Metabolic priming of GD2 -CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence.

Manufacturing chimeric antigen receptor (CAR) T cell therapies is complex, with limited understanding of how medium composition impacts T cell phenotypes. CRISPR-Cas9 ribonucleoproteins can precisely insert a CAR sequence while disrupting the endogenous T cell receptor alpha constant () gene resulting in -CAR T cells with an enriched stem cell memory T cell population, a process that could be further optimized through modifications to the medium composition. In this study we generated anti-GD2 -CAR T cells using "metabolic priming" (MP), where the cells were activated in glucose/glutamine-low medium and then expanded in glucose/glutamine-high medium.

Metabolic priming of GD2 -CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence.

Manufacturing Chimeric Antigen Receptor (CAR) T cell therapies is complex, with limited understanding of how media composition impact T-cell phenotypes. CRISPR/Cas9 ribonucleoproteins can precisely insert a CAR sequence while disrupting the endogenous T cell receptor alpha constant ( ) gene resulting in -CAR T cells with an enriched stem cell memory T-cell population, a process that could be further optimized through modifications to the media composition. In this study we generated anti-GD2 -CAR T cells using "metabolic priming" (MP), where the cells were activated in glucose/glutamine low media and then expanded in glucose/glutamine high media.

Ultrasound targeted microbubble destruction using docetaxel and Rose Bengal loaded Microbubbles for targeted Chemo-Sonodynamic therapy treatment of prostate cancer.

Docetaxel (DTX) chemotherapy is commonly used in the treatment of patients with advanced prostate cancer demonstrating modest improvements in survival. As these patients are often elderly and the chemotherapy treatment is not targeted, it is often poorly tolerated. More targeted approaches that increase therapeutic efficacy yet reduce the amount of toxic chemotherapy administered are needed.

Nanotechnology-augmented sonodynamic therapy and associated immune-mediated effects for the treatment of pancreatic ductal adenocarcinoma.

Purpose: Sonodynamic therapy (SDT) is emerging as a cancer treatment alternative with significant advantages over conventional therapies, including its minimally invasive and site-specific nature, its radical antitumour efficacy with minimal side effects, and its capacity to raise an antitumour immune response. The study explores the efficacy of SDT in combination with nanotechnology against pancreatic ductal adenocarcinoma.

Methods: A nanoparticulate formulation (HPNP) based on a cathepsin B-degradable glutamate-tyrosine co-polymer that carries hematoporphyrin was used in this study for the SDT-based treatment of PDAC.

Competition between Heterogeneous Nucleation and Flow-Induced Crystallization of Polyamide 66 and Its Carbon Nanotube Composites.

Both heterogeneous nucleation and flow-induced entropy reduction are the two well-known factors that accelerate polymer crystallization. However, the interplay of nucleation and flow-induced acceleration is still poorly understood. This work investigates the nucleating effect of carbon nanotubes (CNT) on both the quiescent and flow-induced crystallization kinetics of polyamide 66 (PA 66).

Cortical Granularity Shapes the Organization of Afferent Paths to the Amygdala and Its Striatal Targets in Nonhuman Primate.

The prefrontal cortex (PFC) and insula, amygdala, and striatum form interconnected networks that drive motivated behaviors. We previously found a connectional trend in which granularity of the ventromedial and orbital PFC/insula predicted connections to the amygdala, and also the breadth of amygdalo-striatal efferents, including projections beyond the "classic" ventral striatum. To further interrogate connectional relationships among the cortex, amygdala, and striatum, and to further define the "limbic" (amygdala-recipient) striatum, we conducted tract tracing studies in two cohorts of macaques (male = 14, female = 1).

A single microbubble formulation carrying 5-fluorouridine, Irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction.

FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer.

Combining sonodynamic therapy with chemoradiation for the treatment of pancreatic cancer.

Treatment options for patients with pancreatic cancer are limited and survival prospects have barely changed over the past 4 decades. Chemoradiation treatment (CRT) has been used as neoadjuvant therapy in patients with borderline resectable disease to reduce tumour burden and increase the proportion of patients eligible for surgery. Antimetabolite drugs such as gemcitabine and 5-fluorouracil are known to sensitise pancreatic tumours to radiation treatment.

Sonodynamic therapy complements PD-L1 immune checkpoint inhibition in a murine model of pancreatic cancer.

The emergence of immune checkpoint inhibitors (ICI's) in the past decade has proven transformative in the area of immuno-oncology. The PD-1/PD-L1 axis has been particularly well studied and monoclonal antibodies developed to block either the receptor (anti PD-1) or its associated ligand (anti PD-L1) can generate potent anti-tumour immunity in certain tumour models. However, many "immune cold" tumours remain unresponsive to ICI's and strategies to stimulate the adaptive immune system and make these tumours more susceptible to ICI treatment are currently under investigation.

Synthesis of a gemcitabine-modified phospholipid and its subsequent incorporation into a single microbubble formulation loaded with paclitaxel for the treatment of pancreatic cancer using ultrasound-targeted microbubble destruction.

