scholarly journals Dendritic Cell-Based Immunotherapy for Prostate Cancer

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Hanka Jähnisch ◽  
Susanne Füssel ◽  
Andrea Kiessling ◽  
Rebekka Wehner ◽  
Stefan Zastrow ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Cancer Patients ◽  
Mononuclear Cells ◽  
The United States ◽  
Peripheral Blood Mononuclear ◽  
United States Food ◽  
Clinical Responses ◽  
Antigen Presenting

Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which display an extraordinary capacity to induce, sustain, and regulate T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Thus, clinical trials enrolling prostate cancer patients were conducted, which were based on the administration of DCs loaded with tumor-associated antigens. These clinical trials revealed that DC-based immunotherapeutic strategies represent safe and feasible concepts for the induction of immunological and clinical responses in prostate cancer patients. In this context, the administration of the vaccine sipuleucel-T consisting of autologous peripheral blood mononuclear cells including APCs, which were pre-exposedin vitroto the fusion protein PA2024, resulted in a prolonged overall survival among patients with metastatic castration-resistent prostate cancer. In April 2010, sipuleucel-T was approved by the United States Food and Drug Administration for prostate cancer therapy.

scholarly journals Extracellular Vesicle-Associated Tissue Factor Activity in Prostate Cancer Patients with Disseminated Intravascular Coagulation

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1487
Author(s):  
Lena Hell ◽  
Thomas Däullary ◽  
Vanessa Burghart ◽  
Lisa-Marie Mauracher ◽  
Ella Grilz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Tissue Factor ◽  
Disseminated Intravascular Coagulation ◽  
Mononuclear Cells ◽  
Coagulation Cascade ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Intravascular Coagulation

Patients with advanced prostate cancer may develop fulminant disseminated intravascular coagulation (DIC). Circulating extracellular vesicles (EVs)-exposing tissue factor (TF), the initiator of the coagulation cascade, may play an important role. We included 7 prostate cancer patients with DIC, 10 age- and stage-matched cancer controls without DIC, and 10 age-matched healthy male individuals. EV-TF activity was highly elevated in prostate cancer patients with DIC (11.40 pg/mL; range: 4.34–27.06) compared with prostate cancer patients without DIC (0.09 pg/mL; range: 0.00–0.30, p = 0.001) and healthy controls (0.18 pg/mL; range: 0.09–0.54; p = 0.001). Only EVs from patients with DIC showed reduced fibrin clot formation time of pooled plasma in a TF-dependent manner. Next, we performed in vitro co-culture experiments including EVs derived from a prostate cancer cell line with high (DU145) and low (LNCaP) TF expression, peripheral blood mononuclear cells (PBMCs), and platelets. Co-incubation of DU145 EVs with PBMCs and platelets significantly increased EV-TF activity in conditioned medium and induced TF activity on monocytes. No such effects were seen in co-culture experiments with LNCaP EVs. In conclusion, the findings indicate that elevated EV-TF activity plays a role in the development of prostate-cancer-related DIC and may result from interactions between tumor-derived EVs, monocytes, and platelets.

scholarly journals α-Particle-induced DNA damage tracks in peripheral blood mononuclear cells of [223Ra]RaCl2-treated prostate cancer patients

2021 ◽  
Author(s):  
S. Schumann ◽  
U. Eberlein ◽  
C. Lapa ◽  
J. Müller ◽  
S. Serfling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cancer Patients ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Absorbed Dose ◽  
Peripheral Blood Mononuclear ◽  
Absorbed Doses ◽  
Blood Mononuclear Cells

