A5103198733- CAR-T cell therapy research
- Virus-based gene therapy research
- Immunotherapy and Immune Responses
- CRISPR and Genetic Engineering
- RNA Interference and Gene Delivery
- Viral Infectious Diseases and Gene Expression in Insects
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- Pancreatic and Hepatic Oncology Research
- Tribology and Wear Analysis
- Monoclonal and Polyclonal Antibodies Research
- HIV Research and Treatment
- Polymer Nanocomposites and Properties
- Railway Engineering and Dynamics
- Genetic factors in colorectal cancer
- Biosimilars and Bioanalytical Methods
- Cancer Genomics and Diagnostics
- Hemophilia Treatment and Research
- T-cell and B-cell Immunology
- Surface Roughness and Optical Measurements
- Animal Genetics and Reproduction
- Click Chemistry and Applications
- Nanowire Synthesis and Applications
- Transportation Safety and Impact Analysis
- Herpesvirus Infections and Treatments
National Institutes of Health
2007-2023
Center for Cancer Research
2005-2023
National Cancer Institute
2007-2023
University of California, Los Angeles
2017-2022
Duke University
2022
Film Independent
2022
University of Glasgow
2020
Charles R. Drew University of Medicine and Science
2017-2020
Editas Medicine (United States)
2020
Bluebird Bio (United States)
2014-2019
Adoptive immunotherapy using tumor-infiltrating lymphocytes represents an effective cancer treatment for patients with metastatic melanoma. The NY-ESO-1 cancer/testis antigen, which is expressed in 80% of synovial cell sarcoma and approximately 25% melanoma common epithelial tumors, attractive target immune-based therapies. current trial was carried out to evaluate the ability adoptively transferred autologous T cells transduced a T-cell receptor (TCR) directed against mediate tumor...
Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five experienced clinical regression of their cancers including 2 on-going responders. Beginning 1–2 days postinfusion, 3 (#'s 5, 7, and 8) mental status changes, (5 lapsed into comas subsequently died. Magnetic resonance imagining analysis 5 8 demonstrated periventricular leukomalacia, examination brains at autopsy revealed necrotizing leukoencephalopathy...
During acute human immunodeficiency virus type 1 (HIV-1) infection or after transfection of the tat gene, Tat protein is released into cell culture supernatant. In this extracellular form, stimulates both HIV-1 gene expression and growth cells derived from Kaposi's sarcoma (KS) lesions HIV-1-infected individuals (AIDS-KS cells). its biological activities appear in supernatants at peak expression, when rate death low (infection) undetectable (transfection) increased levels cytoplasmic are...
Abstract Purpose: Although adoptive cell therapy can be highly effective for the treatment of patients with melanoma, application this approach to other solid tumors has been limited. The observation that cancer germline (CG) antigen NY-ESO-1 is expressed in 70% 80% and approximately 25% synovial sarcoma respectively, prompted us perform first-in-man clinical trial using transfer autologous peripheral blood mononuclear cells were retrovirally transduced an NY-ESO-1–reactive T-cell receptor...
Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim this study was to determine clinicopathologic and genetic features poorly NECs compare them other types pancreatic neoplasms. We investigated alterations KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens 9 small cell NECs, 10 large 11 well-differentiated...
T cells can be engineered to express the genes of chimeric antigen receptors (CARs) that recognize tumor-associated antigens. We constructed and compared 2 CARs contained a single chain variable region moiety recognized CD19. One CAR signaling 4-1BB molecule other did not. selected not contain for further preclinical development. demonstrated gammaretroviruses encoding this receptor could transduce human cells. Anti-CD19-CAR-transduced CD8+ CD4+ produced interferon-γ interleukin-2...
A deletion variant of epidermal growth factor receptor (EGFRvIII) is a known driver mutation in subset primary and secondary glioblastoma multiforme. Adoptive transfer genetically modified chimeric antigen (CAR) lymphocytes has demonstrated efficacy hematologic malignancies but still early development for solid cancers. The surface expression the truncated extracellular ligand domain created by EGFRvIII makes it an attractive target CAR-based cancer treatment. Patients with recurrent...
No curative treatment exists for glioblastoma, with median survival times of less than 2 years from diagnosis. As an approach to develop immune-based therapies we sought target antigens expressed in glioma stem cells (GSCs). GSCs have multiple properties that make them significantly more representative tumors established cell lines. Epidermal growth factor receptor variant III (EGFRvIII) is the result a novel tumor-specific gene rearrangement produces unique protein approximately 30%...
