Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers.

Interleukin-15 (IL-15) promotes the survival of T lymphocytes and enhances the antitumour properties of chimeric antigen receptor (CAR) T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy. Glypican-3 (GPC3) is expressed in a group of solid cancers, and here we report the evaluation in humans of the effects of IL-15 co-expression on GPC3-expressing CAR T cells (hereafter GPC3 CAR T cells). Cohort 1 patients ( NCT02905188 and NCT02932956 ) received GPC3 CAR T cells, which were safe but produced no objective antitumour responses and reached peak expansion at 2 weeks.

Eighteen-year survival after GD2-directed Chimeric Antigen Receptor-Modified Immune Effector Cell Treatment for Neuroblastoma.

We report long-term outcomes up to 18 years of a clinical trial treating children with neuroblastoma with EBV-specific T lymphocytes and CD3-activated T cells - each expressing a first-generation chimeric antigen receptor targeting GD2 with barcoded transgenes to allow tracking of each population. Of 11 patients with active disease at infusion, three patients achieved a complete response that was sustained in 2, one for 8 years until lost to follow up and one for 18+ years. Of eight patients with a history of relapse or at high risk of recurrence, five are disease-free at their last follow-up between 10-14 years post-infusion.

Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial.

In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 10 T cells per m after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 10 CAR T cells per m after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome.

Interleukin-15-armored GPC3-CAR T cells for patients with solid cancers.

Interleukin-15 (IL15) promotes the survival of T lymphocytes and enhances the antitumor properties of CAR T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy. Glypican-3 (GPC3) is expressed in a group of solid cancers, and here we report the first evaluation in humans of the effects of IL15 co-expression on GPC3-CAR T cells. Cohort 1 patients (NCT02905188/NCT02932956) received GPC3-CAR T cells, which were safe but produced no objective antitumor responses and reached peak expansion at two weeks.

Incipient clonal hematopoiesis is accelerated following CD30.CAR-T therapy.

Chimeric antigen receptor (CAR) T-cells are an emerging therapy for refractory lymphomas. Clonal hematopoiesis (CH), the preferential outgrowth of mutated bone marrow progenitors, is enriched in lymphoma patients receiving CAR-T cells. CAR-T therapy requires conditioning chemotherapy and often induces systemic inflammatory reactions, both of which have been shown to promote expansion of CH clones.

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results.

Vα24-invariant natural killer T cells (NKTs) have anti-tumor properties that can be enhanced by chimeric antigen receptors (CARs). Here we report updated interim results from the first-in-human phase 1 evaluation of autologous NKTs co-expressing a GD2-specific CAR with interleukin 15 (IL15) (GD2-CAR.15) in 12 children with neuroblastoma (NB).

Feasibility and preclinical efficacy of CD7-unedited CD7 CAR T cells for T cell malignancies.

Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases.

Immunogenicity of Antigen Adjuvanted with AS04 and Its Deposition in the Upper Respiratory Tract after Intranasal Administration.

Adjuvant system 04 (AS04) is in injectable human vaccines. AS04 contains two known adjuvants, 3--desacyl-4'-monophosphoryl lipid A (MPL) and insoluble aluminum salts. Data from previous studies showed that both MPL and insoluble aluminum salts have nasal mucosal vaccine adjuvant activity.

A solid lipid nanoparticle formulation of 4-(N)-docosahexaenoyl 2', 2'-difluorodeoxycytidine with increased solubility, stability, and antitumor activity.

Previously, we synthesized 4-(N)-docosahexaenoyl 2', 2'-difluorodeoxycytidine (DHA-dFdC), a novel lipophilic compound with a potent, broad-spectrum antitumor activity. Herein, we report a solid lipid nanoparticle (SLN) formulation of DHA-dFdC with improved apparent aqueous solubility, chemical stability, as well as efficacy in a mouse model. The SLNs were prepared from lecithin/glycerol monostearate-in-water emulsions emulsified with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and Tween 20.

Intranasal immunization with aluminum salt-adjuvanted dry powder vaccine.

Intranasal vaccination using dry powder vaccine formulation represents an attractive, non-invasive vaccination modality with better storage stability and added protection at the mucosal surfaces. Herein we report that it is feasible to induce specific mucosal and systemic antibody responses by intranasal immunization with a dry powder vaccine adjuvanted with an insoluble aluminum salt. The dry powder vaccine was prepared by thin-film freeze-drying of a model antigen, ovalbumin, adsorbed on aluminum (oxy)hydroxide as an adjuvant.

Lipid nanoparticles with minimum burst release of TNF-α siRNA show strong activity against rheumatoid arthritis unresponsive to methotrexate.