Abstract Purpose One therapy option for prostate cancer patients with bone metastases is the use of [223Ra]RaCl2. The α-emitter 223Ra creates DNA damage tracks along α-particle trajectories (α-tracks) in exposed cells that can be revealed by immunofluorescent staining of γ-H2AX+53BP1 DNA double-strand break markers. We investigated the time- and absorbed dose-dependency of the number of α-tracks in peripheral blood mononuclear cells (PBMCs) of patients undergoing their first therapy with [223Ra]RaCl2. Methods Multiple blood samples from nine prostate cancer patients were collected before and after administration of [223Ra]RaCl2, up to 4 weeks after treatment. γ-H2AX- and 53BP1-positive α-tracks were microscopically quantified in isolated and immuno-stained PBMCs. Results The absorbed doses to the blood were less than 6 mGy up to 4 h after administration and maximally 16 mGy in total. Up to 4 h after administration, the α-track frequency was significantly increased relative to baseline and correlated with the absorbed dose to the blood in the dose range < 3 mGy. In most of the late samples (24 h – 4 weeks after administration), the α-track frequency remained elevated. Conclusion The γ-H2AX+53BP1 assay is a potent method for detection of α-particle-induced DNA damages during treatment with or after accidental incorporation of radionuclides even at low absorbed doses. It may serve as a biomarker discriminating α- from β-emitters based on damage geometry.

Hormone Refractory Prostate Cancer: Focus on Sipuleucel-T

2009 ◽  
Vol 1 ◽  
pp. CMT.S1084
Author(s):  
Christian Doehn ◽  
Martin Sommerauer ◽  
Xiyuan Guo ◽  
Ingo Kausch ◽  
Dieter Jocham
Keyword(s):  
Prostate Cancer ◽  
Prostatic Acid Phosphatase ◽  
The United States ◽  
Phase Iii ◽  
Fusion Product ◽  
Hormone Refractory Prostate Cancer ◽  
Clinical Responses ◽  
Hormone Refractory ◽  
Macrophage Colony ◽  
Antigen Presenting

Sipuleucel-T is a vaccine based on autologous antigen presenting cells that are loaded with an antigen-cytokine (prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor) fusion product. Sipuleucel-T is given intravenous in weeks 0, 2, and 4. Within phase I–III trials, patients with metastatic hormone-refractory prostate cancer have been treated. In these trials an activation of the immune system could be demonstrated. Also, some clinical responses could be documented. Moreover, in a placebo-controlled phase III trial including 127 patients a statistical significantly prolongation of survival was achieved. Side effects from the vaccine are rather mild and included fever, myalgia, fatigue and others. The Food and Drug Administration in the United States requested further data before possible approval of sipuleucel-T.

A prostate cancer clinical trials consortium trial of disulfiram (D) in men with nonmetastatic recurrent prostate cancer (PCa).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 219-219
Author(s):  
Michael Thomas Schweizer ◽  
Aditya Bardia ◽  
Amanda L. Blackford ◽  
Jianqing Lin ◽  
Andrew J. Armstrong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Primary Endpoint ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Local Therapy ◽  
Median Number ◽  
Open Label ◽  
Peripheral Blood Mononuclear ◽  
Psa Progression

219 Background: Epigenetic silencing of tumor suppressor genes (TSG) by promoter methylation contributes to carcinogenesis and progression. Targeting these epigenetic changes in PCa has been hindered by a paucity of available agents. D potently inhibits PCa growth in vitro and can cause demethylation and re-expression of known TSGs in PCa cells lines. Methods: To determine if D leads to demethylation changes [i.e. decreased global 5meC DNA content from peripheral blood mononuclear cells (PBMC)] we conducted an open-label, dose escalation trial of D in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating “response” (i.e. >10% decrease in global 5meC content) in <3 patients was observed in cohort 1. Cohort 1 and 2 received D 250 mg and 500 mg daily respectively; 1 cycle equaled 4 weeks. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months (i.e. confirmed >50% rise over baseline and >2 ng/mL above nadir), changes in PSA doubling time (PSADT) and safety/tolerability. Results: Two patients out of 9 (22.2%) in cohort 1 met our primary endpoint. Cohort 2 accrued a total of 10 patients, 3 (30.0%) of which had >10% decrease in global 5meC content. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. Median PSADT change post-treatment was not significantly different between responders and non-responders (266.9 vs -7.8 days, P=0.18) or between cohorts 1 and 2 (22.5 vs -39.7 days, P=0.54). While there were no grade (G) 4 adverse events (AE), the drug was poorly tolerated with 6 patients experiencing G3 AE (3 per cohort). There was a trend toward fewer median number of completed cycles in cohort 2 vs cohort 1 (5 vs 9 cycles, P=0.12). Common AE included: fatigue, GI toxicity, ataxia/dizziness, and constitutional symptoms. Conclusions: A minority of patients had global PBMC demethylation changes, consistent with D acting as a probable demethylating agent in those individuals. Given the toxicities associated with D and no significant clinical benefits, further development of this agent should not be pursued in this population. Clinical trial information: NCT01118741.

