A5089187345- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Glioma Diagnosis and Treatment
- Single-cell and spatial transcriptomics
- Cancer Immunotherapy and Biomarkers
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Immune cells in cancer
- Multiple Myeloma Research and Treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Tryptophan and brain disorders
- vaccines and immunoinformatics approaches
- Epigenetics and DNA Methylation
- Cancer Research and Treatments
- Cell Adhesion Molecules Research
- Cancer Cells and Metastasis
- Garlic and Onion Studies
- Genetic Syndromes and Imprinting
- Mosquito-borne diseases and control
- Gut microbiota and health
- Inflammatory Biomarkers in Disease Prognosis
- Fibroblast Growth Factor Research
- Antimicrobial Peptides and Activities
- Cancer, Lipids, and Metabolism
German Cancer Research Center
2017-2025
Heidelberg University
2017-2025
University Hospital Heidelberg
2021-2025
University Medical Centre Mannheim
2021-2024
Brigham and Women's Hospital
2023-2024
Harvard University
2024
Broad Institute
2024
Deutschen Konsortium für Translationale Krebsforschung
2023-2024
Bernstein Center for Computational Neuroscience Heidelberg-Mannheim
2021-2023
Abstract The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define cellular states in gliomas by longitudinal single-cell profiling demonstrate their strict control the genotype: isocitrate dehydrogenase (IDH)-mutant tumors, differentiation infiltrating is blocked, resulting an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment microenvironment, thus preventing T cell response. We...
Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but immunological mechanism and molecular determinants primary acquired resistance to TCEs remain poorly understood. Here, we identify conserved behaviors bone marrow-residing cells multiple myeloma patients undergoing BCMAxCD3 TCE therapy. We show that immune repertoire reacts therapy with state-dependent clonal expansion find evidence supporting coupling tumor recognition via major histocompatibility...
Abstract Genome editing using CRISPR-Cas systems is a promising avenue for the treatment of genetic diseases. However, cellular and humoral immunogenicity genome tools, which originate from bacteria, complicates their clinical use. Here we report reduced (Red)(i)-variants two clinically relevant nucleases, SaCas9 AsCas12a. Through MHC-associated peptide proteomics (MAPPs) analysis, identify putative immunogenic epitopes on each nuclease. Using computational modeling, rationally design these...
Abstract Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated showing response. Modeling patient-individual resistance is challenging due the lack of predictive biomarkers and limited accessibility tissue for serial biopsies. Here, we investigate mechanisms anti-PD-1 anti-CTLA-4 therapy in syngeneic experimental gliomas show a clear dichotomy acquired heterogeneity ICB-responder non-responder tumors. We...
Abstract Background Dendritic cells (DC), the most potent professional antigen presenting capable of effective cross-presentation, have been demonstrated to license T helper induce antitumor immunity in solid tumors. Specific DC subtypes are recruited injured brain by microglial chemokines, locally adapting distinct transcriptional profiles. In isocitrate dehydrogenase (IDH) type 1 mutant gliomas, monocyte-derived macrophages recently shown display an attenuated intratumoral presentation...
Understanding the mechanisms that regulate T cell immunity is critical for development of effective therapies diseases associated with dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory “checkpoint molecules,” such as programmed death protein-1, balance excessive or prolonged immune activation by cell–intrinsic signaling. Here, screening mediators natural killer (NK) recognition on cells, we identified immunoglobulin superfamily ligand B7H6 to be highly...
Abstract T cell receptor-engineered cells (TCR-T) could be advantageous in glioblastoma by allowing safe and ubiquitous targeting of the glioblastoma-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), is a clinically targetable antigen associated with stemness. Here, we identify therapeutic HLA-A*02-restricted PTPRZ1-reactive TCR retrieved from vaccinated patient. Single-cell sequencing primary brain tumors shows PTPRZ1 overexpression malignant cells, especially stem...
Rationale: Intrinsic brain tumors, such as gliomas are largely resistant to immunotherapies including immune checkpoint blockade. Adoptive cell therapies (ACT) chimeric antigen receptor (CAR) or T (TCR)-transgenic therapy targeting glioma-associated antigens an emerging field in glioma immunotherapy. However, imaging techniques for non-invasive monitoring of adoptively transferred cells homing the microenvironment currently lacking. Methods: Ultrasmall iron oxide nanoparticles (NP) can be...
Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A*02-restricted tumor-associated antigen, overexpressed in gliomas, that was found to induce specific cytotoxic T cell responses following multi-peptide vaccination patients with newly diagnosed glioblastoma. receptor (TCR) discovery performed using droplet-based single-cell TCR sequencing of NLGN4X-tetramer-sorted cells postvaccination. The identified delivered Jurkat and primary (NLGN4X-TCR-T). Functional profiling...
Abstract Purpose: Gliomas are intrinsic brain tumors with a high degree of constitutive and acquired resistance to standard therapeutic modalities such as radiotherapy alkylating chemotherapy. Glioma subtypes recognized by characteristic mutations. Some these mutations have shown generate immunogenic neoepitopes suitable for targeted immunotherapy. Experimental Design: Using peptide-based ELISpot assays, we screened potential recurrent glioma in MHC-humanized mice. Following vaccination,...
Glioblastoma (GBM) is characterized by low numbers of glioma-infiltrating lymphocytes (GIL) with a dysfunctional phenotype. Whether this phenotype fixed or can be reversed upon ex vivo culturing poorly understood. The aim study was to assess T cell receptor (TCR)-dynamics and -specificities as well determinants in vitro GIL expansion sequencing-based technologies functional assays explore the use for therapy. By means flow cytometry, functionality cultures assessed from 9 GBM patients. TCR...
Multiple myeloma (MM) is a hematological malignancy originating from malignant and clonally expanding plasma cells. MM can be molecularly stratified, its clonal evolution deciphered based on the Ig heavy light chains of respective cell clone. Of all subtypes, IgE type accounts for only <0.1% cases associated with an aggressive clinical course consequentially dismal prognosis. In such malignancies, adoptive transfer autologous lymphocytes specifically targeting presented (neo)epitopes...
Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional states in the tumor microenvironment (TME) are a major cause resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), key drivers dysfunction TME. We show here that histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation bbm is essential control growth brain tumors. Loss MHCII drives dysfunctional intratumoral...
Dendritic cell (DC) vaccination has proven to be an effective and safe adjuvant for cancer immunotherapies. As the presence of DCs within tumor microenvironment promotes adaptive antitumor immunity, enhancement DC migration toward following might represent one possible approach increase its therapeutic efficacy. While recent findings suggest activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) as critical regulator in context autoimmune diseases, we...
Glioblastomas, the most common primary malignant brain tumors, are considered immunologically cold malignancies due to growth in an immune sanctuary site. While peptide vaccines have shown generate intra-tumoral antigen-specific T cells, identification of these tumor-specific cells is challenging and requires detailed analyses tumor tissue. Several studies that CNS antigens may be transported via lymphatic drainage cervical lymph nodes, where T-cell responses can generated. Therefore, we...
Depletion of tryptophan and the accumulation metabolites mediated by immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1), trigger immune cells to undergo apoptosis. However, cancer in same microenvironment appear not be affected. Mechanisms whereby resist accelerated degradation are completely understood. We hypothesize that co-opt IMPACT (the product IMPrinted AnCienT gene), withstand periods deficiency. A range bioinformatic techniques including correlation gene set variation...
Abstract Innovative immunotherapy approaches such as adoptive transfer of chimeric antigen receptor (CAR) T cells or tumor infiltrating lymphocytes (TILs) have shown great success in the treatment solid tumors and hematological malignancies. Although multiple myeloma with CAR can induce deep responses, relapses frequently occur due to escape limited cell persistence. TCR-engineered may show prolonged persistence vivo could mediate sustained antitumor effects. A further benefit TCR transgenic...
<title>Abstract</title> Response to CAR-T cell therapy in glioblastoma (GB) patients is limited, particularly because of the paucity surface immunotherapeutic targets or low antigen sensitivity. Moreover, tonic CAR signaling leads T dysfunction eventually resulting non-durable responses. receptor-engineered (TCR-T) circumvents latter limitation by allowing safe and ubiquitous targeting GB-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), a GB associated with...