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Background Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient’s mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA. Methods Short-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections. Results Forty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to > 60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio = 0.304, p  = 0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination. Conclusions This is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine. Trial registration Clinical trials.gov NCT00948480 retrospectively registered 28 July 2009.

Purpose Trial E1609 demonstrated superior overall survival with ipilimumab 3 mg/kg (ipi3) compared to high-dose interferon (HDI) for patients with resected high-risk melanoma. To inform treatment tolerability, we compared health-related quality of life (HRQoL), gastrointestinal (GI), and treatment-specific physical and cognitive/emotional symptoms. We also compared treatment-specific concerns between all arms. Methods We assessed HRQoL using the Functional Assessment of Cancer Therapy-General, physical and cognitive/emotional concerns using the FACT-Biologic Response Modifier subscale, and GI symptoms with the Functional Assessment of Chronic Illness Therapy-Diarrhea subscale pre-treatment and every 3 months. The primary outcome was the difference in HRQoL at 3 months between ipi3/ipi10 vs. HDI. Results 549 patients ( n  = 158 ipi3; n  = 191 ipi10; n  = 200 HDI) were analyzed. 3-month completion was 58.7%. Compared to HDI, ipilimumab patients reported better HRQoL (ipi3 = 87.5 ± 14.6 vs. HDI = 74.7 ± 15.4, p  < .001; ipi10 = 84.9 ± 16.5 vs. HDI, p  < .001) and fewer physical (ipi3 = 22.3 ± 4.6 vs. HDI = 17.1 ± 5.4, p  < .001; ipi10 = 21.8 ± 5.0 vs. HDI p  < .001) and cognitive/emotional (ipi3 = 18.6 ± 4.4 vs. HDI = 15.0 ± 5.3, p  < .001; ipi10 = 17.7 ± 4.8 vs. HDI p  < .001) concerns, but worse GI symptoms (ipi3 = 40.8 ± 5.0 vs. HDI = 42.2 ± 2.9, p  =  . 011; ipi10 = 39.5 ± 7.0 vs. HDI, p  < .001). Fewer ipilimumab patients reported worsening treatment-specific concerns (e.g., 52% of ipi3 and 58% of ipi10 reported worsening fatigue vs. 82% HDI, p’s  < .001). Conclusion PROs demonstrated less toxicity of ipi3 compared to HDI and ipi10. Priorities for symptom management among patients receiving ipilimumab include GI toxicities, fatigue, weakness, appetite loss, arthralgia, and depression. Trial Registration: NCT01274338, January 11, 2011 (first posted date) https://clinicaltrials.gov/ct2/show/NCT01274338?term=NCT01274338&draw=2&rank=1 .

In patients with metastatic melanoma, sequential single-arm and randomized phase II trials with a therapeutic vaccine consisting of autologous dendritic cells (DCs) loaded with antigens from self-renewing, proliferating, irradiated autologous tumor cells (DC-TC) showed superior survival compared with similar patients immunized with irradiated tumor cells (TC). We wished to determine whether this difference was evident in cohorts who at the time of treatment had (1) no evidence of disease (NED) or (2) had detectable disease. Eligibility criteria and treatment schedules were the same for all three trials. Pooled data confirmed that overall survival (OS) was longer in 72 patients treated with DC-TC compared with 71 patients treated with TC (median OS 60 versus 22 months; 5-year OS 51% versus 32%, p=0.004). Treatment with DC-TC was associated with longer OS in both cohorts. Among 70 patients who were NED at the time that treatment was started, OS was better for DC-TC: 5-year OS 73% versus 43% (p=0.015). Among 73 patients who had detectable metastases, OS was better for DC-TC: median 38.8 months versus 14.7 months, 5-year OS 33% versus 20% (p=0.025). This approach is promising as an adjunct to other therapies in patients who have had metastatic melanoma.

