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In a randomized trial involving 542 patients with relapsed urothelial cancer, treatment with pembrolizumab resulted in overall survival of more than 10 months, as compared with 7 months with chemotherapy. Urothelial cancer is highly lethal in the metastatic state. 1 Platinum-based combination chemotherapy remains the standard first-line treatment for metastatic disease. Carboplatin-based combinations are associated with a median overall survival of 9 months, 2 and cisplatin-based combinations with a median overall survival of 12 to 15 months. 3 However, after platinum-based chemotherapy, there is no internationally accepted standard of care. Single-agent paclitaxel and docetaxel are commonly used worldwide, 4 , 5 and in Europe, vinflunine has been approved on the basis of an overall survival advantage of 2 months over best supportive care. 6 , 7 Because the median overall survival with second-line therapy is only 6 . . .

Tumor tissue mutational burden (TMB) has emerged as a promising predictive biomarker for immune checkpoint therapy. Measuring TMB from circulating tumor DNA (ctDNA) found in plasma is attractive in tissue-constrained indications. We compared the performance of two plasma-based commercial TMB assays including the effect of two different collection methods. Our findings suggest that the two plasma based TMB assays are highly correlated and they are also both correlated with a tissue-based TMB assay for relatively high TMB samples. The two collection methods are also found to be very comparable. Plasma-based TMB assays may be mature enough to be clinically useful in mCRPC and potentially other indications.

Purpose Sipuleucel-T, the first FDA-approved autologous cellular immunotherapy for treatment of advanced prostate cancer, is manufactured by activating peripheral blood mononuclear cells, including antigen presenting cells (APCs), with a fusion protein containing prostatic acid phosphatase. Analysis of data from three phase 3 trials was performed to immunologically characterize this therapy during the course of the three doses, and to relate the immunological responses to overall survival (OS). Methods Sipuleucel-T product characteristics [APC numbers, APC activation (CD54 upregulation), and total nucleated cell (TNC) numbers] were assessed in three randomized, controlled phase 3 studies ( N  = 737). Antigen-specific cellular and humoral responses were assessed in a subset of subjects. The relationships between these parameters and OS were assessed. Results APC activation occurred in the first dose preparation [6.2-fold, (4.65, 7.70); median (25th, 75th percentile)] and increased in the second [10.6-fold (7.83, 13.65)] and third [10.5-fold (7.89, 13.65)] dose preparations. Cytokines and chemokines associated with activated APCs were produced during the manufacture of each dose; T-cell activation-associated cytokines were detected in the second and third dose preparations. Antigen-specific T cells were detectable after administration of the first sipuleucel-T dose. Cumulative APC activation, APC number, and TNC number correlated with OS ( P  < 0.05). Antigen-specific immune responses were observed in 78.8 % of monitored subjects and their presence correlated with OS ( P  = 0.003). Conclusion Sipuleucel-T broadly engages the immune system by activating APCs ex vivo and inducing long-lived immune responses in vivo. These data indicate antigen-specific immune activation as a mechanism by which sipuleucel-T prolongs OS.

The past 20 years have seen remarkable advances in our understanding of the molecular and cellular processes controlling the development of an anticancer immune response. These advances have spawned a renaissance in the field of cancer immunotherapy, the original targeted therapy, during which investigators have pushed the envelope and translated promising strategies into investigational therapeutics in patients with cancer. An approach that combined nonmyeloablative lymphodepleting chemotherapy with adoptive transfer of tumor-specific CD4 and CD8 T cells exhibited an initial objective response rate of 51% for patients with stage IV melanoma. Although this strategy is extremely challenging, one can expect technological advances that may simplify this approach and further improve outcome.