scholarly journals Dendritic Cell Immaturity during Infancy Restricts the Capacity To Express Vaccine-Specific T-Cell Memory

2006 ◽  
Vol 74 (2) ◽  
pp. 1106-1112 ◽  
Author(s):  
John W. Upham ◽  
Angela Rate ◽  
Julie Rowe ◽  
Merci Kusel ◽  
Peter D. Sly ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Memory ◽  
Effector Memory ◽  
Cell Memory ◽  
Peripheral Blood Mononuclear ◽  
Key Factor ◽  
Antigen Presenting ◽  
Autologous Cd14

ABSTRACT The capacity of the immune system in infants to develop stable T-cell memory in response to vaccination is attenuated, and the mechanism(s) underlying this developmental deficiency in humans is poorly understood. The present study focuses on the capacity for expression of in vitro recall responses to tetanus and diphtheria antigens in lymphocytes from 12-month-old infants vaccinated during the first 6 months of life. We demonstrate that supplementation of infant lymphocytes with “matured” dendritic cells (DC) cultured from autologous CD14+ precursors unmasks previously covert cellular immunity in the form of Th2-skewed cytokine production. Supplementation of adult lymphocytes with comparable prematured autologous DC also boosted vaccine-specific T-cell memory expression, but in contrast to the case for the infants, these cytokine responses were heavily Th1 skewed. Compared to adults, infants had significantly fewer circulating myeloid DC (P < 0.0001) and plasmacytoid DC (P < 0.0001) as a proportion of peripheral blood mononuclear cells. These findings suggest that deficiencies in the numbers of antigen-presenting cells and their functional competence at 12 months of age limit the capacity to express effector memory responses and are potentially a key factor in reduced vaccine responsiveness in infants.

scholarly journals Preservation of Lymphocyte Immunophenotype and Proliferative Responses in Cryopreserved Peripheral Blood Mononuclear Cells from Human Immunodeficiency Virus Type 1-Infected Donors: Implications for Multicenter Clinical Trials

2000 ◽  
Vol 7 (3) ◽  
pp. 352-359 ◽  
Author(s):  
Keith A. Reimann ◽  
Miriam Chernoff ◽  
Cynthia L. Wilkening ◽  
Christine E. Nickerson ◽  
Alan L. Landay
Keyword(s):  
Clinical Trials ◽  
Mononuclear Cells ◽  
Lymphocyte Subsets ◽  
In Vitro Assays ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Multicenter Clinical Trials ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection results in impaired immune function that can be measured by changes in immunophenotypically defined lymphocyte subsets and other in vitro functional assays. These in vitro assays may also serve as early indicators of efficacy when new therapeutic strategies for HIV-1 infection are being evaluated. However, the use of in vitro assays of immune function in multicenter clinical trials has been hindered by their need to be performed on fresh specimens. We assessed the feasibility of using cryopreserved peripheral blood mononuclear cells (PBMC) for lymphocyte immunophenotyping and for lymphocyte proliferation at nine laboratories. In HIV-1-infected patients with moderate CD4+ lymphocyte loss, the procedures of density gradient isolation, cryopreservation, and thawing of PBMC resulted in significant loss of CD19+ B cells but no measurable loss of total T cells or CD4+ or CD8+ T cells. No significant changes were seen in CD28− CD95+lymphocytes after cell isolation and cryopreservation. However, small decreases in HLA-DR+ CD38+ lymphocytes and of CD45RA+ CD62L+ were observed within both the CD4+ and CD8+ subsets. Fewer than 10% of those specimens that showed positive PBMC proliferative responses to mitogens or microbial antigens lost their responsiveness after cryopreservation. These results support the feasibility of cryopreserving PBMC for immunophenotyping and functional testing in multicenter AIDS clinical trials. However, small changes in selected lymphocyte subsets that may occur after PBMC isolation and cryopreservation will need to be assessed and considered in the design of each clinical trial.

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