Bench-to-bedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokinetic-pharmacodynamic model: A case study with anti-BCMA CAR-T.

Despite tremendous success of chimeric antigen receptor (CAR) T cell therapy in clinical oncology, the dose-exposure-response relationship of CAR-T cells in patients is poorly understood. Moreover, the key drug-specific and system-specific determinants leading to favorable clinical outcomes are also unknown. Here we have developed a multiscale mechanistic pharmacokinetic (PK)-pharmacodynamic (PD) model for anti-B-cell maturation antigen (BCMA) CAR-T cell therapy (bb2121) to characterize (i) in vitro target cell killing in multiple BCMA expressing tumor cell lines at varying effector to target cell ratios, (ii) preclinical in vivo tumor growth inhibition and blood CAR-T cell expansion in xenograft mice, and (iii) clinical PK and PD biomarkers in patients with multiple myeloma. Our translational PK-PD relationship was able to effectively describe the commonly observed multiphasic CAR-T cell PK profile in the clinic, consisting of the rapid distribution, expansion, contraction, and persistent phases, and 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 CAR-T cell functionality and suggested that patient baseline tumor burden could be more sensitive than dose levels toward overall extent of exposure after CAR-T cell infusion. Virtual patient simulations also suggested a very steep dose-exposure-response relationship with CAR-T cell therapy and indicated the presence of a "threshold" dose, beyond which a flat dose-response curve could be observed. Our simulations were concordant with multiple clinical observations discussed in this article. Moving forward, this framework could be leveraged a priori to explore multiple infusions and support the preclinical/clinical development of future CAR-T cell therapies.

Development of a quantitative relationship between CAR-affinity, antigen abundance, tumor cell depletion and CAR-T cell expansion using a multiscale systems PK-PD model.

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.

Complications of ganciclovir implant surgery in patients with cytomegalovirus retinitis: the Ganciclovir Cidofovir Cytomegalovirus Retinitis Trial.

PURPOSE: To describe the complications of ganciclovir implant surgery in patients with cytomegalovirus retinitis. METHODS: Prospective data collection within the context of a randomized, controlled clinical trial, comparing a regimen of the ganciclovir implant plus oral ganciclovir to one of intravenous cidofovir for the treatment of cytomegalovirus retinitis in patients with AIDS. Adverse events were compared for patients undergoing implant surgery in the following groups: primary versus replacement implant surgery, inpatient versus outpatient surgery, and general versus local anesthesia. RESULTS: Fifty-six eyes of 42 patients underwent a total of 74 ganciclovir implant surgeries. Vitreous hemorrhage was the most common adverse event, occurring in 10% of eyes undergoing surgery with local anesthesia but in no eyes undergoing surgery with general anesthesia. All vitreous hemorrhages resolved within 60 days. Patients in the general anesthesia and inpatient surgery groups tended to have a lower risk of complications in the first 30 days than did patients in the local anesthesia and outpatient surgery groups, but no differences in the complication rate were found after 60 days. Visual acuity was similar among these different groups. There were no cases of endophthalmitis. CONCLUSION: Ganciclovir implant surgery in patients with AIDS and cytomegalovirus retinitis was associated with a low risk of serious complications in the first 60 days after surgery. Vitreous hemorrhage was the most commonly observed complication and resolved in all cases.