Signal-transduction pathways mediated by guanine nucleotide-binding regulatory proteins (G proteins) determine many of the responses of hematopoietic cells. A recently identified gene encoding a G protein α subunit, Gα16, is specifically expressed in human cells of the hematopoietic lineage. The Gα16 cDNA encodes a protein with predicted Mrof 43,500, which resembles the Gqclass of α subunits and does not include a pertussis toxin ADP-ribosylation site. In comparison with other G protein α subunits, the Gα16 predicted protein has distinctive amino acid sequences in the amino terminus, the region A guanine nucleotide-binding domain, and in the carboxyl-terminal third of the protein. Cell lines of myelomonocytic and T-cell phenotype express the Gα16 gene, but no expression is detectable in two B-cell lines or in nonhematopoietic cell lines. Gα16 gene expression is down-regulated in HL-60 cells induced to differentiate to neutrophils with dimethyl sulfoxide. Antisera generated from synthetic peptides that correspond to two regions of Gα16 specifically react with a protein of 42- to 43-kDa in bacterial strains that overexpress Gα16 and in HL-60 membranes. This protein is decreased in membranes from dimethyl sulfoxide-differentiated HL-60 cells and is not detectable in COS cell membranes. The restricted expression of this gene suggests that Gα16 regulates cell-type-specific signal-transduction pathways, which are not inhibited by pertussis toxin.

Two distinct β subunits of guanine nucleotide-binding regulatory proteins have been identified by cDNA cloning and are referred to as β1and β2subunits. The bovine transducin β subunit (β1) has been cloned previously. We have now isolated and analyzed cDNA clones that encode the β2subunit from bovine adrenal, bovine brain, and a human myeloid leukemia cell line, HL-60. The 340-residue Mr37,329 β2protein is 90% identical with β1in predicted amino acid sequence, and it is also organized as a series of repetitive homologous segments. The major mRNA that encodes the bovine β2subunit is 1.7 kilobases in length. It is expressed at lower levels than β1subunit mRNA in all tissues examined. The β1and β2messages are expressed in cloned human cell lines. Hybridization of cDNA probes to bovine DNA showed that β1and β2are encoded by separate genes. The amino acid sequences for the bovine and human β2subunit are identical, as are the amino acid sequences for the bovine and human β1subunit. This evolutionary conservation suggests that the two β subunits have different roles in the signal transduction process.

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers. Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 – a physiological driver of proliferation of osteo-chondrogenic progenitors – by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol. Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy. Ewing sarcoma is characterized by the fusion of EWSR1 and FLI1. Here, the authors show that EWSR1-FLI1 increases the activity of the developmental transcription factor SOX6, which promotes tumor growth but also increases sensitivity to oxidative stress.

Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.

Undifferentiated small round cell sarcomas (SRCSs) of bone and soft tissue comprise a heterogeneous group of highly aggressive tumours associated with a poor prognosis, especially in metastatic disease. SRCS entities mainly occur in the third decade of life and can exhibit striking disparities regarding preferentially affected sex and tumour localization. SRCSs comprise new entities defined by specific genetic abnormalities, namely EWSR1 –non- ETS fusions, CIC -rearrangements or BCOR genetic alterations, as well as EWSR1 – ETS fusions in the prototypic SRCS Ewing sarcoma. These gene fusions mainly encode aberrant oncogenic transcription factors that massively rewire the transcriptome and epigenome of the as yet unknown cell or cells of origin. Additional mutations or copy number variants are rare at diagnosis and, depending on the tumour entity, may involve TP53 , CDKN2A and others. Histologically, these lesions consist of small round cells expressing variable levels of CD99 and specific marker proteins, including cyclin B3, ETV4, WT1, NKX3-1 and aggrecan, depending on the entity. Besides locoregional treatment that should follow standard protocols for sarcoma management, (neo)adjuvant treatment is as yet ill-defined but generally follows that of Ewing sarcoma and is associated with adverse effects that might compromise quality of life. Emerging studies on the molecular mechanisms of SRCSs and the development of genetically engineered animal models hold promise for improvements in early detection, disease monitoring, treatment-related toxicity, overall survival and quality of life. Small round cell sarcomas are a group of aggressive tumours of bone and soft tissue that result from specific genetic alterations and fusions, typically involving EWSR1 , BCOR or CIC . This Primer reviews the epidemiology, pathogenesis, diagnosis, and management of these entities and the effects of the tumour and its treatment on quality of life.

Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20017-2