Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-T alone in patients with metastatic castrate resistant prostate cancer

Twardowski, Przemyslaw; Wong, Jeffrey Y.C.; Pal, Sumanta K.; Maughan, Benjamin L.; Frankel, Paul; Franklin, Kelly Lora; Junqueira, Maribel; Prajapati, Manisha; Nachaegari, Gayatri; Harwood, Deborah; Agarwal, Neeraj

doi:10.1016/j.ctarc.2018.100116

Cited by 32 publications

(26 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relevance of filling this gap in knowledge is highlighted by negative results or minimal benefits recorded in subsequent clinical trials testing immunotherapeutic approaches in patients with PCa. [66][67][68][69][70][71][72] Therefore, a thorough understanding of the mechanism by which PCa evades the immune system and limits T-cell infiltration could have significant translational consequences.…”

Section: Discussionmentioning

confidence: 99%

WHSC1/NSD2 regulates immune infiltration in prostate cancer

Want

Tsuji

Singh

et al. 2021

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundImmunotherapy in prostate cancer (PCa) lags behind the progresses obtained in other cancer types partially because of its limited immune infiltration. Tumor-resident immune cells have been detected in the prostate, but the regulatory mechanisms that govern tumor infiltration are still poorly understood. To address this gap, we investigated the role of Wolf-Hirschhorn syndrome candidate 1 (WHSC1), a histone methyltransferase enzyme that targets dimethyl and trimethyl H3K36. WHSC1 is known to promote malignant growth and progression in multiple tumors, but its role in the interface between PCa and immune system is unknown.MethodsRNA Sequencing (RNASeq) data from patients with PCa from The Cancer Genome Atlas (TCGA) were collected and divided into top/bottom 30% based on the expression of WHSC1 and disease-free survival was calculated. Publicly available chromatin immunoprecipitation (ChIPSeq) data were obtained from Cistrome and integrated with the available RNASeq data. RNASeq, ATACSeq and methylomic were analyzed using R Bioconductor packages comparing C42 cells with or without stable knockdown on WHSC1. Flow cytometry was used to measure Major Histocompatibility complex (MHC) levels, MHC-bound ovalbumin and tumor infiltration. C57B6 and NOD scid gamma (NSG) mice were subcutaneously grafted with TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) C2 cells and treated with MCTP39 (10 mg/kg); tumor size was monitored over time and curves were compared using permutation analyses. All analyses used a significance threshold of 0.05.ResultsLeveraging TCGA data, we demonstrated that elevated WHSC1 levels positively correlate with the presence of an immunosuppressive microenvironment. We validated those results in vitro, demonstrating that genetic and pharmacological inhibition of WHSC1 restores antigen presentation. This occurs via an elegant epigenetic regulation of gene expression at the chromatin and DNA methylation levels. In vivo studies in immunocompetent mice also show an increased frequency of CD8+ T cells in tumors from mice treated with WHSC1 inhibitor, supporting the hypothesis that the antitumor effect following WHSC1 inhibition requires a fully functional immune system.ConclusionsThis study demonstrates a novel role for WHSC1 in defining immune infiltration in PCa, with significant future implications for the use of immunotherapies in prostate malignancies.

show abstract

Section: Discussionmentioning

confidence: 99%

WHSC1/NSD2 regulates immune infiltration in prostate cancer

Want

Tsuji

Singh

et al. 2021

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…For example, we used the OQS scoring method used in some quality evaluation articles, as well as all the entries in the 28 CONSORT statements in some quality evaluation articles. Compared with other quality evaluation articles, our article is more comprehensive and advanced 35‐53 …”

Section: Methodsmentioning

confidence: 98%

Reporting quality of randomized, controlled trials evaluating immunotherapy in lung cancer

Du¹,

Zhang

Dong

et al. 2021

Thoracic Cancer

View full text Add to dashboard Cite

Background With the improvement of therapeutic strategies from cytotoxic chemotherapy to immunotherapy, the possibility of achieving timely intervention for lung cancer has dramatically increased. This study aimed to systematically evaluate the reporting quality of randomized controlled trials (RCT) on immunotherapy in lung cancer. Methods The RCTs evaluating the efficacy of immunotherapy in lung cancer published up to 2021 were searched and collected from PUBMED and EMBASE by two investigators. The 2010 Consolidated Standards for Test Reports (CONSORT) statement‐based 28‐point overall quality score (OQS) and the 2001 CONSORT statement‐based 19‐point OQS was utilized for assessing the overall quality of each report. Results One hundred and fifty‐two related RCTs were retrieved in this study, including 81,931 patients. The average OQS in 2010 was 17.89 (range, 7.5–24.5). Overall, studies have sufficiently reported the eligibility criteria (143/152; 94.07%), described the scientific background (150/152; 98.7%) and discussed interventions (147/152; 96.7%). However, the RCTs did not consistently report the changes to trial after commencement (48/152; 31.6%), allocation, enrollment and assignment personnel (34/152; 22.4%), blinding (48/152; 31.6%), or randomization method (58/152; 38.2%). Conclusions The overall reporting quality of RCTs on immunotherapy in lung cancer was found to be unsatisfactory despite the fact that the CONSORT statement was issued more than a decade ago. Furthermore, there was virtual selectivity and heterogeneity in reporting some key issues in these trials. This is the first study to enlighten lung cancer researchers especially focusing on immunotherapy, and also to remind editors and peer reviewers to strengthen their due diligence.

show abstract

“…In a phase 2 trial, 51 mCRPC patients were randomized to sipuleucel-T alone or sipuleucel-T initiated 1 wk after completion of sensitizing RT (total 3000 cGy) to a single metastatic site. Sensitizing RT completed 1 wk before administration of sipuleucel-T did not affect the majority of the sipuleucel-T parameters or the ability to deliver the therapy; the authors concluded that RT did not enhance the humoral and cellular responses associated with sipuleucel-T therapy [43]. Results from a phase 3 multicenter trial enrolling mCRPC patients treated with a combination of RT and sipuleucel-T (NCT02232230) are expected in the next months.…”

Section: Icis In Combination With Rtmentioning

confidence: 99%

A Systematic Review of the Emerging Role of Immune Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer: Will Combination Strategies Improve Efficacy?

Heidegger

Necchi

Pircher

et al. 2021

European Urology Oncology

View full text Add to dashboard Cite

Context: The role of immune checkpoint inhibition (ICI) in the treatment of prostate cancer (PC) still remains elusive. It has been proposed that combination of ICI with other molecules increases the efficacy of immunotherapy in PC. Objective: To systematically review the literature to assess the potential role of ICI in combination with additional therapies for the management of metastatic castration-resistant PC (mCRPC). Evidence acquisition: A systematic review using Medline and scientific meeting records was carried out in September 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. Ongoing trials of immunotherapy with standard mCRPC therapeutics were identified via a systematic search on ClinicalTrials.gov. Evidence synthesis: A total of five full-text papers, ten congress abstracts, and 15 trials on ClinicalTrials.gov were identified. Preclinical evidence suggests that combinational approaches might be considered to enhance the efficacy of ICI in PC patients. This led to the design of more than 50 immunotherapy-based clinical

show abstract

Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-T alone in patients with metastatic castrate resistant prostate cancer

Cited by 32 publications

References 14 publications

WHSC1/NSD2 regulates immune infiltration in prostate cancer

WHSC1/NSD2 regulates immune infiltration in prostate cancer

Reporting quality of randomized, controlled trials evaluating immunotherapy in lung cancer

A Systematic Review of the Emerging Role of Immune Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer: Will Combination Strategies Improve Efficacy?

Contact Info

Product

Resources

About