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With the promise of a potentially single‐dose curative regimen, CAR‐T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies with 6 approved products in the USA. However, there are no approved CAR‐T cell therapies for solid tumors. Herein, we report the clinical pharmacology profile of AMG 119, the first CAR‐T cell therapy targeting delta‐like ligand 3 (DLL3), in patients with relapsed/refractory (R/R) small cell lung cancer (SCLC). AMG 119 demonstrated robust cellular expansion with long‐lasting cell persistence and a favorable exposure–response relationship. AMG 119 has been demonstrated to be clinically safe and well tolerated at the doses tested, with no dose‐limiting toxicities (DLTs) reported. This is the first publication of the clinical pharmacology profile of a CAR‐T cell therapy in SCLC, with encouraging cellular kinetics data supporting the potential for CAR‐T cell therapy in solid tumor space. [ABSTRACT FROM AUTHOR]

Keywords: CAR-T cell therapies; cellular kinetics; exposure-response models; fixed and body-weight-based dosing EN CAR-T cell therapies cellular kinetics exposure-response models fixed and body-weight-based dosing 1130 1135 6 10/06/22 20221001 NES 221001 Historically, body-size-based dosing has been utilized for many anticancer drugs. For example, the CK curves of lisocabtagene maraleucel overlapped across 50, 100, and 150 million cells dose levels, and no dose-exposure or dose-efficacy relationships were identified.16 BW was not identified as a significant covariate.16 Although there was a positive trend for the E-R between CAR-T cell growth and tumor response, FDA evaluation (lisocabtagene maraleucel BLA 125714 Clinical Pharmacology Review document) suggested it should not be interpreted as causally connected between dose and response, given the observed flat dose-exposure-response relationship. At a dose of 0.5 × 10 SP 6 sp CAR-T cells/kg, the C SB max sb and AUC SB 0-28d sb of brexucabtagene autoleucel were approximately 60% of that in subjects treated at a dose of 2 × 10 SP 6 sp CAR-T cells/kg, exhibiting a potential underexposure. A Consideration of Fixed Dosing Versus Body Size-Based Dosing Strategies for Chimeric Antigen Receptor T-Cell Therapies. [Extracted from the article]

Background: Despite numerous chimeric antigen receptor T‐cell (CAR‐T) trials conducted in China, no CAR‐T has been registered in the country. Furthermore, China law and regulations restrict the export of patient material for CAR‐T manufacture abroad. Relma‐cel (JWCAR029), an anti‐CD19 product produced with a commercial‐ready process in China, was evaluated in the first prospective, single‐arm, multicenter, pivotal study of CAR‐T therapy conducted under Chinese IND to support an NMPA‐accepted BLA submission in relapsed/refractory (r/r) LBCL (NCT04089215). Methods: Patients were randomized to receive either 100 × 106 (low dose, n = 27) or 150 × 106 (high dose, n = 32) CAR+ T‐cells as a single infusion following lymphodepleting chemotherapy (fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 daily × 3), and then, monitored for efficacy and safety outcomes and pharmacokinetics. The primary endpoint was ORR at 3 months, as assessed by the investigators. Secondary endpoints included DOR, PFS, OS, and adverse event frequency/severity and cell expansion kinetics. Results: As of the data cutoff on 17 June 2020, 68 patients were enrolled, and 59 were treated. Among the 58 efficacy‐evaluable patients, the primary endpoint of 3 month ORR was 60.3% (95% CI, 46.6–73.0), excluding the null hypothesis rate of 20%. Any grade and severe grade CRS occurred in 47.5% and 5.1%, respectively, and any grade and severe grade neurotoxicity events occurred in 20.3% and 5.1%. Conclusions: Relma‐cel met the primary endpoint analysis and demonstrated a high rate of durable responses and low rate of CAR‐T‐associated toxicities in patients with r/r LBCL in a multicenter trial supporting regulatory submission in China. [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that studying cell biology in classical two-dimensional formats, such as cell culture plasticware, results in misleading, non-physiological findings. This paper describes the optimization of a microsphere-based system permitting 3D cell culture incorporating physiological extracellular matrix components. Bio-electrospraying, the most advanced method currently available, is used to produce microspheres containing THP-1 cells as a model cell line. The bio-electrospraying para­meters of nozzle size, polymer flow rate, and voltage are systematically investigated in order to allow stable production of size-controlled microspheres containing extracellular matrix material and human cells. The effect of bio-electrospraying parameters, alginate type and cell concentration on cell viability are investigated using trypan blue and propidium iodide staining. Bio-electrospraying has no effect on cell viability nor the ability of cells to proliferate. Cell viability is similarly minimally affected by encapsulation in all types of alginate tested (MVM, MVG, chemical and food-grade). Cell density of 5 × 106 cells mL−1 within microspheres is the optimum for cell survival and proliferation. The stable generation of microspheres incorporating cells and extracellular matrix for use in a 3D cell culture will benefit study of many diverse diseases and permit investigation of cellular biology within a 3D matrix. [ABSTRACT FROM AUTHOR]

The methods currently used to evaluate the risk of developmental defects in humans from exposure to potential toxic agents do not reflect biological processes in extrapolating estimated risks to low doses and from test species to humans. We develop a mathematical model to describe aspects of the dynamic process of organogenesis, based on branching process models of cell kinetics. The biological information that can be incorporated into the model includes timing and rates of dynamic cell processes such as differentiation, migration, growth, and replication. The dose-response models produced can explain patterns of malformation rates as a function of both dose and time of exposure, resulting in improvements in risk assessment and understanding of the underlying mechanistic processes. To illustrate the use of the model, we apply it to the prediction of the effects of methylmercury on brain development in rats. [ABSTRACT FROM AUTHOR]