The development of mechanism-based, multiscale pharmacokinetic–pharmacodynamic (PK-PD) models for chimeric antigen receptor (CAR)-T cells is needed to enable investigation of in vitro and in vivo correlation of CAR-T cell responses and to facilitate preclinical-to-clinical translation. Toward this goal, we first developed a cell-level in vitro PD model that quantitatively characterized CAR-T cell-induced target cell depletion, CAR-T cell expansion and cytokine release. The model accounted for key drug-specific (CAR-affinity, CAR-densities) and system-specific (antigen densities, E:T ratios) variables and was able to characterize comprehensive in vitro datasets from multiple affinity variants of anti-EGFR and anti-HER2 CAR-T cells. Next, a physiologically based PK (PBPK) model was developed to simultaneously characterize the biodistribution of untransduced T-cells, anti-EGFR CAR-T and anti-CD19 CAR-T cells in xenograft -mouse models. The proposed model accounted for the engagement of CAR-T cells with tumor cells at the site of action. Finally, an integrated PBPK-PD relationship was established to simultaneously characterize expansion of CAR-T cells and tumor growth inhibition (TGI) in xenograft mouse model, using datasets from anti-BCMA, anti-HER2, anti-CD19 and anti-EGFR CAR-T cells. Model simulations provided potential mechanistic insights toward the commonly observed multiphasic PK profile (i.e., rapid distribution, expansion, contraction and persistence) of CAR-T cells in the clinic. Model simulations suggested that CAR-T cells may have a steep dose-exposure relationship, and the apparent Cmax upon CAR-T cell expansion in blood may be more sensitive to patient tumor-burden than CAR-T dose levels. Global sensitivity analysis described the effect of other drug-specific parameters toward CAR-T cell expansion and TGI. The proposed modeling framework will be further examined with the clinical PK and PD data, and the learnings can be used to inform design and development of future CAR-T therapies.

T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure–response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

Despite tremendous success of chimeric antigen receptor (CAR) T cell therapy in clinical oncology, the dose-exposure-response relationship of CART cells in patients is poorly understood. Moreover, the key drug-and system-specific determinants leading to favourable clinical outcomes are also unknown. Here, we have developed a multiscale mechanistic PK-PD model for anti-BCMA (bb2121) CART cell therapy to characterize 1) in vitro target cell killing in multiple BCMA expressing tumor cell lines at varying E:T ratios, 2) preclinical in vivo tumor growth inhibition (TGI) and blood CART cell expansion in xenograft mice, and 3) clinical PK and PD biomarkers in multiple myeloma (MM) patients. Our translational PK-PD relationship was able to effectively describe the commonly observed multiphasic CART cell PK profile in clinic, consisting of rapid distribution, expansion, contraction and persistent phases, as well as accounted for the categorical individual responses in multiple myeloma to effectively calculate progression-free survival rates. Preclinical and clinical data analysis revealed comparable parameter estimates pertaining to CART cell functionality and suggested that patient baseline tumor burden could be more sensitive than dose levels towards overall extent of exposure (Cmax) after CART cell infusion. Virtual patient simulations also suggested a very steep dose-exposure-response relationship with CART cell therapy and indicated presence of a 'threshold' dose, beyond which a flat dose-response curve could be observed. Our simulations were concordant with multiple clinical observations discussed within this paper. Moving forward, this framework could be leveraged a priori, to explore multiple infusions and support preclinical/clinical development of future CART cell therapies.

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We performed a randomized, placebo-controlled, double-blind study to compare the efficacy of intravenous (I.V.) lidocaine and topical nitroglycerin ointment in preventing pain during propofol injection. Nitroglycerin or placebo ointments were applied to the back of the hand over the skin area overlying the I.V. catheter tip; lidocaine was or was not added to the propofol solution. One hundred twenty-four patients were randomly assigned to receive one of four treatments: placebo and plain propofol, propofol mixed with lidocaine, nitroglycerin ointment and plain propofol, and nitroglycerin ointment and propofol mixed with lidocaine. Hence, there were 31 patients in each treatment group. Patients receiving nitroglycerin ointment and plain propofol had the highest incidence of pain on propofol injection (23 of 31 patients, 74%), and the highest median pain score. Only when lidocaine was added to propofol did it effectively reduce the incidence and severity of pain. Patients aged 50 yr and older had a significantly lower incidence and less severe pain. We conclude that lidocaine and age, but not topical nitroglycerin ointment, are factors associated with a decreased incidence of propofol-induced pain.

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Objectives.-The present study investigated the peripheral inflammatory changes of the trigeminovascular system by measuring the inflammatory mediators leukotriene B 4 (LTB 4 ), prostaglandin E 2 (PGE 2 ), and thromboxane B 2 (TXB 2 ) in the nasal fluid, as well as saliva, of patients with migraine.Background.-Migraine has been hypothesized to be as a result of changes in the peripheral or central nervous system or both. It is still unclear whether peripheral changes in the trigeminovascular system are involved in the pathogenesis of migraine.Methods.-Participants were 18 subjects, 9 patients with migraine and 9 controls, matched for age and sex. Each subject took part in one experimental session during which nasal lavage fluid and saliva samples were collected. These samples were analyzed by competitive enzyme immunoassay using goat anti-rabbit polyclonal antibody.Results.-With the exception of TXB 2 , correlational analyses indicated good correlations between results obtained using nasal lavage or saliva (LTB 4 , r 18 ϭ 0.91; PGE 2 , r 18 ϭ 0.95). When comparing inflammatory mediators measured in controls and migraineurs, the LTB 4 level was significantly lower in migraineurs, while no differences were found for PGE 2 and TXB 2 .Conclusions.-The study demonstrated that nasal lavage, a noninvasive method, can be easily used for investigations of pathophysiological mechanisms of migraine. In addition, the results may indicate that there is no peripheral trigeminal sensitization in the headache-free period of migraineurs compared with controls when PGE 2 , LTB 4 , and TXB 2 in saliva and nasal lavage samples are measured.