A5026203504- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Virus-based gene therapy research
- Immune cells in cancer
- CRISPR and Genetic Engineering
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- Cancer, Stress, Anesthesia, and Immune Response
- Chromosomal and Genetic Variations
- Cancer Mechanisms and Therapy
- Phagocytosis and Immune Regulation
- Ovarian cancer diagnosis and treatment
- PI3K/AKT/mTOR signaling in cancer
- Tissue Engineering and Regenerative Medicine
- Nuclear Receptors and Signaling
- Mechanisms of cancer metastasis
- Mesenchymal stem cell research
- Hedgehog Signaling Pathway Studies
- Monoclonal and Polyclonal Antibodies Research
- Estrogen and related hormone effects
- Cancer therapeutics and mechanisms
- Immune Response and Inflammation
- Lymphoma Diagnosis and Treatment
- Viral Infectious Diseases and Gene Expression in Insects
Ono Pharmaceutical (United States)
2020-2024
Littelfuse (United States)
2024
Research & Development Institute
2020-2022
The University of Texas MD Anderson Cancer Center
2007-2016
Evergen Biotechnologies (United States)
2016
Pediatrics and Genetics
2013-2014
Oregon Health & Science University
2012
McGill University
2012
Peter MacCallum Cancer Centre
2012
University of California, Irvine
2012
Significance We describe an approach based on cytokine therapeutics to enhance the persistence and effectiveness of T-cell–based immunotherapies using chimeric antigen receptors (CARs). This strategy is effective without use high-dose exogenous cytokines that are typically associated with toxicities. Moreover, we report least differentiated memory T cell, T-memory stem was promoted by signaling induced a membrane-bound IL-15 cytokine-fusion molecule. These findings may contribute improving...
KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA) but remains an intractable pharmacologic target. Consequently, defining RAS effector pathway(s) required for PDA initiation and maintenance critical to improve treatment this disease. Here, we show that expression BRAF(V600E), not PIK3CA(H1047R), in the mouse pancreas leads intraepithelial neoplasia (PanIN) lesions. Moreover, concomitant BRAF(V600E) TP53(R270H) result lethal PDA. We tested inhibitors effectors against...
A prerequisite for strong adaptive antiviral immunity is the robust initial activation of innate immune system, which frequently mediated by TLR-activated plasmacytoid DCs (pDCs). Natural antitumor often comparatively weak, potentially due to lack TLR-mediated signals within tumor microenvironment. To assess whether pDCs are capable directly facilitating effective responses, mice bearing established subcutaneous B16 melanoma tumors were administered TLR9-activated into tumor. We found that...
Clinical-grade T cells are genetically modified ex vivo to express chimeric antigen receptors (CARs) redirect their specificity target tumor-associated antigens in vivo. We now have developed this molecular strategy render cytotoxic specific for fungi. adapted the pattern-recognition receptor Dectin-1 activate via CD28 and CD3-ζ (designated "D-CAR") upon binding with carbohydrate cell wall of Aspergillus germlings. Sleeping Beauty system D-CAR stably were propagated selectively on artificial...
We assessed whether freshly isolated human adipose tissue-derived cells (fhADCs) or cultured stem (hASCs) have beneficial effects on cardiac function after myocardial infarction (MI), the injected can survive long term, and their result from direct differentiation paracrine mechanisms.Myocardial was experimentally induced in severe combined immunodeficient mice, either fhADCs, hASCs, phosphate-buffered saline into peri-infarct region. Myocardial improved significantly mice treated with hASCs...
Abstract We demonstrate that IL-2-activated NK cells or lymphokine-activated killer recognize and kill syngeneic CD4+ CD8+ T have been activated by APCs. Induction with APC required TCR-specific Ag, lysis was perforin mediated. Brefeldin A, which disrupts protein transport, inhibited the sensitivity induced activation. In BALB/c, expression of NKG2D ligands correlated could be brefeldin A. As well, addition anti-NKG2D mAb to a killing assay completely abrogated lysis. Transduction mouse into...
Abstract Purpose: One of the most important rate-limiting steps in adoptive cell transfer (ACT) is inefficient migration T cells to tumors. Because melanomas specifically express chemokines CXCL1 and CXCL8 that are known facilitate CXCR2-dependent by monocytes, our aim evaluate whether introduction CXCR2 gene into tumor-specific could further improve effectiveness ACT enhancing T-cell tumor. Experimental Design: In this study, we used transgenic pmel-1 cells, which recognize gp100 context...
Antigen specific T cell migration to sites of infection or cancer is critical for an effective immune response. In mouse models cancer, the number lymphocytes reaching tumor typically only a few hundred, yet technology capable imaging these cells using bioluminescence has be achieved. A combination codon optimization, removal cryptic splice and retroviral modification was used engineer enhanced firefly luciferase (ffLuc) vector. Compared with ffLuc, expressing our construct generated >100...
Abstract Hedgehog (Hh) signaling plays an important role in several malignancies but its clinical significance breast cancer is unclear. In a cohort of 279 patients with invasive ductal carcinoma the breast, expression Hh ligand was significantly associated increased risk metastasis, cancer-specific death, and basal-like phenotype. A paracrine signature, encompassing high epithelial stromal Gli1, independent predictor for overall survival multivariate analysis. 2 histological progression...
