Here we have investigated whole-body pharmacokinetics (PK) of exogenously administered T cells in a mouse model of
melanoma and have developed a physiologically based pharmacokinetic (PBPK) model to quantitatively characterize the data. T cells were isolated from the spleen of
tumor-bearing mice, activated, and labeled with
chromium-51 to facilitate the quantification. Labeled T cells were injected in the
tumor-bearing mice, and PK was measured in 19 different tissues. It was found that T cells disappear from the blood rapidly after administration and accumulate in the tissues to various extents. Spleen, liver, lung, kidney, bone, and lymph nodes accounted for more than 90% of T cells in the body. The distribution of T cells in solid
tumors was found to be very low, hovering below 1%ID/g (percent of injected dose per gram of tissue) during the entire study. However, this observation may differ for targeted TCR-T and CAR-T cells. Observed PK profiles also suggest that T-cell-based
therapies may be more successful in treating
cancers of the lymphatic system and bone marrow
metastases compared to solid
tumors. A PBPK model was developed to characterize the whole-body PK of T cells, which incorporated key processes such as extravasation, elimination, and recirculation of T cells via lymph flow. Retention factors were incorporated into the spleen, liver, and kidney compartment to adequately capture the PK profiles. The model was able to characterize observed PK profiles reasonably well, and parameters were estimated with good confidence. The PK data and PBPK model presented here provide unprecedented insight into the biodistribution of exogenously administered T cells.