A5073654041- CAR-T cell therapy research
- Virus-based gene therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- Cancer Research and Treatments
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Neuroblastoma Research and Treatments
- RNA Interference and Gene Delivery
- Nanowire Synthesis and Applications
- Immunotherapy and Immune Responses
Texas Children's Hospital
2017-2024
Baylor College of Medicine
2016-2024
Houston Methodist
2017-2024
Methodist Hospital
2017-2024
In solid tumors, chimeric antigen receptor (CAR)-modified T cells must overcome the challenges of immunosuppressive tumor microenvironment. We hypothesized that pre-treating tumors with our binary oncolytic adenovirus (CAd), which produces local oncolysis and expresses immunostimulatory molecules, would enhance antitumor activity HER2-specific CAR cells, alone are insufficient to cure tumors. tested multiple cytokines in conjunction PD-L1-blocking antibody found Ad-derived IL-12p70 prevents...
No single cancer immunotherapy will likely defeat all evasion mechanisms of solid tumors, including plasticity tumor antigen expression and active immune suppression by the environment. In this study, we increase breadth, potency, duration anti-tumor activity chimeric receptor (CAR) T cells using an oncolytic virus (OV) that produces cytokine, checkpoint blockade, a bispecific tumor-targeted cell engager (BiTE) molecule. First, constructed BiTE molecule specific for CD44 variant 6 (CD44v6),...
Abstract Chimeric antigen receptor (CAR)-redirected immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in nonphysiological regulation of CAR-signaling limits their accessibility due to logistical challenges, high costs biosafety requirements. Random transfer modalities pose a risk malignant transformation...
We show that a binary oncolytic/helper-dependent adenovirus (CAdVEC) both lyses tumor cells and locally expresses the proinflammatory cytokine IL-12 PD-L1 blocking antibody has potent antitumor activity in humanized mouse models. On basis of these preclinical studies, we treated four patients with single intratumoral injection an ultralow dose CAdVEC (NCT03740256), representing oncolytic more than 100-fold lower used previous trials. While caused no significant toxicities, it repolarized...
Abstract High expression levels of human epidermal growth factor receptor 2 (HER2) have been associated with poor prognosis in patients pancreatic adenocarcinoma (PDAC). However, HER2-targeting immunotherapies unsuccessful to date. Here we increase the breadth, potency, and duration anti-PDAC HER2-specific CAR T-cell (HER2.CART) activity an oncolytic adeno-immunotherapy that produces cytokine, immune checkpoint blockade, a safety switch (CAd Trio ). Combination treatment CAd HER2.CARTs cured...
For decades, Adenoviruses (Ads) have been staple cancer gene therapy vectors. Ads are highly immunogenic, making them effective adjuvants. These viruses well characterized genomes, allowing for substantial modifications including capsid chimerism and therapeutic transgene insertion. Multiple generations of Ad vectors generated with reduced or enhanced immunogenicity, depending on their intended purpose, increased capacity. The latest-generation vector is the Helper-dependent (HDAd), in which...
TPS2679 Background: Urgent therapies are needed for patients with refractory Human Epidermal Growth Factor Receptor 2 (HER2) positive solid malignancies. Our group has previously shown potent antitumor effect of a binary oncolytic/helper-dependent adenovirus (CAdVEC) dual expression IL-12 and PD-L1 blocker. Initial preclinical clinical studies direct tumor injection CAdVEC it to be safe result in increased infiltration CD8 T cells into the microenvironment, on locoregional distant metastatic...
The fertilized chicken egg chorioallantoic membrane (CAM), a highly vascularized nourishing the developing embryo, also supports rapid growth of three-dimensional tumors from engrafted cells and tumor explants. Because murine xenograft models suffer limitations time, cost, scalability, we propose CAM as rapid, efficient screening tool for assessing anti-tumor efficacy chimeric Ag receptor (CAR) T against solid tumors. We tested human epidermal factor 2 (HER2)-specific CAR luminescent,...
Systemic administration of oncolytic viruses (OVs) is a promising approach for targeting metastatic solid tumors, but their anti-tumor activity limited by pre-existing neutralizing antibodies against common human viruses. Therefore, investigators have developed OVs derived from non-human host Successful implementation this strategy requires that the viral vector selectively infects and replicates within cancer cells. Newcastle disease virus (NDV) an avian paramyxovirus that, as NDV-based...
I. Abstract Chimeric antigen receptor (CAR)-reprogrammed immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in non-physiological regulation of CAR-signaling limits their accessibility due to logistical challenges, high costs biosafety requirements. Here, we propose a novel approach utilizing CRISPR-Cas...
Abstract Background: Metastatic breast cancer (MBC) which causes significant morbidity and mortality worldwide is in need of more effective treatment regimens. In combination with chemotherapy, anti-PD1 antibody pembrolizumab has been shown to prolong progression-free survival (PFS) patients triple-negative subtype MBC (TN-MBC), however, its efficacy remains low for the other 80% MBC. MBC’s heterogenous pattern immune infiltration expression make it challenging treat single immunotherapeutic...
Abstract HER2, commonly referred to as ErbB2, is a receptor tyrosine kinase that, along with EGFR, makes up one of the four members ErbB family proteins. These proteins are expressed in most epithelial cell layers and play key role differentiation. HER2 has been found be overexpressed number human cancers, including breast gastric carcinomas. Overexpression represents potential target for chimeric antigen (CAR) T therapy. CAR clinical trials leukemia lymphoma have demonstrated durable...
Background Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, “Armed” OAds show limited antitumor effects in patients with various tumors even increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), which coinfected an OAd non-replicating helper-dependent Ad (HDAd). recently demonstrated that single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker,...
HER2, commonly referred to as ErbB2, is a receptor tyrosine kinase that, along with EGFR, makes up one of the four members ErbB family proteins. These proteins are expressed in most epithelial cell layers and play key role differentiation. HER2 has been found be overexpressed number human cancers, including breast gastric carcinomas. Overexpression represents potential target for chimeric antigen (CAR) T therapy. CAR clinical trials leukemia lymphoma have demonstrated durable remission...
Intratumoral treatment with oncolytic adenoviral vectors expressing an immunomodulatory molecule (Armed Onc.Ads) is safe and has shown some clinical benefit in patients solid tumors. However, local Armed Onc.Ad limited anti-tumor effect against metastasized T cells modified tumor-directed chimeric antigen receptors (CARs) have promise for the systemic of hematological malignancies, but been less effective treating Major reasons this failure include lack T-cell migration into tumors...
<h3>Background</h3> While chimeric antigen receptor T cell (CAR T) treatment has been efficacious in blood cancers, mirroring this success solid tumors, like head and neck squamous carcinoma (HNSCC) proven difficult due to the challenge of identifying validating suitable target antigens. To rapidly model CAR-T against HNSCC antigens, we have developed a robust, scalable using fertilized chicken eggs facilitate screening vascularized tumors. The egg inner shell membrane, chorioallantoic...