSMA-617-treated animals; 177Lu-RIMS-1 improves therapeutic outcomes in a syngeneic model of mouse prostate cancer and elicits greater T-cell infiltration to the tumor compared to 177Lu-PSMA-617. These results support further investigation of the RIMS paradigm as the first example of a single molecular entity combining radiotherapy and immunostimulation.

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Now the dust has settled over immune checkpoint blockade in metastatic prostate cancer

Abstract: Selected ongoing trials for patients with castration-resistant prostate cancer currently recruiting or awaiting results.

Cited by 5 publications

References 21 publications

Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer

Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer

Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance

Evaluation of a Radio-IMmunoStimulant (RIMS) in a Syngeneic Model of Murine Prostate Cancer and ImmunoPET Analysis of T-cell Distribution

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