Gemcitabine and nab-paclitaxel (Abraxane®) is a standard of care chemotherapy combination used in the treatment of patients with advanced pancreatic cancer. While the combination has shown a survival benefit when compared to gemcitabine monotherapy, it is associated with significant off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the site-specific deposition of drug-payloads.

Exploiting a Rose Bengal-bearing, oxygen-producing nanoparticle for SDT and associated immune-mediated therapeutic effects in the treatment of pancreatic cancer.

Sonodynamic therapy (SDT) is an emerging stimulus-responsive approach for the targeted treatment of solid tumours. However, its ability to generate stimulus-responsive cytotoxic reactive oxygen species (ROS), is compromised by tumour hypoxia. Here we describe a robust means of preparing a pH-sensitive polymethacrylate-coated CaO nanoparticle that is capable of transiently alleviating tumour hypoxia.

Evaluation of Loading Strategies to Improve Tumor Uptake of Gemcitabine in a Murine Orthotopic Bladder Cancer Model Using Ultrasound and Microbubbles.

In this study we compared three different microbubble-based approaches to the delivery of a widely used chemotherapy drug, gemcitabine: (i) co-administration of gemcitabine and microbubbles (Gem+MB); (ii) conjugates of microbubbles and gemcitabine-loaded liposomes (GemlipoMB); and (iii) microbubbles with gemcitabine directly bound to their surfaces (GembioMB). Both in vitro and in vivo investigations were carried out, respectively, in the RT112 bladder cancer cell line and in a murine orthotopic muscle-invasive bladder cancer model. The in vitro (in vivo) ultrasound exposure conditions were a 1 (1.

Investigating the performance of a novel pH and cathepsin B sensitive, stimulus-responsive nanoparticle for optimised sonodynamic therapy in prostate cancer.

Nano-formulations that are responsive to tumour-related and externally-applied stimuli can offer improved, site-specific antitumor effects, and can improve the efficacy of conventional therapeutic agents. Here, we describe the performance of a novel stimulus-responsive nanoparticulate platform for the targeted treatment of prostate cancer using sonodynamic therapy (SDT). The nanoparticles were prepared by self-assembly of poly(L-glutamic acid-L-tyrosine) co-polymer with hematoporphyrin.

An ultrasound responsive microbubble-liposome conjugate for targeted irinotecan-oxaliplatin treatment of pancreatic cancer.

Survival rates in pancreatic cancer have remained largely unchanged over the past four decades with less than 5% of patients surviving five years following initial diagnosis. FOLFIRINOX chemotherapy, a combination of folinic acid, 5-fluoruracil, irinotecan and oxaliplatin, has shown the greatest survival benefit for patients with advanced disease but is only indicated for those with good physical performance status due to its extreme off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the targeted delivery of drug payloads to solid tumours and involves using low intensity ultrasound to disrupt (burst) MBs in the tumour vasculature, releasing encapsulated or attached drugs in a targeted manner.

Rose Bengal-Amphiphilic Peptide Conjugate for Enhanced Photodynamic Therapy of Malignant Melanoma.

Malignant melanoma is an aggressive skin cancer with poor survival outcomes for patients diagnosed at an advanced stage. While targeted serine/threonine-protein kinase B-Raf (BRAF) and immune checkpoint inhibitors have improved survival outcomes for a proportion of these patients, response rates remain variable. There is a need, therefore, for more effective treatments to bolster the options available for melanoma patients.

Phthalocyanine-loaded nanostructured lipid carriers functionalized with folic acid for photodynamic therapy.

Breast cancer is a serious public health problem that causes thousands of deaths annually. Chemotherapy continues to play a central role in the management of breast cancer but is associated with extreme off-target toxicity. Therefore, treatments that directly target the tumor and display reduced susceptibility to resistance could improve the outcome and quality of life for patients suffering from this disease.

Magnetic microbubble mediated chemo-sonodynamic therapy using a combined magnetic-acoustic device.

Recent pre-clinical studies have demonstrated the potential of combining chemotherapy and sonodynamic therapy for the treatment of pancreatic cancer. Oxygen-loaded magnetic microbubbles have been explored as a targeted delivery vehicle for this application. Despite preliminary positive results, a previous study identified a significant practical challenge regarding the co-alignment of the magnetic and ultrasound fields.

Targeted chemo-sonodynamic therapy treatment of breast tumours using ultrasound responsive microbubbles loaded with paclitaxel, doxorubicin and Rose Bengal.

Mastectomy is a common surgical treatment used in the management of breast cancer but has associated physical and psychological consequences for the patient. Breast conservation surgery (BCS) is an alternative to mastectomy but is only possible when the tumour is of an appropriate size. Neo-adjuvant chemotherapy has been successfully used to downstage tumours and increase the number of patients eligible for BCS.

The Role of PEG-40-stearate in the Production, Morphology, and Stability of Microbubbles.

Phospholipid coated microbubbles are currently in widespread clinical use as ultrasound contrast agents and under investigation for therapeutic applications. Previous studies have demonstrated the importance of the coating nanostructure in determining microbubble stability and its dependence upon both composition and processing method. While the influence of different phospholipids has been widely investigated, the role of other constituents such as emulsifiers has received comparatively little attention.