ISSN / EISSN : 1078-8956 / 1546-170X
Published by: Springer Science and Business Media LLC (10.1038)
Total articles ≅ 13,002
Latest articles in this journal
Nature Medicine, Volume 27, pp 1121-1121; doi:10.1038/s41591-021-01447-x
Telehealth has emerged as an unexpected silver lining of the COVID-19 pandemic, improving access to care and facilitating a transition toward digital medicine. Cementing these gains now could help make healthcare more equitable once the pandemic has ended.
Nature Medicine pp 1-2; doi:10.1038/s41591-021-01438-y
Nature Medicine pp 1-9; doi:10.1038/s41591-021-01404-8
Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children’s evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients. In an interim analysis of a phase 1 trial, repeated intracranial infusions of HER2-specific CAR T cells were well tolerated with no observed dose-limiting toxicities in three young adult patients with CNS tumors.
Nature Medicine pp 1-3; doi:10.1038/s41591-021-01435-1
Nature Medicine pp 1-7; doi:10.1038/s41591-021-01443-1
Clinical evidence suggests the central nervous system is frequently impacted by SARS-CoV-2 infection, either directly or indirectly, although the mechanisms are unclear. Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral ‘replication hubs’, with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new ‘assembloid’ model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection. Findings from a pericyte-containing cortical organoid model suggests that pericytes provide an infection portal for SARS-CoV-2 and can serve as a viral amplification hub within neural tissue.
Nature Medicine pp 1-8; doi:10.1038/s41591-021-01446-y
The SARS-CoV-2 pandemic continues to be a global health concern. The mRNA-1273 (Moderna) vaccine was reported to have an efficacy of 94.1% at preventing symptomatic COVID-19 due to infection with ‘wild-type’ variants in a randomized clinical trial. Here, we assess the real-world effectiveness of this vaccine against SARS-CoV-2 variants of concern, specifically B.1.1.7 (Alpha) and B.1.351 (Beta), in Qatar, a population that comprises mainly working-age adults, using a matched test-negative, case-control study design. We show that vaccine effectiveness was negligible for 2 weeks after the first dose, but increased rapidly in the third and fourth weeks immediately before administration of a second dose. Effectiveness against B.1.1.7 infection was 88.1% (95% confidence interval (CI): 83.7–91.5%) ≥14 days after the first dose but before the second dose, and was 100% (95% CI: 91.8–100.0%) ≥14 days after the second dose. Analogous effectiveness against B.1.351 infection was 61.3% after the first dose (95% CI: 56.5–65.5%) and 96.4% after the second dose (95% CI: 91.9–98.7%). Effectiveness against any severe, critical or fatal COVID-19 disease due to any SARS-CoV-2 infection (predominantly B.1.1.7 and B.1.351) was 81.6% (95% CI: 71.0–88.8%) and 95.7% (95% CI: 73.4–99.9%) after the first and second dose, respectively. The mRNA-1273 vaccine is highly effective against B.1.1.7 and B.1.351 infections, whether symptomatic or asymptomatic, and against any COVID-19 hospitalization and death, even after a single dose. A matched test-negative, case-control study using real-world data from a predominantly working-age population demonstrates efficacy of the mRNA-1273 vaccine to be 100% and 96.4% against the B.1.1.7 (Alpha) and B.1.351 (Beta) SARS-CoV-2 variants of concern, respectively.
Nature Medicine pp 1-2; doi:10.1038/s41591-021-01432-4
Recent studies suggest that neutralizing antibodies could serve as a correlate of protection for vaccines against SARS-CoV-2 in humans.
Nature Medicine pp 1-11; doi:10.1038/s41591-021-01411-9
Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH. Analysis of single-nucleotide variants and copy number alterations gives a more complete picture of clonal hematopoiesis and its impact on hematological malignancy and cardiovascular disease.
Nature Medicine pp 1-10; doi:10.1038/s41591-021-01406-6
Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB. Clinical benefit or intestinal toxicity resulting from combined immune checkpoint blockade in patients with melanoma associates with prevalent commensal bacteria and can be decoupled by IL-1R inhibition.
Nature Medicine pp 1-12; doi:10.1038/s41591-021-01398-3
Inhibitors of the PD-1–PD-L1 axis have been approved as therapy for many human cancers. In spite of the evidence for their widespread clinical activity, little is known about the immunological alterations that occur in human cancer tissue after PD-1 blockade. We developed and employed a patient-derived tumor fragment platform to dissect the early immunological response of human tumor tissue to ex vivo PD-1 blockade. We observed that the capacity of immune cells to be reactivated ex vivo was predictive of clinical response, and perturbation analyses identified tumor-resident T cells as a key component of this immunological response. In addition, through combined analysis of baseline properties and immune response capacity, we identified a new subgroup of infiltrated tumors that lacks the capacity to respond to PD-1 blockade. Finally, the baseline presence of tertiary lymphoid structures and their components correlated with the capacity of cancers to undergo intratumoral immune cell reactivation. An ex vivo platform of patient-derived tumor fragments enables the assessment of intratumoral immune reactivation after PD-1 blockade that is predictive of clinical outcomes in patients with cancer.