Abstract To generate chimeric Ag receptors (CARs) for the adoptive immunotherapy of cancer patients with ErbB2-expressing tumors, a single-chain Ab derived from humanized mAb 4D5 Herceptin (trastuzumab) was initially linked to T cell signaling domains CD28 and CD3ζ CAR against ErbB2. Human PBLs expressing demonstrated Ag-specific activities ErbB2+ tumors. However, gradual loss transgene expression noted transduced this CAR. When domain truncated or mutated, not observed, suggesting that...
The use of nonviral gene transfer methods in primary lymphocytes has been hampered by low efficiency and high transfection-related toxicity. In this report, transfection with toxicity was achieved electroporation using vitro-transcribed mRNA. Using these methods, >90% transgene expression >80% viable cells observed stimulated human murine T transfected GFP or mCD62L. Electroporation unstimulated PBMCs splenocytes RNA yielded 95 56% GFP+ cells, respectively. mRNA for NY-ESO-1, MART-1, p53...
The alpha- and beta-chains of the TCR from a highly avid anti-gp100 CTL clone were isolated used to construct retroviral vectors that can mediate high efficiency gene transfer into primary human lymphocytes. Expression this was confirmed by Western blot analysis, immunocytometric HLA Ag tetramer staining. Gene efficiencies >50% lymphocytes obtained without selection for transduced cells using method prebinding cell culture vessels before addition biological activity cytokine production...
Abstract We examined the activity of human T cells engineered to express variants a single TCR (1G4) specific for cancer/testis Ag NY-ESO-1, generated by bacteriophage display with wide range affinities (from 4 μM 26 pM). CD8+ expressing intermediate- and high-affinity 1G4 bound NY-ESO-1/HLA-A2 tetramers high avidity specificity, but increased affinity was associated loss target cell specificity gene-modified cells. highest (KD value pM) completely lost specificity. The TCRs in midrange, KD...
Adoptive immunotherapy using TCR-engineered PBLs against melanocyte differentiation Ags mediates objective tumor regression but is associated with on-target toxicity. To avoid toxicity to normal tissues, we targeted cancer testis Ag (CTA) MAGE-A3, which widely expressed in a range of epithelial malignancies not most tissues. generate high-avidity TCRs employed transgenic mouse model that expresses the human HLA-A*0201 molecule. Mice were immunized two HLA-A*0201-restricted peptides MAGE-A3:...
The development of immunotherapy has led to significant progress in the treatment metastatic cancer, including genetic engineering technologies that redirect lymphocytes recognize and target a wide variety tumor antigens. Chimeric antigen receptors (CARs) are hybrid proteins combining antibody recognition domains linked T cell signaling elements. Clinical trials CAR-transduced peripheral blood (PBL) have induced remission both solid organ hematologic malignancies. Chondroitin sulfate...
There has been significant progress in the last two decades on design of chimeric antigen receptors (CAR) for adoptive immunotherapy targeting tumor-associated antigens. Structurally CARs consist a single chain antibody fragment directed against fused to an extracellular spacer and transmembrane domain followed by T cell cytoplasmic signaling moieties. Currently several clinical trials are underway using gene modified peripheral blood lymphocytes (PBL) with variety tumor associated Despite...
ABSTRACT Adoptive transfer of CD8 T cells genetically engineered to express “chimeric antigen receptors” (CARs) represents a potential approach toward an HIV infection “functional cure” whereby durable virologic suppression is sustained after discontinuation antiretroviral therapy. We describe novel bispecific CAR in which CD4 segment linked single-chain variable fragment the 17b human monoclonal antibody recognizing highly conserved CD4-induced epitope on gp120 involved coreceptor binding....
Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) after lymphodepletion mediates regression in 50% patients with metastatic melanoma. In vivo persistence and telomere length the transferred cells correlate antitumor response. an attempt to prolong survival cells, TILs were genetically engineered produce interleukin (IL)-2. vitro, these transduced secreted IL-2 while retaining tumor specificity exhibited prolonged withdrawal. a phase I/II clinical trial, seven evaluable received...
Abstract Purpose: Immune responses to gene-modified cells are a concern in the field of human gene therapy, as they may impede effective treatment. We conducted 2 clinical trials which cancer patients were treated with lymphocytes genetically engineered express murine T-cell receptors (mTCR) specific for tumor-associated antigens p53 and gp100. Experimental Design: Twenty-six autologous expressing mTCR had blood serum samples available analysis. Patient sera assayed development humoral...