PII-219 - QUANTITATIVE CHARACTERIZATION OF ENHANCED TISSUE DISTRIBUTION AND INNATE KILLING POTENTIAL OF UN-ENGINEERED GAMMA DELTA Ɣδ T CELLS USING A MECHANISTIC MODEL

A. Singh¹, D. Desai², G. Mugundu¹; ¹Takeda Pharmaceuticals, ²Center of Pharmacometrics and Systems Pharmacology, University of Florida.

Background: Gamma Delta (Ɣδ) T Cells are currently being evaluated as a therapeutic alternative to traditional alpha-beta (αβ) T-cells due to their superior safety profile and enhanced tissue retention properties. Unengineered ƔδT cells have a T-cell receptor (TCR) and they perform their function via recognition of the antigens. VƔ9Vδ2 represent about 90% of the blood ƔδT cell, and exhibit a strong expression of CCR3, CXCR3 and CCR5 receptor. These cells exhibit their mechanisms via different pathways such as 1) Stimulation of IFN-γ, 2) Reduction of tumor and 3) Indirect mechanisms via Ɣδ T cells for tumor reduction. Within this work, we describe a mechanistic QSP relationship for ƔδT cells in patients.

Methods: Dataset was obtained from multiple myeloma case study where patients (n=5) were dosed at following dose-levels: 0.2-5.2 X 109 cells Ɣδ T cells. Cellular kinetics (CK) was measured in blood and bone marrow compartments and the CK was compartmentalized with following immunophenotypic profiles (Tcm, Tem, Ttd). The current model structure in which the model consists of two compartments blood and peripheral compartments. The model accounts for the processes such as differentiation of central memory cells to effector memory to terminally differentiated cells. The model also accounts for stimulation of IFN-Ɣ which is one of the mechanisms of Ɣδ T cells.

Results: The model was able to adequately capture the reported cellular kinetic dataset for different immunophenotypes of gamma-delta T-cells for both blood as well as the peripheral compartment. Parameters associated within the distribution from peripheral blood to other tissues/site of action revealed enhanced distribution in tissues where distribution clearance (CLd) was estimated to be 0.952 L/d (2.93%). The rate of differentiation for different immunophenotypes of ƔδT cells was estimated to be 0.0951 (6.28%), the EC50 for stimulation of IFN-Ɣ was estimated to be 132 cells/L (40.9%). The distribution as well as the mechanism of action was found to be distinctive in comparison to αβ T cells.

Conclusion: With continued discovery and development along with limited clinical experience with Ɣδ T cells, developed QSP model is expected to bring more mechanistic insights and help understand the dose-exposure-response relationship in patients.