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

ABSTRACT: 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 68Ga-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-?-producing (IFN-?+) 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-?+ antigen-specific T cells median rPFS was 18.8?months (n =?5) vs. 5.1?months (n =?16) in patients without IFN-?-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. CONCLUSIONS:Immunotherapy with blood-derived DC subsets was feasible and safe and induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with an improved clinical outcome. TRIAL REGISTRATION:ClinicalTrials.gov identifier NCT02692976, registered 26 February 2016, retrospectively registered.

SUBMITTER: Westdorp H

PROVIDER: S-EPMC6854814 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Westdorp Harm H Creemers Jeroen H A JHA van Oort Inge M IM Schreibelt Gerty G Gorris Mark A J MAJ Mehra Niven N Simons Michiel M de Goede Anna L AL van Rossum Michelle M MM Croockewit Alexandra J AJ Figdor Carl G CG Witjes J Alfred JA Aarntzen Erik H J G EHJG Mus Roel D M RDM Brüning Mareke M Petry Katja K Gotthardt Martin M Barentsz Jelle O JO de Vries I Jolanda M IJM Gerritsen Winald R WR

Journal for immunotherapy of cancer 20191114 1

<h4>Background</h4>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<sup>+</sup> myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs).<h4>Methods</h4>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 wer ...[more]

PMID: 31727154

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Project description:Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting.We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (??50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models.One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P?=?0.089). Median TTPP was 7.2 months (95% CI?=?4.5?-?17.2) in the D-naïve group versus 2.6 mo (95% CI?=?1.9?-?3.5) in the D-pretreated group (P?<?0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI?=?2.5?-?4.8) for D-pretreated men (P?<?0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR?=?2.32; 95% CI?=?1.19?-?4.50; P?=?0.013) and marginally significant for PFS (HR?=?1.90; 95% CI?=?0.94?-?3.84; P?=?0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n?=?34), results suggested a trend towards shorter duration of response in D-pretreated patients.The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross-resistance between these two agents.

Project description:BackgroundWe aimed to evaluate cost-effectiveness of enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer patients in Japan.MethodsA Markov model was developed to capture time spent by patients in various health states: stable, progression and death. Abiraterone acetate and docetaxel were set as active comparators. Clinical outcomes were obtained from the PREVAIL, COU-AA-302 and TAX327 trials. Treatment sequence, concomitant drugs and therapies for adverse events were estimated from responses to a survey by 14 Japanese prostate cancer experts. The analytic perspective was public healthcare payer, with a 10-year time horizon. The incremental cost-effectiveness ratio was estimated from quality-adjusted life-years and Japanese public healthcare costs. Probabilistic sensitivity analysis was performed to assess the robustness of the findings.ResultsAccording to the survey, the most common treatment sequences were (i) enzalutamide → docetaxel → cabazitaxel (enzalutamide-first sequencing), (ii) abiraterone → enzalutamide → docetaxel (abiraterone-first sequencing) and (iii) docetaxel→ enzalutamide → cabazitaxel (docetaxel-first sequencing). In the base-case analysis, enzalutamide-first sequencing saved 1.74 million Japanese Yen versus abiraterone-first sequencing, with a 0.129 quality-adjusted life-year gain (dominant). Enzalutamide-first sequencing had a cost increase of 4.44 million Japanese Yen over docetaxel-first sequencing, with a 0.371 quality-adjusted life-years gain. The incremental cost-effectiveness ratio of enzalutamide-first sequencing versus docetaxel-first sequencing was estimated as 11.94 million Japanese Yen/quality-adjusted life-years. Probabilistic sensitivity analyses demonstrated that, compared with abiraterone-first sequencing, enzalutamide-first sequencing had an 87.4% probability of being dominant.ConclusionsResults modeled herein suggest that the enzalutamide-first sequencing is more cost-effective than the abiraterone-first sequencing, but less cost-effective than docetaxel-first sequencing for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

Dataset Information

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

Publications

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

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