A5049435418- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Lymphoma Diagnosis and Treatment
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- Immune cells in cancer
- vaccines and immunoinformatics approaches
- RNA Interference and Gene Delivery
- Immunodeficiency and Autoimmune Disorders
- Virus-based gene therapy research
- Hematopoietic Stem Cell Transplantation
- Cancer-related Molecular Pathways
- Bacterial Genetics and Biotechnology
- HIV Research and Treatment
- Viral Infectious Diseases and Gene Expression in Insects
- Pneumocystis jirovecii pneumonia detection and treatment
- Multiple Myeloma Research and Treatments
- Glycosylation and Glycoproteins Research
- Acute Myeloid Leukemia Research
- Redox biology and oxidative stress
- Neuroinflammation and Neurodegeneration Mechanisms
- Circular RNAs in diseases
- Photosynthetic Processes and Mechanisms
Washington University in St. Louis
2015-2025
James S. McDonnell Foundation
2019
Immunovaccine (Canada)
2009
Alvin J. Siteman Cancer Center
2005
University of Basel
2004
Howard Hughes Medical Institute
1998-2003
Cancer Research Center
1995-1998
Berry (United States)
1995-1998
Molecular Oncology (United States)
1998
Merck & Co., Inc., Rahway, NJ, USA (United States)
1992
T cell immunity directed against tumor-encoded amino acid substitutions occurs in some melanoma patients. This implicates missense mutations as a source of patient-specific neoantigens. However, systematic evaluation these putative neoantigens targets antitumor is lacking. Moreover, it remains unknown whether vaccination can augment such responses. We found that dendritic vaccine led to an increase naturally occurring neoantigen-specific and revealed previously undetected human leukocyte...
NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, CD56dim cell subset is thought to mediate antitumor responses, whereas CD56bright involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced response cells. Priming improved multiple functions: degranulation, cytotoxicity, cytokine production. Primed cells from leukemia patients demonstrated...
Natural killer (NK)-cell recognition and function against NK-resistant cancers remain substantial barriers to the broad application of NK-cell immunotherapy. Potential solutions include bispecific engagers that target activity via an NK-activating receptor when simultaneously targeting a tumor-specific antigen, as well enhancing functionality using IL12/15/18 cytokine pre-activation.
Natural killer (NK) cells are innate lymphoid that eliminate cancer cells, produce cytokines, and being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these is cytokine-induced memory-like (ML) differentiation, whereby acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, IL-18. Here, reduced-intensity conditioning (RIC)
The retinoblastoma tumor suppressor protein (pRB) negatively regulates early-G 1 cell cycle progression, in part, by sequestering E2F transcription factors and repressing E2F-responsive genes.Although pRB is phosphorylated on up to 16 cyclin-dependent kinase (Cdk) sites multiple G cyclin-Cdk complexes, the active form(s) of vivo remains unknown.pRB present as an unphosphorylated 0 quiescent cells becomes hypophosphorylated (ϳ2 mol PO 4 pRB) early hyperphosphorylated (ϳ10 late phase.Here, we...
Hepatocyte growth factor (HGF) signaling via its receptor, the proto-oncogene Met, alters cell proliferation and motility has been associated with tumor metastasis. HGF treatment of HepG2 human hepatocellular carcinoma cells induces migration concomitant increased levels p27(kip1) cyclin-cdk inhibitor. resulted in nuclear export endogenous p27 to cytoplasm, Ser-10 phosphorylation, where it colocalized F-actin. Introduction transducible protein (TATp27) was sufficient for actin cytoskeletal...
Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but dose-limiting toxicities have hindered its incorporation vaccine formulations. Here, we report on the immunological and outcomes upon vaccination with CD40L/IFN-γ-matured, IL-12p70-producing DCs.7 HLA-A*0201+ newly diagnosed stage IV melanoma patients were immunized against gp100 antigen using autologous peptide-pulsed, CD40L/IFN-γ-matured DCs. PBMCs taken weekly for immune monitoring by tetramer...
Natural killer (NK) cells are an emerging cancer cellular therapy and potent mediators of antitumor immunity. Cytokine-induced memory-like (ML) NK is safe induces remissions in patients with acute myeloid leukemia (AML). However, the dynamic changes phenotype that occur after NK-cell transfer affect patient outcomes remain unclear. Here, we report comprehensive multidimensional correlates from ML cell-treated AML using mass cytometry. These data identify a unique vivo differentiated distinct...
Since T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement mature homeostasis, function, molecular programming remains unclear. To address this, were deleted in unexpanded primary human cells using CRISPR/Cas9. Deleting these TFs compromised vivo anti-tumor response cells. Mechanistically, required normal proliferation persistence vivo. lacking also exhibited defective responses to cytokine stimulation. Single-cell...
Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, underlying epigenetic transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, functional analyses, we discovered that IL-12/15/18 activation results in two main human fates: reprogramming enriched (eML) or priming effector conventional (effcNK) cells. eML had distinct profiles enhanced function, whereas...
Melanoma is one of the most devastating malignancies with a rising incidence and lack effective treatments for advanced disease. Constitutive activation mitogen-activated protein kinase (MAPK) pathway altered expression alpha(v)beta(3) integrin are critical melanoma development progression. Ras-associated protein-1 (Rap1), Ras family member small GTPases, has emerged as key mediator in these two important processes. In this study, we have shown Rap1 cells derived from human metastatic...
The impact of intratumoral heterogeneity (ITH) and the resultant neoantigen landscape on T cell immunity are poorly understood. ITH is a widely recognized feature solid tumors poses distinct challenges related to development effective therapeutic strategies, including cancer vaccines. Here, we performed deep targeted DNA sequencing multiple metastases from melanoma patients observed ubiquitous sharing clonal subclonal single nucleotide variants (SNVs) encoding putative HLA class I-restricted...
Natural killer (NK) cells are a promising cellular therapy for cancer, with challenges in the field including persistence, functional activity, and tumor recognition. Briefly, priming blood NK recombinant human (rh)IL-12, rhIL-15, rhIL-18 (12/15/18) results memory-like cell differentiation enhanced responses against cancer. However, lack of available, scalable Good Manufacturing Process (GMP)-grade reagents required to advance this approach beyond early-phase clinical trials is limiting. To...
Abstract Background Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized immunotherapies. DNA vaccines can be rapidly efficiently manufactured integrate multiple simultaneously. We therefore sought to optimize design polyepitope test optimized neoantigen in preclinical models translation. Methods developed vaccine platform target neoantigens. The was first using model antigens vitro vivo....
Abstract Purpose: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are promising cellular therapy for T cell–refractory cancers, but frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers the therapeutics field, resulting potent cytotoxicity and enhanced cytokine production against blood cancer targets....
Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen prioritization relies on correctly whether the presenting sequence successfully induce an immune response. Because most mutations...
N-803 is an IL15 receptor superagonist complex, designed to optimize in vivo persistence and trans-presentation, thereby activating expanding natural killer (NK) cells CD8+ T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK recognize eliminate cancer targets. The ability of IL15R agonists enhance tumor-targeting mAbs patients has not been reported previously.Relapsed/refractory with indolent non-Hodgkin lymphoma were treated rituximab intravenous or...