Testing for Homologous Recombination Repair or Homologous Recombination Deficiency for Poly (ADP-ribose) Polymerase Inhibitors: A Current Perspective

Poly (ADP-ribose) polymerase inhibitors (PARPis) have demonstrated clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. Notably, BRCA mutations are associated with defects in the homologous recombination repair (HRR) pathway. This homologous recombination deficiency (HRD) phenotype can also be observed as genomic instability in tumour cells. Accordingly, PARPi sensitivity has been observed in various tumours with HRD, independent of BRCA mutations. Currently, four PARPis are approved by regulatory agencies for the treatment of cancer across multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, mutations in other HRR-related genes, HRD evidenced by genomic instability, or evidence of platinum sensitivity. Regulatory agencies have also approved companion and complementary diagnostics to facilitate patient selection for each PARPi indication. This review aims to summarise the biological basis, clinical validation, and clinical relevance of the available diagnostic methods and assays to assess HRD

Systematic techniques for assisting recruitment to trials (START): study protocol for embedded, randomized controlled trials

BACKGROUND: Randomized controlled trials play a central role in evidence-based practice, but recruitment of participants, and retention of them once in the trial, is challenging. Moreover, there is a dearth of evidence that research teams can use to inform the development of their recruitment and retention strategies. As with other healthcare initiatives, the fairest test of the effectiveness of a recruitment strategy is a trial comparing alternatives, which for recruitment would mean embedding a recruitment trial within an ongoing host trial. Systematic reviews indicate that such studies are rare. Embedded trials are largely delivered in an ad hoc way, with interventions almost always developed in isolation and tested in the context of a single host trial, limiting their ability to contribute to a body of evidence with regard to a single recruitment intervention and to researchers working in different contexts. METHODS/DESIGN: The Systematic Techniques for Assisting Recruitment to Trials (START) program is funded by the United Kingdom Medical Research Council (MRC) Methodology Research Programme to support the routine adoption of embedded trials to test standardized recruitment interventions across ongoing host trials. To achieve this aim, the program involves three interrelated work packages: (1) methodology - to develop guidelines for the design, analysis and reporting of embedded recruitment studies; (2) interventions - to develop effective and useful recruitment interventions; and (3) implementation - to recruit host trials and test interventions through embedded studies. DISCUSSION: Successful completion of the START program will provide a model for a platform for the wider trials community to use to evaluate recruitment interventions or, potentially, other types of intervention linked to trial conduct. It will also increase the evidence base for two types of recruitment intervention. TRIAL REGISTRATION: The START protocol covers the methodology for embedded trials. Each embedded trial is registered separately or as a substudy of the host trial

61MO Biomarker analysis of men with enzalutamide (enza)-resistant metastatic castration-resistant prostate cancer (mCRPC) treated with pembrolizumab (pembro) + enza in KEYNOTE-199

Background: In KEYNOTE-199 (NCT02787005), pembro + enza had durable antitumor activity in enza-refractory mCRPC. We evaluated the association between prespecified biomarkers and clinical outcomes. Methods: Cohorts 4 (C4; RECIST-measurable disease) and 5 (C5; nonmeasurable, bone-predominant disease) enrolled men with chemotherapy-naive mCRPC, irrespective of PD-L1 status, that progressed after initial response to enza. We evaluated TMB by whole exome sequencing (n = 64), PD-L1 combined positive score (CPS) by IHC (n = 124), and 18-gene T-cell–inflamed gene expression profile (TcellinfGEP) by NanoString (n = 51). Outcomes were DCR, PFS, PSA response, PSA progression, OS, and ORR per blinded independent review (C4 only). Significance of continuous biomarkers (CPS, TMB, GEP) was prespecified at 0.05 for 1-sided P values from logistic (ORR, DCR, PSA response) and Cox proportional hazard (PFS, OS, PSA progression) regression adjusted for ECOG PS. Results: In C4, ORR was 10% (5/48) in pts with evaluable TMB data and 12% (10/81) in pts with CPS data. In C4 and C5, 16% (10/64) and 14% (17/124) of pts with TMB and CPS data, respectively, achieved a PSA response. TMB was significantly associated with DCR (P = 0.03) and trended toward an association with PSA response (P = 0.08). TMB (AUROC [95% CI]: 0.68 [0.51-0.86]), but not CPS (0.54 [0.41-0.67]) or TcellinfGEP (0.55 [0.37-0.74]), enriched for PSA response. TMB (P = 0.04), but not CPS (P = 0.57) or TcellinfGEP (P = 0.32), was significantly associated with PSA progression. There was 1 MSI-H pt (per Promega PCR assay); this pt achieved an objective and PSA response and had PFS \u3e6 months. TMB, CPS, and TcellinfGEP were not associated with PFS or OS. There was a low prevalence of TMB ≥175 mut/exome (11%) and TcellinfGEP-high (≥−0.318; 16%). Conclusions: In this biomarker analysis of KEYNOTE-199 C4-C5, PD-L1 CPS and TcellinfGEP were not significantly associated with clinical outcome. Despite the low prevalence of TMB ≥175 mut/exome, TMB was positively associated with outcomes of pembro + enza in pts with mCRPC. The sample sizes for the exploratory analyses were small, and results should be interpreted with caution