In the phase 3 PROpel trial (NCT03732820) patients with metastatic castration‐resistant prostate cancer (mCRPC) treated with olaparib plus abiraterone in the first‐line setting showed significantly prolonged radiographic progression‐free survival (rPFS; primary data cutoff [DCO]: 30 July 2021; hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.54–0.81; p < 0.001), and at prespecified final OS analysis DCO (12 October 2022) numerically prolonged overall survival (OS; HR 0.81, 95% CI, 0.67–1.00; p = 0.054), versus placebo plus abiraterone for the global population. Here, we report efficacy, safety, and patient‐reported outcome data for the Asian subset in PROpel. Eligible patients were randomly assigned (1:1) to either olaparib (300 mg twice daily) or placebo in combination with abiraterone (1000 mg once daily). The primary endpoint was investigator‐assessed rPFS, and a key secondary endpoint was OS. In the Asian subset (n = 133) at primary analysis, median rPFS was 27.6 months in the olaparib plus abiraterone arm (n = 63), compared with 19.3 months in the placebo plus abiraterone arm (n = 70; HR 0.55, 95% CI, 0.32–0.95). Median OS at the final analysis was not reached in the olaparib plus abiraterone arm versus 43.7 months in the placebo plus abiraterone arm (HR 0.59, 95% CI, 0.32–1.06). The safety profile was generally similar in the Asian subset and the global population. Efficacy and safety results for olaparib plus abiraterone in the Asian subset were generally consistent with the global PROpel population supporting the combination of olaparib plus abiraterone as an important first‐line treatment for consideration in Asian patients with mCRPC. Trial Registration: Clinicaltrials.gov identifier: NCT03732820 In the phase 3 PROpel trial (NCT03732820), first‐line treatment with olaparib plus abiraterone significantly prolonged radiographic progression‐free survival (rPFS) and numerically prolonged overall survival (OS) versus placebo plus abiraterone in patients with metastatic castration‐resistant prostate cancer (mCRPC). Results of preplanned subgroup analyses of efficacy and safety in the Asian subset of PROpel (n = 133; rPFS hazard ratio [HR] 0.55, 95% CI 0.32–0.95; OS HR 0.59, 95% CI 0.32–1.06) were generally consistent with the global population. Our findings support consideration of the combination of olaparib plus abiraterone as an important first‐line treatment for Asian patients with mCRPC.

Background The intestinal microbiota plays a crucial role in protecting the host from pathogenic microbes, modulating immunity and regulating metabolic processes. We studied the simplified human intestinal microbiota (SIHUMIx) consisting of eight bacterial species with a particular focus on the discovery of novel small proteins with less than 100 amino acids (= sProteins), some of which may contribute to shape the simplified human intestinal microbiota. Although sProteins carry out a wide range of important functions, they are still often missed in genome annotations, and little is known about their structure and function in individual microbes and especially in microbial communities. Results We created a multi-species integrated proteogenomics search database (iPtgxDB) to enable a comprehensive identification of novel sProteins. Six of the eight SIHUMIx species, for which no complete genomes were available, were sequenced and de novo assembled. Several proteomics approaches including two earlier optimized sProtein enrichment strategies were applied to specifically increase the chances for novel sProtein discovery. The search of tandem mass spectrometry (MS/MS) data against the multi-species iPtgxDB enabled the identification of 31 novel sProteins, of which the expression of 30 was supported by metatranscriptomics data. Using synthetic peptides, we were able to validate the expression of 25 novel sProteins. The comparison of sProtein expression in each single strain versus a multi-species community cultivation showed that six of these sProteins were only identified in the SIHUMIx community indicating a potentially important role of sProteins in the organization of microbial communities. Two of these novel sProteins have a potential antimicrobial function. Metabolic modelling revealed that a third sProtein is located in a genomic region encoding several enzymes relevant for the community metabolism within SIHUMIx. Conclusions We outline an integrated experimental and bioinformatics workflow for the discovery of novel sProteins in a simplified intestinal model system that can be generically applied to other microbial communities. The further analysis of novel sProteins uniquely expressed in the SIHUMIx multi-species community is expected to enable new insights into the role of sProteins on the functionality of bacterial communities such as those of the human intestinal tract. EtVDiT6mSbNC8m7xJtMZ7w Video abstract