scholarly journals Treatment Combinations with DNA Vaccines for the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2831
Author(s):  
Melissa Gamat-Huber ◽  
Donghwan Jeon ◽  
Laura E. Johnson ◽  
Jena E. Moseman ◽  
Anusha Muralidhar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Large Scale ◽  
Dna Vaccines ◽  
Clinical Effects ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Investigational Drugs ◽  
Clinical Responses ◽  
Antitumor Vaccine ◽  
Poor Outcomes

Metastatic castration-resistant prostate cancer (mCRPC) is a challenging disease to treat, with poor outcomes for patients. One antitumor vaccine, sipuleucel-T, has been approved as a treatment for mCRPC. DNA vaccines are another form of immunotherapy under investigation. DNA immunizations elicit antigen-specific T cells that cause tumor cell lysis, which should translate to meaningful clinical responses. They are easily amenable to design alterations, scalable for large-scale manufacturing, and thermo-stable for easy transport and distribution. Hence, they offer advantages over other vaccine formulations. However, clinical trials with DNA vaccines as a monotherapy have shown only modest clinical effects against tumors. Standard therapies for CRPC including androgen-targeted therapies, radiation therapy and chemotherapy all have immunomodulatory effects, which combined with immunotherapies such as DNA vaccines, could potentially improve treatment. In addition, many investigational drugs are being developed which can augment antitumor immunity, and together with DNA vaccines can further enhance antitumor responses in preclinical models. We reviewed the literature available prior to July 2020 exploring the use of DNA vaccines in the treatment of prostate cancer. We also examined various approved and experimental therapies that could be combined with DNA vaccines to potentially improve their antitumor efficacy as treatments for mCRPC.

scholarly journals BRCA Mutations in Prostate Cancer: Prognostic and Predictive Implications

2020 ◽  
Vol 2020 ◽  
pp. 1-7 ◽  
Author(s):  
Carlo Messina ◽  
Carlo Cattrini ◽  
Davide Soldato ◽  
Giacomo Vallome ◽  
Orazio Caffo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Brca Mutations ◽  
Primary Tumors ◽  
Receptor Signalling ◽  
Castration Resistant ◽  
Damage Repair ◽  
Poor Outcomes

Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles.

Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 195-195
Author(s):  
Simon Yuen Fai Fu ◽  
Elie Ritch ◽  
Steven Yip ◽  
Daniel Khalaf ◽  
Sinja Taavitsainen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Somatic Mutation ◽  
Nonnegative Matrix ◽  
Castration Resistant Prostate Cancer ◽  
Control Cohort ◽  
Castration Resistant ◽  
Whole Exome ◽  
Mutation Burden ◽  
Selection For ◽  
Poor Outcomes

195 Background: A small proportion of metastatic PC exhibit outlier somatic mutation rates. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing of 1047 plasma cell-free DNA samples and calculated somatic mutation burden. HM samples and available matched archival tissue were additionally subjected to whole exome sequencing. Trinucleotide mutational signatures and microsatellite instability (MSI) were determined via nonnegative matrix factorization and mSINGS, respectively. We evaluated PSA decline ≥50% from baseline (PSA50), time from androgen deprivation therapy (ADT) to castration-resistant prostate cancer (CRPC), median duration of 1st line CRPC therapy (1L CRPCT) and median OS (time from CRPC to death). The control cohort consisted of 199 CRPC pts treated with 1L abiraterone + prednisone (ABI+P) or enzalutamide (ENZ). Results: 671 samples from 434 pts had ctDNA% > 2 and were evaluable. The median mutation rate was 2.59/Mb (range, 0.9 – 155.6/Mb). 32 samples from 24 pts had > 11/Mb and fell above the 95th percentile for mutational burden. 10/24 pts had biallelic loss of mismatch repair (MMR) genes MSH2/6, and a further 5 pts without confirmed MMR defects had enrichment of trinucleotide signatures associated with MMR and/or were MSI high by mSINGS. The remaining 9 pts had either BRCA2 mutations or Kataegis (localized hypermutation). Clinical data was available for 10/15 MMR defective pts. Median age was 73.6 y. At diagnosis, 70% had Gleason score ≥8, 50% with M1 disease, median PSA was 22.8 (6.8 – 820). PSA50 with ADT (n = 8) or ADT + docetaxel (n = 2) was 100% in the castration sensitive setting. 5 pts had ENZ, 4 ABI + P, and 1 cabazitaxel in 1L CRPCT. Comparing the MMR defective with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9 – 11.4) vs. 18.2 m (95% CI 15.1 – 21.3), p = 0.001; 1L CRPCT duration was 3.9 m (95% CI 1.3 – 6.5) vs. 8.4 m (95% CI 7.2 – 9.6), p = < 0.001; median OS was 13.1 m (95% CI 0.33 – 25.9) vs. 40.1 m (95% CI 32.4 – 47.8), p < 0.001. Conclusions: HM and MMR defects can be identified in a liquid biopsy. Although these pts can have poor outcomes with standard therapy, ctDNA may help selection for immunotherapy.

