Zj-7

Axicabtagene ciloleucel (axi-cel, Yescarta) is an autologous, anti-CD19, chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed and refractory non-Hodgkin's lymphoma. Substantial inter-individual variability in cellular kinetics has been observed with CAR-T therapies and factors impacting CAR-T cellular kinetics remain poorly understood. This work reports a population cellular kinetic model of axi-cel in relapsed and patients with refractory non-Hodgkin's lymphoma and investigated the impact of covariates on early and late kinetic phases of CAR-T exposure.

A population cellular kinetic model (NONMEM^® version 7.4) for axi-cel was developed using data from 410 patients (2050 transgene observations) after a single intravenous infusion of 2 × 10⁶ anti-CD19 CAR+ T cells/kg in patients with non-Hodgkin's lymphoma (ZUMA-1, ZUMA-5, and ZUMA-7 clinical studies). A large panel of covariates was assessed to decipher the variability of CAR-T cell kinetics including patient characteristics, product characteristics, and disease types.

Axi-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics characterized by an exponential growth phase followed by a triphasic decline phase including a long-term persistence phase. The final cellular kinetic model retained in vitro doubling time during CAR-T cell manufacturing and total number of T cells infused as covariates impacting the duration of the growth phase, which, however, did not substantially influence maximum concentration, area under the concentration-time curve over the first 28 days, or long-term persistence. A statistically significant relationship was observed between maximum concentration and the probability to receive tocilizumab and/or corticosteroids.

No covariates considered in this study were found to significantly and substantially predict the exposure profile of axi-cel. Tocilizumab and steroid use were related to maximum concentration, but they were used reactively to treat toxicities that are associated with a higher maximum concentration. Further CAR-T kinetic analyses should consider additional factors to explain the observed variability in cellular kinetics or help establish a dose-exposure relationship.

NCT02348216 (ZUMA-1), NCT03105336 (ZUMA-5), and NCT03391466 (ZUMA-7).

Most importantly, the authors screened a series of compounds targeting the nNOS-SERT interaction using cultured HEK293T cells co-transfected with nNOS- and SERT- encoding plasmids, and discovered ZLL-7 as a blocker of the nNOS-SERT interaction to specifically reduce the intercellular serotonin concentration in the DRN of the brain, which exerted an antidepressant effect 2 h after intragastric or i.p. administration in 28 d-CMS-experienced mice.Overall, this study provides a novel target and a lead compound for further development of first-in-class fast-onset antidepressants.Given that traditional Chinese medicines have been used for the treatment of depression, effective natural products may also provide a valuable source for the discovery of novel blockers of the nNOS-SERT interaction, which would be further developed into a new class of fast-on- set antidepressants.