Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial

Nature Medicine, Год журнала: 2024, Номер 30(3), С. 772 - 784

Опубликована: Янв. 18, 2024

Abstract There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 interleukin-15 (CAR19/IL-15) in 37 patients with CD19 + B malignancies. The primary objectives were safety efficacy, defined as day 30 overall response (OR). Secondary included 100 response, progression-free survival, survival CAR19/IL-15 NK persistence. No notable toxicities such cytokine release syndrome, neurotoxicity or graft-versus-host disease observed. OR rates 48.6% both. 1-year 68% 32%, respectively. Patients who achieved had higher levels longer persistence CAR-NK cells. Receiving from blood unit (CBU) nucleated red ≤ 8 × 10 7 collection-to-cryopreservation time 24 h was the most significant predictor superior outcome. these optimal CBUs highly functional enriched effector-related genes. In contrast, suboptimal upregulation inflammation, hypoxia cellular stress programs. Finally, using multiple mouse models, we confirmed antitumor activity CAR/IL-15 vivo. These findings uncover new features biology underscore importance donor selection therapies. ClinicalTrials.gov identifier: NCT03056339 .

Язык: Английский

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Natural killer cell therapies

Nature, Год журнала: 2024, Номер 626(8000), С. 727 - 736

Опубликована: Фев. 21, 2024

Язык: Английский

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High-dimensional single-cell analysis of human natural killer cell heterogeneity

Nature Immunology, Год журнала: 2024, Номер 25(8), С. 1474 - 1488

Опубликована: Июль 2, 2024

Abstract Natural killer (NK) cells are innate lymphoid (ILCs) contributing to immune responses microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) cellular indexing transcriptomes epitopes by (CITE-seq) dissect the heterogeneity NK cells. We identified three prominent cell subsets in healthy human blood: NK1, NK2 NK3, further differentiated into six distinct subgroups. Our findings delineate molecular characteristics, key transcription factors, biological functions, metabolic traits cytokine each subgroup. These data also suggest two separate ontogenetic origins for cells, leading divergent transcriptional trajectories. Furthermore, analyzed distribution lung, tonsils intraepithelial lymphocytes isolated from individuals 22 tumor types. This standardized terminology aims at fostering clarity consistency future research, thereby improving cross-study comparisons.

Язык: Английский

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Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 24, 2024

Immune cell dysfunction within the tumor microenvironment (TME) undermines control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, temporal dynamics, mechanistic underpinning and functional significance NK compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic cellular analyses, to interrogate fate intratumoral cells. We reveal that cells rapidly lose effector functions adopt a distinct phenotypic state features associated tissue residency. depletion from established did not alter growth, indicating cease actively contribute anti-tumor responses. IL-15 administration prevented loss function improved control, generating both tissue-residency characteristics enhanced function. Collectively, our data reveals after recruitment into provides insight how their may be revived.

Язык: Английский

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Pan-cancer single-cell dissection reveals phenotypically distinct B cell subtypes

Cell, Год журнала: 2024, Номер 187(17), С. 4790 - 4811.e22

Опубликована: Июль 23, 2024

Characterizing the compositional and phenotypic characteristics of tumor-infiltrating B cells (TIBs) is important for advancing our understanding their role in cancer development. Here, we establish a comprehensive resource human by integrating single-cell RNA sequencing data from 649 patients across 19 major types. We demonstrate substantial heterogeneity total abundance subtype composition observe immunoglobulin G (IgG)-skewness antibody-secreting cell isotypes. Moreover, identify stress-response memory tumor-associated atypical (TAABs), two tumor-enriched subpopulations with prognostic potential, shared pan-cancer manner. In particular, TAABs, characterized high clonal expansion level proliferative capacity as well close interactions activated CD4 T tumors, are predictive immunotherapy response. Our integrative depicts distinct clinically relevant TIB subsets, laying foundation further exploration functional commonality diversity cancer.

Язык: Английский

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scImmOmics: a manually curated resource of single-cell multi-omics immune data

Nucleic Acids Research, Год журнала: 2024, Номер 53(D1), С. D1162 - D1172

Опубликована: Ноя. 4, 2024

Single-cell sequencing technology has enabled the discovery and characterization of subpopulations immune cells with unique functions, which is critical for revealing responses under healthy or disease conditions. Efforts have been made to collect curate single-cell RNA (scRNA-seq) data, yet an immune-specific multi-omics atlas harmonized metadata still lacking. Here, we present scImmOmics (https://bio.liclab.net/scImmOmics/home), a manually curated database constructed based on high-quality known cell labels. Currently, documents >2.9 million cell-type labeled derived from seven technologies, involving 131 types, 47 tissues 4 species. To ensure data consistency, standardized nomenclature types presented them in hierarchical tree structure clearly describe lineage relationships within system. also provides comprehensive regulatory information, including T-cell/B-cell receptor clonotype cell-specific information (e.g. gene/chromatin accessibility/protein/transcription factor states cell-to-cell communication co-expression networks) cytokines. Collectively, valuable platform unraveling heterogeneity diversity elucidating specific mechanisms at level.

Язык: Английский

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Pan-cancer profiling of tumor-infiltrating natural killer cells through transcriptional reference mapping

Nature Immunology, Год журнала: 2024, Номер 25(8), С. 1445 - 1459

Опубликована: Июль 2, 2024

The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor-ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map healthy human blood- tissue-derived NK cells, with temporal resolution fate-specific expression gene-regulatory networks defining differentiation. Transfer learning facilitated incorporation tumor-infiltrating transcriptomes (39 datasets, 7 solid tumors, 427 patients) into analyze tumor microenvironment (TME)-induced perturbations. Of six functionally distinct states identified, dysfunctional stressed CD56

Язык: Английский

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Consensus, debate, and prospective on pancreatic cancer treatments

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Окт. 10, 2024

Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite improvement multi-modality treatment strategies, prognosis pancreatic was not improved dramatically. For resectable or borderline patients, surgical strategy centered on improving R0 resection rate is consensus; however, role neoadjuvant therapy in patients and optimal chemotherapy with without radiotherapy were debated. Postoperative adjuvant gemcitabine/capecitabine mFOLFIRINOX recommended regardless margin status. Chemotherapy as first-line for advanced metastatic included FOLFIRINOX, gemcitabine/nab-paclitaxel, NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan only standard care second-line therapy. Immunotherapy an innovative although anti-PD-1 antibody currently agent approved by MSI-H, dMMR, TMB-high tumors, which represent very small subset cancers. Combination strategies to increase immunogenicity overcome immunosuppressive tumor microenvironment may sensitize immunotherapy. Targeted therapies represented PARP KRAS inhibitors are also under investigation, showing benefits progression-free survival objective response rate. This review discusses current modalities highlights cancer.

Язык: Английский

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Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Ноя. 21, 2024

Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth contributes treatment resistance. In primary breast metabolic shifts such as the Warburg effect enhanced lipid synthesis are closely linked chemotherapy failure. Similarly, metastatic lesions often display distinct profiles that not only sustain but also confer resistance targeted therapies immunotherapies. The review emphasizes two major aspects: mechanisms driving in both how unique environments sites further complicate treatment. By targeting vulnerabilities at stages, new strategies could improve efficacy existing provide better outcomes for cancer patients.

Язык: Английский

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Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 24, 2024

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of

Язык: Английский

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