TNF-α siRNA has shown promising therapeutic benefits in animal models of rheumatoid arthritis. However, there continues to be a need for siRNA delivery systems that have high siRNA encapsulation efficiency and minimum burst release of TNF-α siRNA, and can target inflamed tissues after intravenous administration. Herein we report a novel acid-sensitive sheddable PEGylated solid-lipid nanoparticle formulation of TNF-α-siRNA, AS-TNF-α-siRNA-SLNs, prepared by incorporating lipophilized TNF-α-siRNA into solid-lipid nanoparticles composed of biocompatible lipids such as lecithin and cholesterol.

Uric acid and the vaccine adjuvant activity of aluminium (oxy)hydroxide nanoparticles.

In an effort to improve the adjuvanticity of insoluble aluminium salts, we discovered that the adjuvant activity of aluminium salt nanoparticles is significantly stronger than aluminium salt microparticles, likely related to nanoparticle's stronger ability to directly activate NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome as the nanoparticles are more efficiently taken up by phagocytic cells. Endogenous signals such as uric acid from cell damage or death caused by the cytotoxicity of aluminium salts are thought to indirectly activate inflammasome, prompting us to hypothesise that the potent adjuvant activity of aluminium salt nanoparticles is also related to their ability to stimulate uric acid production. In the present study, we prepared aluminium (oxy)hydroxide nanoparticles (∼ 30-100 nm) and microparticles (X, 9.

Nasal aluminum (oxy)hydroxide enables adsorbed antigens to induce specific systemic and mucosal immune responses.

Some insoluble aluminum salts are commonly used in injectable vaccines as adjuvants to accelerate, prolong, or enhance the antigen-specific immune responses. Data from previous studies testing the nasal mucosal vaccine adjuvant activity of aluminum salts are conflicting. The present study is designed to further assess the feasibility of using aluminum salts in injectable vaccines as nasal mucosal vaccine adjuvants.

Aluminum (Oxy)Hydroxide Nanosticks Synthesized in Bicontinuous Reverse Microemulsion Have Potent Vaccine Adjuvant Activity.

Insoluble aluminum salts such as aluminum (oxy)hydroxide are commonly used as vaccine adjuvants. Recently, there is evidence suggesting that the adjuvant activity of aluminum salt-based materials is tightly related to their physicochemical properties, including nanometer-scale size, shape with long aspect ratio, and low degree of crystallinity. Herein, for the first time, the bicontinuous reverse microemulsion (RM) technique was utilized to synthesize stick-like monodisperse aluminum (oxy)hydroxide nanoparticles with a long aspect ratio of ∼10, length of ∼80 nm, and low degree of crystallinity (denoted as Al-nanosticks).

The immunogenicity of thin-film freeze-dried, aluminum salt-adjuvanted vaccine when exposed to different temperatures.

Insoluble aluminum salts such as aluminum oxyhydroxide have been used for decades as adjuvants in human vaccines, and many vaccines contain aluminum salts as adjuvants. Aluminum salt-adjuvanted vaccines must be managed in cold-chain (2-8° C) during transport and storage, as vaccine antigens in general are too fragile to be stable in ambient temperatures, and unintentional slowing freezing causes irreversible aggregation and permanent damage to the vaccines. Previously, we reported that thin-film freeze-drying can be used to convert vaccines adjuvanted with an aluminum salt from liquid suspension into dry powder without causing particle aggregation or decreasing in immunogenicity following reconstitution.

Methods to Prepare Aluminum Salt-Adjuvanted Vaccines.

Many human vaccines contain certain insoluble aluminum salts such as aluminum oxyhydroxide and aluminum hydroxyphosphate as vaccine adjuvants to boost the immunogenicity of the vaccines. Aluminum salts have been used as vaccine adjuvants for decades and have an established, favorable safety profile. However, preparing aluminum salts and aluminum salt-adjuvanted vaccines in a consistent manner remains challenging.

Amorphous or Crystalline? A Comparison of Particle Engineering Methods and Selection.

This review is intended to provide a critical account of the current goals and technologies of particle engineering regarding the production of crystalline and amorphous particles. The technologies discussed here cover traditional crystallization technologies, supercritical fluid technologies, spray drying, controlled solvent crystallization, and sonocrystallization. Also recent advancements in particle engineering including spray freezing into liquid, thin-film freeze-drying, PRINT technology are presented.

A method of lyophilizing vaccines containing aluminum salts into a dry powder without causing particle aggregation or decreasing the immunogenicity following reconstitution.

Many currently licensed and commercially available human vaccines contain aluminum salts as vaccine adjuvants. A major limitation with these vaccines is that they must not be exposed to freezing temperatures during transport or storage such that the liquid vaccine freezes, because freezing causes irreversible coagulation that damages the vaccines (e.g.

Toll-deficient Drosophila are resistant to infection by Pneumocystis spp.: additional evidence of specificity to mammalian hosts.

Pneumocystis spp. are significant pathogens in a variety of mammals. We tried to establish a Drosophila model of pneumocystosis using either P.