scholarly journals Castration-mediated IL-8 Promotes Myeloid Infiltration and Prostate Cancer Progression

2019 ◽  
Author(s):  
Zoila A. Lopez-Bujanda ◽  
Michael C. Haffner ◽  
Matthew G. Chaimowitz ◽  
Nivedita Chowdhury ◽  
Nicholas J. Venturini ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Prostate Cancer Progression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Intrinsic Factors ◽  
Castration Resistant ◽  
Clinical Responses

SummaryImmunotherapy is a treatment for many types of cancer, primarily due to deep and durable clinical responses mediated by immune checkpoint blockade (ICB)1, 2. Prostate cancer is a notable exception in that it is generally unresponsive to ICB. The standard treatment for advanced prostate cancer is androgen-deprivation therapy (ADT), a form of castration (CTX). ADT is initially effective, but over time patients eventually develop castration-resistant prostate cancer (CRPC). Here, we focused on defining tumor-cell intrinsic factors that contribute to prostate cancer progression and resistance to immunotherapy. We analyzed cancer cells isolated from castration-sensitive and castration-resistant prostate tumors, and discovered that castration resulted in significant secretion of Interleukin-8 (IL-8) and it’s likely murine homolog Cxcl15. These chemokines drove subsequent intra-tumoral infiltration with polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), promoting tumor progression. PMN-MDSC infiltration was abrogated when IL-8 was deleted from prostate cancer epithelial cells using CRISPR/Cas9, or when PMN-MDSC migration was blocked with antibodies against the IL-8 receptor CXCR2. Blocking PMN-MDSC infiltration in combination with anti-CTLA-4 delayed the onset of castration resistance and increased the density of polyfunctional CD8 T cells in tumors. Taken together, our findings establish castration-mediated IL-8 secretion and subsequent PMN-MDSC infiltration as a key suppressive mechanism in the progression of prostate cancer. Targeting of the IL-8/CXCR2 axis around the time of ADT, in combination with ICB, represents a novel therapeutic approach to delay prostate cancer progression to advanced disease.

Examination of the additive value of CTC biomarkers of heterogeneity (Het) and chromosomal instability to nuclear-localized (nl) AR-V7+ CTCs in prediction of poor outcomes to androgen receptor signaling inhibitor (ARSi) in metastatic castration resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5075-5075 ◽  
Author(s):  
Howard I. Scher ◽  
Joseph Schonhoft ◽  
Ryon P Graf ◽  
Adam Jendrisak ◽  
Ethan Barnett ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Large Scale ◽  
Predictive Biomarker ◽  
Shannon Index ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Medical Need ◽  
Signaling Inhibitors ◽  
Poor Outcomes ◽  
Relationship Of

5075 Background: Prediction of ARSi benefit in mCRPC is an unmet medical need. Recently, the Epic Sciences CTC based nl AR-V7 test validated as a predictive biomarker in two multi-center validation studies and has received Medicare coverage for use in mCRPC. While the nl AR-V7 biomarker is highly specific to resistance and predictive of improved response with taxane Rx, it is a measure of just one mechanism of resistance to ARSis. CTC Het measured by the Shannon Index and CTC chromosomal instability measured by predicted number of Large Scale Transitions (pLST) have both been associated with poor OS to ARSis in previous analysis. Here we investigate the relationship of Het and pLST to nlAR-V7 in order to assess multi-clonal resistance and determine if these biomarkers can provide added sensitivity in the nlAR-V7 negative patient population. Methods: 275 blood samples from 2nd+ line mCRPC patients prior to treatment with ARSi (n=148) or taxanes (n=137) were obtained between 2012 and 2017 from 3 clinical centers. Detectable CTCs in each blood sample were assayed for nlAR-V7, Het, and pLST using the Epic Sciences platform. Biomarkers were analyzed in context of each other and outcomes including clinical co-variates. Results: 94% of samples had detectable CTCs, 84% were evaluable for Het analysis (> 2 CTCs), and 76% were evaluable for pLST (> 3 CTCs). Conclusions: Addition of CTC Het (Shannon Index) and CTC chromosomal instability (pLST) biomarkers to nlAR-V7 identifies an additional 15% of mCRPC pts (38% of total) that are predicted to have poor survival to AR signaling inhibitors. [Table: see text][Table: see text]

scholarly journals Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

2021 ◽  
Vol 9 (5) ◽  
pp. e002254
Author(s):  
Meenal Sinha ◽  
Li Zhang ◽  
Sumit Subudhi ◽  
Brandon Chen ◽  
Jaqueline Marquez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
T Cell Responses ◽  
Castration Resistant Prostate Cancer ◽  
Cell Responses ◽  
Castration Resistant ◽  
Clinical Responses

BackgroundSipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.MethodsA total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.ResultsWe found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.ConclusionCombining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.

scholarly journals The role of dosimetry and biological effects in metastatic castration–resistant prostate cancer (mCRPC) patients treated with 223Ra: first in human study

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Rosa Sciuto ◽  
Sandra Rea ◽  
Sara Ungania ◽  
Antonella Testa ◽  
Valentina Dini ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Response ◽  
Haematological Parameters ◽  
High Dose ◽  
Clinical Effects ◽  
Chromosome Damage ◽  
Target Tissue ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Dose Dependent

Abstract Background 223Ra is currently used for treatment of metastatic castration resistant prostate cancer patients (mCRPC) bone metastases with fixed standard activity. Individualized treatments, based on adsorbed dose (AD) in target and non-target tissue, are absolutely needed to optimize efficacy while reducing toxicity of α-emitter targeted therapy. This is a pilot first in human clinical trial aimed to correlate dosimetry, clinical response and biological side effects to personalize 223Ra treatment. Methods Out of 20 mCRPC patients who underwent standard 223Ra treatment and dosimetry, in a subset of 5 patients the AD to target and non-target tissues was correlated with clinical effects and radiation-induced chromosome damages. Before each 223Ra administrations, haematological parameters, PSA and ALP values were evaluated. Additional blood samples were obtained baseline (T0), at 7 days (T7), 30 days (T30) and 180 days (T180) to evaluate chromosome damage. After administration WB planar 223Ra images were obtained at 2–4 and 18–24 h. Treatment response and toxicity were monitored with clinical evaluation, bone scan, 18F-choline-PET/CT, PSA value and ALP while haematological parameters were evaluated weekly after 223Ra injection and 2 months after last cycle. Results 1. a correlation between AD to target and clinical response was evidenced with threshold of 20 Gy as a cut-off to obtain tumor control; 2. the AD to red marrow was lower than 2 Gy in all the patients with no apparently correlation between dosimetry and clinical toxicity. 3. a high dose dependent increase of the number of dicentrics and micronuclei during the course of 223Ra therapy was observed and a linear correlation has been found between blood AD (BAD) and number of dicentrics. Conclusions This study provides some interesting preliminary evidence to be further investigated: dosimetry may be useful to identify a more appropriate 223Ra administered activity predicting AD to target tissue; a dose dependent complex chromosome damage occurs during 223Ra administration and this injury is more evident in heavily pre-treated patients; dosimetry could be used for radioprotection purpose. Trial registration The pilot study has been approved from the Ethics Committee of Regina Elena National Cancer Institute (N:RS1083/18–2111).

scholarly journals Comparison of Oncologic Outcomes between Two Alternative Sequences with Abiraterone Acetate and Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 8 ◽  
Author(s):  
Doo Yong Chung ◽  
Dong Hyuk Kang ◽  
Jong Won Kim ◽  
Do Kyung Kim ◽  
Joo Yong Lee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Large Scale ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Oncologic Outcomes ◽  
Castration Resistant Prostate Cancer ◽  
Level Of Evidence ◽  
Positive Effects ◽  
Castration Resistant

Sequential treatment of androgen receptor axis targeted agents (ARAT), abiraterone acetate (ABI) and enzalutamide (ENZA), in metastatic castration-resistant prostate cancer (mCRPC) demonstrated some positive effects, but cross-resistances between ABI and ENZA that reduce activity have been suggested. Therefore, we conducted a meta-analysis to compare oncologic outcomes between the treatment sequences of ABI-ENZA and ENZA-ABI in patients with mCRPC. The primary endpoint was a combined progression-free survival (PFS), and the secondary endpoint was overall survival (OS). A total of five trials on 553 patients were included in this study. Each of the included studies was retrospective. In two studies including both chemo-naïve and post-chemotherapy mCRPC patients, for ABI-ENZA compared with ENZA-ABI, pooled hazard ratios (HRs) for PFS and OS were 0.37 (p < 0.0001; 95% confidence intervals (CIs), 0.23–0.60) and 0.64 (p = 0.10; 95% CIs, 0.37–1.10), respectively. In three studies with chemo-naïve mCRPC patients only, for ABI-ENZA compared with ENZA-ABI, pooled HRs for PFS and OS were 0.57 (p = 0.02; 95% CIs, 0.35–0.92) and 0.86 (p = 0.39; 95% CIs, 0.61–1.21), respectively. The current meta-analysis revealed that ABI-ENZA had a significantly more favorable oncological outcome, but the level of evidence was low. Therefore, large-scale randomized trials may be needed.

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