A5079433380- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Ocular Oncology and Treatments
- Biosimilars and Bioanalytical Methods
- Nanoplatforms for cancer theranostics
- Virus-based gene therapy research
- interferon and immune responses
- Pancreatic and Hepatic Oncology Research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immune cells in cancer
- Renal and related cancers
- Calcium signaling and nucleotide metabolism
- Viral Infectious Diseases and Gene Expression in Insects
- Epigenetics and DNA Methylation
- Phagocytosis and Immune Regulation
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- Protein Degradation and Inhibitors
- Ferroptosis and cancer prognosis
- Advanced Fluorescence Microscopy Techniques
- RNA Interference and Gene Delivery
- Synthesis and Biological Evaluation
- Neuroblastoma Research and Treatments
Center for Cancer Research
2024-2025
Harvard University
2019-2025
Massachusetts General Hospital
2019-2025
Broad Institute
2024-2025
University of Illinois System
2017
Second Military Medical University
2016
Changhai Hospital
2016
Targeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target expression, escape, and the immunosuppressive tumor microenvironment (TME). Pancreatic cancer is characterized by a thick stroma generated cancer-associated fibroblasts (CAF), which may contribute limited efficacy of mesothelin-directed CAR in early-phase clinical trials. To provide more favorable TME for pancreatic ductal adenocarcinoma (PDAC), we an antimesothelin secreted...
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Abstract Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate–dependent enzymes, altering epigenetics and metabolism. Here, developing mIDH1-driven genetically engineered mouse models, we show that supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate–mediated mechanisms: suppression of CD8+ T-cell activity...
Uveal melanoma (UM) is the most common intraocular malignant tumor. Despite successful treatment of primary tumor, about 50% patients will recur with systemic diseases for which there are no effective strategies. Here we investigated preclinical efficacy a chimeric antigen receptor (CAR) T-cell-based immunotherapy targeting B7-H3.
Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment solid tumors. Multiple tumor microenvironmental factors thought contribute resistance CAR T-cell therapy in tumors, and appropriate model systems identify examine these using clinically relevant biospecimens limited. In this study, we examined activity B7-H3-directed (B7-H3.CAR-T) 3D microfluidic cultures patient-derived organotypic spheroids (PDOTS) then confirmed...
<p>Supplemental Figure S7 | Supporting data that targeting TBK1 prevents CAR-T cell dysfunction.</p>
<p>Supplemental Figure S5 | Supporting data that targeting TBK1 prevents CAR-T cell dysfunction.</p>
<p>Supplemental Figure S6 | Supporting data that targeting TBK1 prevents CAR-T cell dysfunction.</p>
<p>PDOTS patient data (accompanying Fig. 1)</p>
<p>Supplemental Figure S8 | Supporting data that targeting TBK1 prevents CAR-T cell dysfunction.</p>
<div>Abstract<p>Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment solid tumors. Multiple tumor microenvironmental factors thought contribute resistance CAR T-cell therapy in tumors, and appropriate model systems identify examine these using clinically relevant biospecimens limited. In this study, we examined activity B7-H3–directed (B7-H3.CAR-T) 3D microfluidic cultures patient-derived organotypic spheroids...
<p>Supplemental Figure S9 | Supporting data for single cell RNA sequencing of CAR-T in 3D co-cultures with PDOTS.</p>
<p>PDOTS patient data (accompanying Fig. 3)</p>
<p>Supplemental Figure S4 | Supporting data for ex vivo profiling of PD-1 blockade and TBK1 inhibition in combination with B7-H3.CAR-T cells using PDOTS.</p>
<p>Supplementary Figure S2 | Supporting data for the In vitro characterization and efficacy of B7-H3.CAR-T cells.</p>
<p>Supplemental Figure S3 | Supporting data for <i>ex vivo</i> profiling of B7-H3.CAR-T cells using PDOTS.</p>
<p>PDOTS patient data (accompanying Fig. 2)</p>
<p>Supplemental Figure S11 | Supporting data that targeting TBK1 sensitizes cancer cells to CAR-T cell-derived TNFα/IFNγ.</p>
<p>Supplementary Figure S1 | Supporting data demonstrating B7-H3 expression in melanoma and other cancers.</p>
<p>Supplemental Figure S10 | Supporting data for single cell RNA sequencing of native tumor-infiltrating lymphocytes following CAR-T challenge in 3D co-cultures with PDOTS.</p>
ABSTRACT The standard of care in high-grade gliomas has remained unchanged the past 20 years. Efforts to replicate effective immunotherapies non-cranial tumors have led only modest therapeutical improvements glioblastoma (GB). Here, we demonstrate that intratumoral administration recombinant interleukin-12 (rIL-12) promotes local cytotoxic CD8 POS T cell accumulation and conversion into an effector-like state, resulting a dose-dependent survival benefit preclinical GB mouse models. This...
Abstract T cell exhaustion is a major driver of immune checkpoint blockade (ICB) resistance and clinically effective strategies to prevent or reverse restore ICB sensitivity are lacking. CD38, an ecto-enzyme involved in NAD+ catabolism, highly expressed exhausted CD8+ cells human melanoma, yet its role remains be elucidated. Here we show that CD38+CD8+ enriched during tumor progression following unsuccessful treatment strongly associated with melanoma. Chronic TCR activation type I...
A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% patients metastatic melanoma 1,2 . T cell exhaustion, resulting from chronic antigen exposure tumour microenvironment, a major driver ICB resistance 3 Here, we show that CD38, an ecto-enzyme involved nicotinamide adenine dinucleotide (NAD + ) catabolism, highly expressed exhausted CD8 cells and associated resistance. Tumour-derived CD38 hi are dysfunctional,...
ABSTRACT Introduction Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose significant barrier to effective immunotherapy. Inhibition MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs tumor microenvironment adopt proinflammatory fragile state, which offers an opportunity impede enhance efficacy checkpoint therapy (ICT). Methods We performed...