A5023082531- Glioma Diagnosis and Treatment
- Pluripotent Stem Cells Research
- Neuroblastoma Research and Treatments
- Virus-based gene therapy research
- Cancer therapeutics and mechanisms
- Cancer Research and Treatments
- 3D Printing in Biomedical Research
- Neurogenesis and neuroplasticity mechanisms
- Cancer Treatment and Pharmacology
- CAR-T cell therapy research
- Nanoparticle-Based Drug Delivery
- Endometriosis Research and Treatment
- Ovarian cancer diagnosis and treatment
- Intraperitoneal and Appendiceal Malignancies
- Nanoplatforms for cancer theranostics
- Viral Infectious Diseases and Gene Expression in Insects
- Neuroscience and Neural Engineering
- Cell Image Analysis Techniques
- Brain Metastases and Treatment
- Histone Deacetylase Inhibitors Research
- Animal Virus Infections Studies
- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- 14-3-3 protein interactions
- RNA Interference and Gene Delivery
City of Hope
2013-2020
Beckman Research Institute
2013-2020
City Of Hope National Medical Center
2016-2017
Purpose: Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) 5-fluorouracil (5-FU).Experimental Design: Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during resection or biopsy. Four days later, began taking...
Abstract CPT-11 (irinotecan) has been investigated as a treatment for malignant brain tumors. However, limitations of therapy include low levels the drug entering tumor sites and systemic toxicities associated with higher doses. Neural stem cells (NSCs) offer novel way to overcome these obstacles because their inherent tropism ability cross blood-brain barrier, which enables them selectively target sites. Carboxylesterases (CEs) are enzymes that can convert prodrug its active metabolite...
Ovarian cancer is particularly aggressive once it has metastasized to the abdominal cavity (stage III). Intraperitoneal (IP) as compared intravenous (IV) administration of chemotherapy improves survival for stage III ovarian cancer, demonstrating that concentrating at tumor sites therapeutic benefit; unfortunately, IP therapy also increases toxic side effects, thus preventing its completion in many patients. The ability target selectively tumors while sparing normal tissue would improve...
Oncolytic virotherapy is a promising approach for treating recurrent and/or drug-resistant ovarian cancer. However, its successful application in the clinic has been hampered by rapid immune-mediated clearance or neutralization of virus, which reduces viral access to tumor foci. To overcome this barrier, patient-derived mesenchymal stem cells have used deliver virus tumors, but variability associated with autologous cell isolations prevents from being broadly clinically applicable. Here, we...
Immunotherapy is emerging as one of the most effective methods for treating many cancers. However, immunotherapy can still introduce significant off-target toxicity, and are sought to enable targeted at tumor sites. Here, we show that relatively large (>100-nm) anionic nanoparticles administered intraperitoneally (i.p.) selectively accumulate in tumor-associated macrophages (TAMs). In a mouse model metastatic ovarian cancer, fluorescently labeled silica, poly(lactic-co-glycolic acid),...
Neural stem cells (NSCs) are inherently tumor-tropic, which allows them to migrate through normal tissue and selectively localize invasive tumor sites in the brain. We have engineered a clonal, immortalized allogeneic NSC line (HB1.F3.CD21; CD-NSCs) that maintains its stem-like properties, karyotype is HLA Class II negative. It genetically functionally stable over time multiple passages, has demonstrated safety phase I glioma trials. These properties enable production of an "off-the-shelf"...
Cell-based therapies hold great promise for a myriad of clinical applications. However, as these move from phase I to II and III trials, there is need improve scale-up adherent cells the production larger good manufacturing practice (GMP) cell banks. As we advanced our neural stem (NSC)-mediated gene therapy trials glioma include dose escalation multiple treatment cycles, GMP using factories (CellStacks) generated insufficient (NSC) yields. To increase yield, developed an expansion method...
Abstract Engineered neural stem cells (NSCs) intrinsically migrating to brain tumors offer a promising mechanism for local therapeutic delivery. However, difficulties in quantitative assessments of NSC migration and estimates tumor coverage by diffusible therapeutics have impeded development refinement NSC-based therapies. To address this need, we developed techniques which conventional serial-sectioned formalin-fixed paraffin-embedded (FFPE) brains can be analyzed their entirety across...
Despite improved survival for children with newly diagnosed neuroblastoma (NB), recurrent disease is a significant problem, treatment options limited by anti-tumor efficacy, patient drug tolerance, and cumulative toxicity. We previously demonstrated that neural stem cells (NSCs) expressing modified rabbit carboxylesterase (rCE) can distribute to metastatic NB tumor foci in multiple organs mice convert the prodrug irinotecan (CPT-11) 1,000-fold more toxic topoisomerase-1 inhibitor SN-38,...
Neuroblastoma (NB), a neuroendocrine tumor, is the most common extracranial solid tumor of childhood. 45% these patients are diagnosed with metastatic high-risk tumors, for which treatment options limited. Neural stem cells (NSCs), engineered to secrete modified carboxylesterase (CE) can home neuroblastoma foci in multiple organs, and convert prodrug CPT-11 (Irinotecan; IRN) 1000 fold more potent topoisomerase-1 inhibitor SN-38. The goal our current efficacy safety/toxicity IND-enabling...
Intro. Targeted drug delivery is a critical goal for effective cancer therapy. Nanoparticles (NPs) have shown promise as platforms targeting drugs to tumors, but major challenges remain controlling the distribution and retention of NPs within tumors. In general, predominantly accumulate in liver spleen difficulty penetrating poorly vascularized hypoxic tumor regions. Neural Stem Cells (NSCs) are ideal candidates use carriers order overcome these biodistribution challenges. NSCs demonstrated...
Human neural stem cells (NSCs) are serving as vehicles for targeted delivery of cytosine deaminase/5-flucytosine enzyme/prodrug therapy to recurrent glioma patients in first human Phase 1 clinical trials (IND 14041). The initial safety/feasibility study demonstrated safety, non-tumorigenicity, non-immunogenicity with round treatment, and proof concept localized conversion 5-Flucytosine the active chemotherapeutic agent, 5-Fluorouracil. We have now developed a second generation NSC brain...
Supplementary Methods from Neural Stem Cell–Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients
Supplementary Methods from Neural Stem Cell–Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients
<div>Abstract<p><b>Purpose:</b> Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) 5-fluorouracil (5-FU).</p><p><b>Experimental Design:</b> Recurrent high-grade glioma patients underwent intracranial...
<div>Abstract<p><b>Purpose:</b> Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) 5-fluorouracil (5-FU).</p><p><b>Experimental Design:</b> Recurrent high-grade glioma patients underwent intracranial...
Human neural stem cells (NSCs) are inherently tumor-tropic, localizing to invasive brain tumor foci following intracerebral administration in preclinical models of primary and secondary tumors, thus overcoming obstacles limiting current therapeutic modalities. These NSCs can be engineered express numerous anti-cancer agents, making them attractive drug delivery vehicles. By concentrating therapy selectively at the sites, toxicity normal tissues associated side effects minimized, improving...
Human NSCs are tumor tropic, making them attractive vehicles for delivery of therapeutics. An immortalized, clonal NSC line was retrovirally transduced to express CD, which converts 5-FC 5-fluorouracil (5-FU). The primary objectives this study were assess the feasibility serially administering CD-NSCs intracranially via a Rickham catheter and determine recommended doses phase II testing (RP2D). Adult patients with recurrent high grade gliomas underwent resection or biopsy placement Rickham....