A Model Perspective Explanation of the Long-Term Sustainability of a Fully Human BCMA-Targeting CAR (CT103A) T-Cell Immunotherapy

Abstract

Different from canonical drugs, CAR T-cells are “living drugs”, which derived from patient’s own blood. Studies of the pharmacokinetics of CAR T-cells could improve our understanding of their efficacy, safety, optimal dosage, and other characterizes. We previously reported a phase I study of a novel fully human BCMA-targeting CAR (CT103A) in 18 patients with relapsed/refractory multiple myeloma. CT103A exhibited extraordinary persistence with low anti-drug antibody positivity. To figure out the pharmacokinetic characterizes and investigate the potential reason of CT103A’s long-term persistence, we established a population pharmacokinetic (PopPK) model of CT103A based on 18 patients cohort by applying nonlinear mixed-effects modeling and analyzed the CAR T-cell clonal evolution. The results suggested that extramedullary spreading was found to impair Cmax and was therefore added as a covariate to the modified model. The model revealed tocilizumab and corticosteroids showed no impact on the CT103A expansion rate. No dominant clone existed in patients with persistently high peripheral CT103A by CAR integration sites analysis. Finally, patients with lower contraction rate constants and higher Cmax as well as memory CT103A fraction could achieve better clinical responses. Taken together, this study developed a PopPK model of a fully human anti-BCMA CAR T-cell therapy, and summarized its model characteristics. We suggested that the long-term persistence of CT103A was attributed to the memory CAR T-cell fraction but not the clonal evolution. This study will improve people’s understanding of pharmacokinetics and PopPK of CAR T-cell immunotherapy.

Development and manufacture of novel locally produced anti-BCMA CAR T cells for the treatment of relapsed/refractory multiple myeloma: results from a phase I clinical trial

“…In addition, responses were significantly deeper in belantamab non-exposed patients. Retargeting of BCMA using belantamab, following anti-BCMA CART cell therapy has been reported [20][21][22] . Our observation suggests that sequential treatment of MM patients with anti-BCMA CART cells following anti-BCMA antibody may impair but does not exclude responses to CART-therapy.…”

Best Practices and Considerations for Clinical Pharmacology and Pharmacometric Aspects for Optimal Development of CAR‐T and TCR‐T Cell Therapies: An Industry Perspective

“…Stein et al 18 published the first population CK model to characterize the clinical CK profiles of tisa-cel and to evaluate the impact of extrinsic and intrinsic factors, specifically CRS-treating therapies on in vivo expansion kinetics. Similar population modeling and covariate assessment was carried out by Ogasawara et al 19 for liso-cel, Wu et al 20 for cilta-cel, and Mu et al 21 for CT103A CAR-T therapies. Such quantitative model-based approaches supported regulatory approvals of CAR-T therapies.…”

“…Optimal dosing in the context of exposureresponse relationships and identifying appropriate covariates of exposure or response are beginning to be explored and reported with varying degrees of model complexity. [18][19][20][21] Lack of relevant preclinical models continue to pose a major hurdle for preclinical to clinical translation that impacts first-in-human (FIH) study design and dose selection. Traditional quantitative tools in drug development leveraged for small molecules or biologics cannot be directly applied but rather require adaption and optimization for the development of ACTs.…”

“…The dose‐exposure and exposure‐response (safety and efficacy) relationships for ACTs is convoluted due to a variety of factors, including unique pharmacokinetic (PK) characteristics, intrinsic and extrinsic patient‐related factors, and product‐related factors due to heterogeneous T‐cell population. Optimal dosing in the context of exposure‐response relationships and identifying appropriate covariates of exposure or response are beginning to be explored and reported with varying degrees of model complexity 18–21 . Lack of relevant preclinical models continue to pose a major hurdle for preclinical to clinical translation that impacts first‐in‐human (FIH) study design and dose selection.…”

Editorial: Predictive short/long-term efficacy biomarkers and resistance mechanisms of CAR-T immunotherapy treatment

“…Patients with a higher peak CAR transgene level in peripheral blood are more likely to achieve long-term remission ( 16 ). By modeling the dynamics of CAR-T cells post-infusion, we can predict their proliferation capacity and identify factors related to their expansion ( 17 ). In B-ALL, rapid disappearance of CAR-T cells or recovery of B cells can inform impending relapse.…”