Pressure enabled drug delivery of anti-CEA CAR-T cells increases intra-hepatic CAR-T tumor penetration and therapeutic index in a murine model of liver metastasis

Abstract

Abstract Introduction We have demonstrated safety and clinical activity with anti-CEA CAR-T (Sorrento/TNK Therapeutics, Inc.) regional infusions for treatment of liver metastases (LM) using a pressure-enabled drug delivery device (PEDD™, TriSalus™ Life Sciences, Inc.) to increase CAR-T penetration. To further explore the potential benefit of PEDD, we developed a pre-clinical murine LM model that enables correlation of infusion pressure with response. Methodology Mice with CEA+ LM were infused with anti-CEA CAR-T into the portal vein with specified rate and pressure levels. Flow cytometry (FC), bioluminescence imaging (BLI), and serum liver function tests (LFTs) were conducted at multiple time points. Results Flow-pressure relationship was established with ΔP of 7.23 mmHg vs 2.33 mmHg (p=0.01) in high-pressure (10 mL/min, HP) and low-pressure (1 mL/min, LP) cohorts. FC assessment of hepatic non-parenchymal cells 1d after infusion demonstrated 15.9% CD3+CAR+ in HP, compared to 5.1% in LP (p=0.0004). Tumor BLI at day 3 (geometric mean relative to baseline) showed significantly enhanced therapeutic effect in HP, −18% relative signal intensity (RSI), compared to +148% RSI in LP (p=0.05) or +178% RSI in controls (p=0.04). LFTs were similar in LP and HP groups with AST 302 vs 437 U/L (p=0.60) and total bilirubin 0.25 vs 0.7 mg/dL (p=0.33), respectively. Conclusions HP delivery correlated with enhanced CAR-T delivery and control of tumor growth, without an increase in liver toxicity. Follow up to this proof of concept study will investigate multiple infusions with combinatorial approaches with the goal of durable tumor eradication. An ongoing clinical study will further explore CAR-T PEDD in patients.