Analyses of 123 Peripheral Human Immune Cell Subsets: Defining Differences with Age and between Healthy Donors and Cancer Patients not Detected in Analysis of Standard Immune Cell Types

Recent advances in human immunology have led to the identification of novel immune cell subsets and the biological function of many of these subsets has now been identified. The recent US Food and Drug Administration approval of several immunotherapeutics for the treatment of a variety of cancer types and the results of ongoing immunotherapy clinical studies requires a more thorough interrogation of the immune system. We report here the use of flow cytometry-based analyses to identify 123 immune cell subsets of peripheral blood mononuclear cells. The use of these panels defines multiple differences in younger (< 40 years) vs. older (≥ 40 years) individuals and between aged-matched apparently healthy individuals and metastatic cancer patients, aspects not seen in the analysis of the following standard immune cell types: CD8, CD4, natural killer, natural killer-T, regulatory T, myeloid derived suppressor cells, conventional dendritic cells (DCs), plasmacytoid DCs and B cells. The use of these panels identifying 123 immune cell subsets may aid in the identification of patients who may benefit from immunotherapy, either prior to therapy or early in the immunotherapeutic regimen, for the treatment of cancer or other chronic or infectious diseases

Samarium-153-EDTMP (Quadramet®) With or Without Vaccine in Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase 2 Trial

PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet®), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point (P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms (P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline \u3e 30% compared with four patients (of 21) in the combination arm, including three with PSA decline \u3e 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM

Chordoma: The Quest for Better Treatment Options

<div><p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>.</b> <a href="https://link.springer.com/article/10.1007/s40487-016-0016-0">https://link.springer.com/article/10.1007/s40487-016-0016-0</a></p> <p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p><br></div

Emerging Treatment Strategies for Metastatic Prostate Cancer: The Next Step Forward

After relatively modest advances in the treatment of metastatic castration-resistant prostate cancer (CRPC) over the past 2 decades, the past 2 years have seen the emergence of four new agents that have improved survival for patients with advanced disease. Among these new agents are therapies that may revolutionize how prostate cancer is treated. They include an agent that targets the androgen biosynthesis pathway and a first-in-class therapeutic cancer vaccine. In addition, several new therapies are in late stages of development. As these newer agents are evaluated clinically, the rationale fir combination therapy will be evaluated based on preclinical and preliminary clinical data. The results of these continued investigations may help develop future treatment strategies for men with metastatic CRPC

An e-science environment for service crystallography: from submission to dissemination

The UK National Crystallography Service (NCS) has developed a prototype e-Science infrastructure for the provision of a small molecule crystallography service from sample receipt to results dissemination. This paper outlines the two strands this service, which a) enable a user to contribute in the conduction of an experiment and b) provides an effective route for the archival and dissemination of the arising results. Access to use the NCS facilities and expertise and a mechanism to submit samples is granted through a secure Grid infrastructure, which seamlessly provides instantaneous feedback and the ability to remotely monitor and guide diffraction experiments and stage the diffraction data to a securely accessible location. Publication of all the data and results generated during the course of the experiment, from processed data to analysed structures is then enabled by means of an open access data repository. The repository publishes its content through established digital libraries protocols, which enable harvester and aggregator services to make the data searchable and accessible

Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer

BackgroundClinical trials have shown the ability of therapeutic vaccines to generate immune responses to tumor-associated antigens (TAAs). What is relatively less known is if this translates into immune-cell (IC) infiltration into the tumor microenvironment. This study examined whether neoadjuvant prostate-specific antigen (PSA)-targeted vaccination with PROSTVAC could induce T-cell immunity, particularly at the tumor site.MethodsAn open-label, phase II study of neoadjuvant PROSTVAC vaccine enrolled 27 patients with localized prostate cancer awaiting radical prostatectomy (RP). We evaluated increases in CD4 and CD8 T-cell infiltrates (RP tissue vs baseline biopsies) using a six-color multiplex immunofluorescence Opal method. Antigen-specific responses were assessed by intracellular cytokine staining after in vitro stimulation of peripheral blood mononuclear cells with overlapping 15-mer peptide pools encoding the TAAs PSA, brachyury and MUC-1.ResultsOf 27 vaccinated patients, 26 had matched prevaccination (biopsy) and postvaccination (RP) prostate samples available for non-compartmentalized analysis (NCA) and compartmentalized analysis (CA). Tumor CD4 T-cell infiltrates were significantly increased in postvaccination RP specimens compared with baseline biopsies by NCA (median 176/mm² vs 152/mm²; IQR 136–317/mm² vs 69–284/mm²; p=0.0249; median ratio 1.20; IQR 0.64–2.25). By CA, an increase in both CD4 T-cell infiltrates at the tumor infiltrative margin (median 198/mm² vs 151/mm²; IQR 123–500/mm² vs 85–256/mm²; p=0.042; median ratio 1.44; IQR 0.59–4.17) and in CD8 T-cell infiltrates at the tumor core (median 140/mm² vs 105/mm²; IQR 91–175/mm² vs 83–163/mm²; p=0.036; median ratio 1.25; IQR 0.88–2.09) were noted in postvaccination RP specimens compared with baseline biopsies. A total of 13/25 patients (52%) developed peripheral T-cell responses to any of the three tested TAAs (non-neoantigens); five of these had responses to more than one antigen of the three evaluated.ConclusionNeoadjuvant PROSTVAC can induce both tumor immune response and peripheral immune response.Trial registration numberNCT02153918

A randomized, double-blind, phase II clinical trial of GI-6301 (yeast-brachyury vaccine) versus placebo in combination with standard of care definitive radiotherapy in locally advanced, unresectable, chordoma

Abstract only 11527 Background: Chordoma is a rare neoplasm of the notochord that overexpresses brachyury, a transcription factor associated with epithelial-to-mesenchymal transition, metastasis, poor prognosis, and chemotherapy resistance. GI-6301 is a recombinant yeast-brachyury vaccine shown to demonstrate brachyury-specific immunogenicity, excellent safety profile, and some evidence of clinical activity in patients with chordoma in a previous phase I trial. Radiation therapy (RT) can modulate the tumor to become an immunostimulatory milieu. Preclinical studies have shown a synergistic effect combining RT with vaccine, thus prompting this clinical trial evaluating the combination of GI-6301 with RT in chordoma (NCT02383498). Methods: Adults with locally advanced, unresectable chordoma were treated on a randomized, double-blind, placebo controlled, phase 2 clinical trial. Patients received 3 doses of GI-6301 (80 x 107 yeast cells) vs placebo followed by photon or proton RT, followed by GI-6301 vs placebo until disease progression. Primary outcome was overall response rate (ORR) defined as a complete response or partial response in the irradiated tumor site at 24 months. Immune assays were conducted to evaluate immunogenicity. Due to slow accrual, an unplanned interim analysis was undertaken. Results: 24 pts were randomized and treated between May 2015 and September 2019. Vaccine was well tolerated with no dose reductions or treatment discontinuation. Treatment-related serious adverse events included: nausea/emesis (2); fatigue (2); dehydration (2); diarrhea (1); radiation necrosis (1); stroke (1); sepsis (1). There was no difference in ORR between the two arms. Pre-existing brachyury-specific T-cells were detected in the majority of patients but did not correlate with response to therapy. Most patients developed T-cell responses during therapy, regardless of treatment arm. Conclusions: There was no difference in ORR between the two arms. GI-6301 was well tolerated with toxicities related to RT, not vaccine. The trial was stopped early due to low conditional power for finding a statistical difference at the planned end of accrual, based on findings to date. Future studies will define utility of vaccines targeting brachyury in chordoma. Clinical trial information: NCT02383498 . [Table: see text