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245 Development and application of physiologically based pharmacokinetic – pharmacodynamic (PBPK-PD) model for dose optimization of TAK-102: GPC3 targeted CAR-T armored with IL-7 and CCL-19
  1. Agnish Dey1,
  2. Hideaki Kagehara2,
  3. Petar Pop-Damkov3,
  4. Eriko Sumi2,
  5. Eiki Maeda4,
  6. Takenori Akaike2,
  7. Kondala Atkuri3,
  8. Kotaro Suzuki3,
  9. Masashi Ochi3,
  10. Takafumi Koyama5,
  11. Yasutoshi Kuboki6,
  12. Takako Eguchi Nakajima7,
  13. Ganesh M Mugundu3 and
  14. Aman Singh3
  1. 1Takeda Pharmaceuticals, Lexington, MA, USA
  2. 2Takeda Pharmaceutical Company Limited, Osaka, Japan
  3. 3Takeda Pharmaceuticals, Cambridge, MA, USA
  4. 4Takeda Pharmaceuticals, Fujisawa, Japan
  5. 5National Cancer Center Hospital, Tokyo, Japan
  6. 6National Cancer Center Hospital East, Kashiwa, Japan
  7. 7Kyoto University Graduate School of Medicine, Kyoto, Japan
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background TAK-102 is a GPC3 targeted CAR-T armored with IL-7 and CCL-19. The program is currently in Phase-1 dose escalation stage enrolling patients with GPC3 expressing solid tumors. Cohort 1 (DL = 10 Million CAR-T cells/body) and cohort 2 (DL = 100 Million CAR-T cells/body) enrollment is now complete. A PBPK-PD model was developed to characterize cellular kinetic (CK) data in peripheral blood by flow cytometry, a ddPCR assay and longitudinal total tumor volume data of enrolled patients. The developed model was further leveraged to explore the impact of GPC3 expression, initial tumor burden and CAR-T cell dose level on observed CK in patients.

Methods Firstly, a kinetic-pharmacodynamic (K-PD) model was developed to describe the recovery kinetics of host T-lymphocytes after lymphodepletion. Then, a fully human PBPK-PD model for of TAK-102, compartmentalized into blood and relevant tissues, was developed – where each tissue was further divided into vascular and extra-vascular sub-compartments. The tumor extra-vascular space consists of both GPC3 expressing and GPC3 non-expressing tumor cells. Target engagement was described by the formation of CAR-target complexes upon interaction between CAR-T and GPC3 expressing tumor cells in the model. These CAR-target complexes induce tumor volume depletion and expansion of total (bound and unbound) CAR-T cells. Effect of host T-lymphocytes on expansion of CAR-T cells (lymphodepletion mediated reduction of host T-lymphocytes would pose less competition for CAR-T cells to expand) was implemented in the model. The developed model was simulated to investigate the effect of initial tumor burden, GPC3 expression and CAR-T cell dose on CK.

Results The K-PD model was able to describe the host T-lymphocytes recovery kinetics post lymphodepleting chemotherapy (Fludarabine with Cyclophosphamide). The PBPK-PD model was able to capture the multiphasic cellular kinetic behaviour of CAR-T cells along with tumor kinetics. Lack of sensitivity of CAR-T expansion towards increasing dose levels (200 million-1 billion) was observed in model simulations. Steady increase in expansion was observed with increasing initial tumor burden (100 ML-1000 ML), keeping the dose and GPC3 expression fixed. Similar correlation between cellular expansion and GPC3 expression (1%-30%) was observed keeping the dose and initial tumor burden fixed.

Conclusions The developed model was able to describe the observed data, while accounting for tumor heterogeneity of CAR-T cells, impact of lymphodepletion regimen on CAR-T expansion and target-mediated expansion of effector CAR-T cells. Using model simulations, CAR-T expansion was found to be driven by initial tumor burden and GPC3 expression.

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