03:54 PM Abstract No. 322 Intratumoral delivery of immunotherapeutics: optimizing drug delivery for improved treatment efficacy

Abstract

Immunotherapy is a paradigm-shifting advance in cancer care, but the overall response rates remain low. There has been a renaissance in the concept of promoting the immune-responsiveness of the tumor immune microenvironment via intratumoral (IT) delivery of immunostimulatory agents. However, the optimal method for IT delivery of such medications that maximizes IT dispersion while minimizing perilesional leakage and systemic distribution is unknown. The purpose of this study was to characterize IT drug distribution and its influence on drug efficacy using conventional end-hole needles (EHNs) versus multi-sidehole needles (MSHN). Syngeneic McArdle RH-7777 hepatoma cells were implanted in the flank of female Buffalo rats (n=20). Once tumors reached 15-20mm in size, 500 uL of iohexol was injected at 100 uL/second under ultrasound visualization using either a 22G EHN (Becton Dickinson) or a 21G MSHN (ProFusion®, Cook Regentec). In-line pressure measurements were obtained during injections (CompassCT®, Cook Regentec). Intratumoral distribution of iohexol was quantified using micro-CT. Next, we performed intratumoral injections of a STING agonist (50 ug ML RR-S2 CDA, Sigma) using either an EHN or MSHN. Tumor tissue was harvested at 24 and 48 hours post-injection. MicroCT imaging demonstrated a greater than 3-fold increase (14.6% ± 1.7 vs 3.4% ± 1.4, P = 0.008) in the percentage of tumor containing iohexol with MSHN versus EHN. The peak IT pressure during the injection was significantly lower with MSHN versus EHN (115 vs 310 mm Hg, P < 0.01). There was an inverse correlation between peak IT pressure and volume of distribution within the tumor (r = -0.7, P = 0.02). The increased IT distribution using the MSHN translated into greater tumor necrosis upon injection of the STING agonist. At 24 and 48 hours post-injection, tumor viability was the lowest in MSHN injected tumors compared to EHN and saline-only injection (37%, 57%, and 81%, respectively at 24 hours and 32%, 54%, and 82% at 48 hours). IT delivery technique has a significant impact in the distribution of drug within a tumor, and optimizing drug distribution has the potential to improve treatment response.