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study

PURPOSE: Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population. METHODS: The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety. RESULTS: Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, = 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%. CONCLUSION: Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging

Combination immunotherapy and active-specific tumor cell vaccination augments anti-cancer immunity in a mouse model of gastric cancer

<p>Abstract</p> <p>Background</p> <p>Active-specific immunotherapy used as an adjuvant therapeutic strategy is rather unexplored for cancers with poorly characterized tumor antigens like gastric cancer. The aim of this study was to augment a therapeutic immune response to a low immunogenic tumor cell line derived from a spontaneous gastric tumor of a CEA424-SV40 large T antigen (CEA424-SV40 TAg) transgenic mouse.</p> <p>Methods</p> <p>Mice were treated with a lymphodepleting dose of cyclophosphamide prior to reconstitution with syngeneic spleen cells and vaccination with a whole tumor cell vaccine combined with GM-CSF (a treatment strategy abbreviated as LRAST). Anti-tumor activity to subcutaneous tumor challenge was examined in a prophylactic as well as a therapeutic setting and compared to corresponding controls.</p> <p>Results</p> <p>LRAST enhances tumor-specific T cell responses and efficiently inhibits growth of subsequent transplanted tumor cells. In addition, LRAST tended to slow down growth of established tumors. The improved anti-tumor immune response was accompanied by a transient decrease in the frequency and absolute number of CD4⁺CD25⁺FoxP3⁺T cells (Tregs).</p> <p>Conclusions</p> <p>Our data support the concept that whole tumor cell vaccination in a lymphodepleted and reconstituted host in combination with GM-CSF induces therapeutic tumor-specific T cells. However, the long-term efficacy of the treatment may be dampened by the recurrence of Tregs. Strategies to counteract suppressive immune mechanisms are required to further evaluate this therapeutic vaccination protocol.</p

Mathematical modelling of clostridial acetone-butanol-ethanol fermentation

Clostridial acetone-butanol-ethanol (ABE) fermentation features a remarkable shift in the cellular metabolic activity from acid formation, acidogenesis, to the production of industrial-relevant solvents, solventogensis. In recent decades, mathematical models have been employed to elucidate the complex interlinked regulation and conditions that determine these two distinct metabolic states and govern the transition between them. In this review, we discuss these models with a focus on the mechanisms controlling intra- and extracellular changes between acidogenesis and solventogenesis. In particular, we critically evaluate underlying model assumptions and predictions in the light of current experimental knowledge. Towards this end, we briefly introduce key ideas and assumptions applied in the discussed modelling approaches, but waive a comprehensive mathematical presentation. We distinguish between structural and dynamical models, which will be discussed in their chronological order to illustrate how new biological information facilitates the ‘evolution’ of mathematical models. Mathematical models and their analysis have significantly contributed to our knowledge of ABE fermentation and the underlying regulatory network which spans all levels of biological organization. However, the ties between the different levels of cellular regulation are not well understood. Furthermore, contradictory experimental and theoretical results challenge our current notion of ABE metabolic network structure. Thus, clostridial ABE fermentation still poses theoretical as well as experimental challenges which are best approached in close collaboration between modellers and experimentalists

A genomic catalog of Earth’s microbiomes

The reconstruction of bacterial and archaeal genomes from shotgun metagenomes has enabled insights into the ecology and evolution of environmental and host-associated microbiomes. Here we applied this approach to >10,000 metagenomes collected from diverse habitats covering all of Earth’s continents and oceans, including metagenomes from human and animal hosts, engineered environments, and natural and agricultural soils, to capture extant microbial, metabolic and functional potential. This comprehensive catalog includes 52,515 metagenome-assembled genomes representing 12,556 novel candidate species-level operational taxonomic units spanning 135 phyla. The catalog expands the known phylogenetic diversity of bacteria and archaea by 44% and is broadly available for streamlined comparative analyses, interactive exploration, metabolic modeling and bulk download. We demonstrate the utility of this collection for understanding secondary-metabolite biosynthetic potential and for resolving thousands of new host linkages to uncultivated viruses. This resource underscores the value of genome-centric approaches for revealing genomic properties of uncultivated microorganisms that affect ecosystem processes