Abstract Purpose: To activate and propagate populations of γδ T cells expressing polyclonal repertoire γ δ T-cell receptor (TCR) chains for adoptive immunotherapy cancer, which has yet to be achieved. Experimental Design: Clinical-grade artificial antigen-presenting (aAPC) derived from K562 tumor were used as irradiated feeders expand human clinical scale. These tested proliferation, TCR expression, memory phenotype, cytokine secretion, killing. Results: proliferation was dependent upon...
Abstract Purpose: The human endogenous retrovirus (HERV-K) envelope (env) protein is a tumor-associated antigen (TAA) expressed on melanoma but not normal cells. This study was designed to engineer chimeric receptor (CAR) T-cell surface, such that they target tumors in advanced stages of melanoma. Experimental Design: Expression HERV-K analyzed 220 samples (with various disease) and 139 organ donor tissues using immunohistochemical (IHC) analysis. env–specific CAR derived from mouse...
Natural killer (NK) cells emerged as a promising effector population that can be harnessed for anti-tumor therapy. In this work, we constructed NK cell engagers (NKCEs) based on NKp30-targeting single domain antibodies (sdAbs) redirect the cytotoxic potential of toward epidermal growth factor receptor (EGFR)-expressing tumor cells. We investigated impact crucial parameters such sdAb location, binding valencies, targeted epitope NKp30, and overall antibody architecture redirection capacity....
The Sleeping Beauty (SB) transposon/transposase DNA plasmid system is used to genetically modify cells for long-term transgene expression. We adapted the SB human application and generated T expressing a chimeric antigen receptor (CAR) specific CD19. Electrotransfer of CD19-specific plasmids in peripheral blood mononuclear propagation on CD19+ artificial presenting was numerically expand CD3+ CAR. By day 28 coculture, >90% expanded expressed CAR+ specifically killed target consisted subsets...
Ligands for the NKG2D receptor are overexpressed on tumors, making them interesting immunotherapy targets. To assess tumoricidal properties of T cells directed to attack ligands, we engineered murine with two distinct NKG2D-based chimeric antigen receptors (CARs): (i) a fusion between and CD3ζ chain (ii) conventional second-generation CAR, where extracellular domain was fused CD28 CD3ζ. enhance CAR surface expression, also coexpress DAP10. In vitro functionality expression levels all three...
During pregnancy, the ETS transcription factor ELF5 establishes milk-secreting alveolar cell lineage by driving a fate decision of mammary luminal progenitor cell. In breast cancer, is key transcriptional determinant tumor subtype and has been implicated in development insensitivity to anti-estrogen therapy. mouse virus-Polyoma Middle T (MMTV-PyMT) model induction levels increased leukocyte infiltration, angiogenesis, blood vessel permeability primary tumors greatly size number lung...
Rationale : Human CD34 + cells have been used in clinical trials for treatment of myocardial infarction (MI). However, it is unknown how long the persist hearts, whether improvement cardiac function sustained, or what are underlying mechanisms. Objective We sought to track fate injected human hearts severe combined immune deficiency (SCID) mice after experimental MI and determine mechanisms action. Methods Results multimodality molecular imaging SCID MI, selective antibody blocking...
Unmethylated CpG oligodeoxynucleotides (CpG) are synthetic toll-like receptor 9 agonists that activate innate immune cells and which have been tested as an therapy in a number of cancer clinical trials. Although some antitumor responses reported, so far the majority studies failed to show significant CpG. Here we showed route administration is critical activity intravenous (i.v.) injection was capable inducing activation expansion tumor antigen-specific T cells, most these activated migrate...
More effective, less toxic treatments for recurrent ovarian cancer are needed. Although more than 60% of cancers express the estrogen receptor (ER), ER-targeted drugs have been disappointing due to drug resistance. In other estrogen-sensitive cancers, activates Src phosphorylate p27 promoting its degradation and increasing cell-cycle progression. Because is activated in most we investigated whether combined ER blockade by saracatinib fulvestrant would circumvent antiestrogen resistance.ER...
Abstract In this work, we have generated novel Fc-comprising NK cell engagers (NKCEs) that bridge human NKp30 on cells to epidermal growth factor receptor (EGFR) tumor cells. Camelid-derived VHH single-domain Abs specific for and a humanized Fab derived from the EGFR-specific therapeutic Ab cetuximab were used as binding arms. By combining camelid immunization with yeast surface display, able isolate diverse panel of NKp30-specific VHHs against different epitopes NKp30. Intriguingly, NKCEs...
The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [18F]FEAU to monitor the (up 5 months) spatial-temporal dynamics MSCs retrovirally transduced sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs induced acute myocardial infarction. Repetitive revealed a biphasic pattern sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33–35 days injection, periinfarct regions major cardiac lymphatic...
Activating NK cell receptors represent promising target structures to elicit potent antitumor immune responses. In this study, novel immunoligands were generated that bridge the activating receptor NKp30 on cells with epidermal growth factor (EGFR) tumor in a bispecific IgG-like format based affinity-optimized versions of B7-H6 and Fab arm derived from cetuximab. To enhance binding, solitary N-terminal IgV domain (ΔB7-H6) was affinity matured by an evolutionary library approach combined...