PII-003 - INTEGRATED CELLULAR KINETIC (CK) – PHARMACODYNAMIC (PD) ANALYSIS FOR FIRST IN HUMAN DOSE-ESCALATION STUDY OF TAK-102: A GPC3 TARGETED AUTOLOGOUS CAR-T CELLS ARMORED WITH IL-7 AND CCL19.

A. Singh¹, A. Okal¹, H. Kagehara², A. Dey³, T. Koyama⁴, Y. Kuboki⁵, T. Akaike², P. Pop-Damkov¹, J. Markman¹, J. Zhang¹, G. Mugundu³; ¹Takeda Development Center Americas, Inc., Cambridge, MA, USA, ²Takeda, Osaka, Japan, ³Takeda Development Center Americas, Inc., Lexington, MA, USA, ⁴National Cancer Center Hospital, Tokyo, Japan, ⁵National Cancer Center Hospital East, Kashiwa, Japan.

Background: TAK-102 is a GPC3 targeted CAR-T cell therapy armored with interleukin (IL)-7 and chemokine (C-C motif) ligand 19 (CCL19) to promote migration and proliferation in immunosuppressive tumor microenvironment (1). This abstract discusses interim clinical pharmacology datasets.

Methods: Phase-1 study (NCT04405778) is implementing BOIN design (2) and enrolling patients with GPC3-expressing solid tumors relapsed or refractory to standard treatments. As of September 8, 2022, 4 patients were enrolled and infused with TAK-102 at 10 million (C1, n=3) and 100 million (C2, n=1) CAR+ cells respectively. TAK-102 CK is quantified using flow cytometry and ddPCR assays.

Results: TAK-102 CK revealed a dose-dependent increase in peak expansion (Cmax: 606.3 (± 510.1, C1) c.f. 36006.1 (C2) Copies/µg gDNA) & persistence (Tlast: 12.3 (±4.2, C1) c.f. 90 (C2) days). The CAR+ CD4:CD8 ratio declined in the peripheral blood in patients with higher GPC3 expression (C1-03, C2-01), and trended with CK reflecting higher expansion of CAR+ CD8+ T-cells. Pre/post treatment paired biopsies for patient C1-03 revealed increased tumor infiltration of activated endogenous T-cells. Kinetics of certain cytokines (e.g., IL-7, IL-15) correlated with nadir of WBCs post lymphodepletion, whereas others (e.g., interferon-g, IL-12/-23p40 and IL-10) correlated with peak TAK-102 expansion (Cmax). Changes in sum of target lesions (based on RECIST 1.1 criteria) showed dependency on CK (Cmax, Tlast) and GPC3 expression, in two patients (C1-03, C2-01) who achieved stable disease.

Conclusion: TAK-102 demonstrated favorable expansion and persistence characteristics at lower doses c.f. comparators (3). The interim CK-PD dataset(s) support further clinical development and will be integrated within a QSP model to answer key scientific questions.

1. Adachi, K. et al. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat. Biotechnol. 36, 346–351 (2018).

2. Yuan, Y. Hess, KR. Hilsenbeck, SG. Gilbert, MR. Bayesian Optimal Interval

Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin. Cancer. Res. 22, 4291–4301 (2016).

3. Shi, D. et al. Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials. Clin. Cancer. Res. 26, 3979–3989 (2020).