PII-002 - DEVELOPMENT OF A MULTISCALE MECHNISM-BASED CELLULAR KINETIC-PHARMACODYNAMIC (CK-PD) MODEL FOR DUAL-TARGETED BICISTRONIC CAR-T CELL THERAPY.
Thursday, March 23, 2023
5:00 PM – 6:30 PM EDT
M. Su1,2, A. Dey3, G. Mugundu3, A. Singh4; 1Takeda Development Center Americas Inc., Cambridge, MA, USA, 2University of Minnesota, Minneapolis, MN, USA, 3Takeda Development Center Americas, Inc., Lexington, MA, USA, 4Takeda Development Center Americas, Inc., Cambridge, MA, USA.
Summer Intern Takeda Development Center Americas Inc. Falcon Heights, Minnesota, United States
Background: CAR-T cell therapies targeting multiple antigens have recently been developed with a promise to avoid antigen escape, promote tumor selectivity, and achieve durable responses. However, the dose-exposure-response relationship for multi-targeted cell therapies is poorly understood. Here, we have extended our prior multiscale CK-PD model[1] towards dual targeted bicistronic CAR-Ts to describe the complex relationship between two CAR affinities, tumor-associated antigen (TAA) densities, longitudinal tumor dynamics and cellular expansion. Methods: Firstly, an in vitro tumor cell killing model was developed by preclinical dataset(s) from CD19/CD22[2] and GPRC5D/BCMA[3] CAR-T cells to estimate in vitro potencies. In vitro model was integrated within whole body multiscale modeling framework, later utilized to characterize the phase-1 dose-escalation CK dataset for CD19/CD22 CAR-T cells (Doses: 0.3-2 × 10^6, 3 × 10^6 and 5 × 10^6 cells/kg) in r/r B-cell acute lymphoblastic leukemia patients. The model accounted for 1) disposition of effector- and memory-phenotype of CD19/CD22 in blood and bone marrow and 2) dual target engagement driven CAR-T cell expansion and tumor cell depletion. Results: The cell level killing model revealed superior potency of GPRC5D/BCMA CAR-Ts with different costimulatory domains (KC50= 2.38 vs.11.8). The full CK-PD model adequately characterized flow and qPCR-based CK datasets. The model performance was evaluated by goodness of fit plots and global sensitivity analysis revealed relative importance of patient’s CD19/CD22 expression levels towards CAR-T cell exposure. Conclusion: The developed CK-PD relationship could be leveraged in forward translation to guide optimal dosing and in reverse translation to identify optimal affinities for dual targeted CAR-T cell therapies.
1. Singh AP, et al. 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. CPT Pharmacometrics Syst Pharmacol. 2021;10:362-376.
2. Cordoba S, et al. CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Nat Med. 2021;27:1797-1805.
3. Fernandez de Larrea C, et al. Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma. Blood Cancer Discov. 2020;1:146-154.