Determinants of Intraparenchymal Infusion Distributions: Modeling and Analyses of Human Glioblastoma Trials

Abstract

Intra-parenchymal injection and delivery of therapeutic agents have been used in clinical trials for brain cancer and other neurodegenerative diseases. The complexity of transport pathways in tissue makes it difficult to envision therapeutic agent distribution from clinical MR images. Computer-assisted planning has been proposed to mitigate risk for inadequate delivery through quantitative understanding of infusion characteristics. We present results from human studies and simulations of intratumoral infusions of immunotoxins in glioblastoma patients. Gd-DTPA and 124I-labeled human serum albumin (124I-HSA) were co-infused with the therapeutic, and their distributions measured in MRI and PET. Simulations were created by modeling tissue fluid mechanics and physiology and suggested that reduced distribution of tracer molecules within tumor is primarily related to elevated loss rates computed from DCE. PET-tracer on the other hand shows that the larger albumin molecule had longer but heterogeneous residence times within the tumor. We found over two orders of magnitude variation in distribution volumes for the same infusion volumes, with relative error ~20%, allowing understanding of even anomalous infusions. Modeling and measurement revealed that key determinants of flow include infusion-induced expansion and loss through compromised BBB. Opportunities are described to improve computer-assisted CED through iterative feedback between simulations and imaging.

Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma

“…Although one solution may be direct intracranial delivery of agents, this highly invasive approach will not be suitable for all patients and faces significant challenges in achieving equal and persistent drug distribution throughout the tumor (33,45,46). Another potential approach may be the use of ex vivo activated autologous T cells combined with T cell engaging therapies.…”

Convection Enhanced Delivery in the Setting of High-Grade Gliomas

“…Fluorouracil, carmustine, cisplatin, and doxorubicin could be delivered in large volumes when administered into relatively isotropic tissue, while paclitaxel and methotrexate were able to cover enlarged regions upon delivery into anisotropic tissues [ 62 ]. Similarly, Brady et al modelled parenchymal fluid mechanics using simulations of intra-tumoral infusions in GBM patients, measuring distributions of traced compounds with MRI and positron emission topography (PET) [ 63 ]. From this, they confirmed that convection dominates over effects of diffusion in the context of biological agents or protein-sized molecules delivered by CED despite very small fluid speeds.…”

“…Specifically, expansion of WM was found to significantly raise its hydraulic conductivity, making the tissue less anisotropic. This suggests that shunting of infusions in WM tracts is not primarily due to anisotropy of the neuronal fibers, but rather due to their expandability that permits conductivity to increase dramatically [ 63 ].…”

Convection Enhanced Delivery in the Setting of High-Grade Gliomas

“…Fluorouracil, carmustine, cisplatin, and doxorubicin could be delivered in large volumes when administered into relatively isotropic tissue, while paclitaxel and methotrexate were able to cover enlarged regions upon delivery into anisotropic tissues 57 . Similarly, Brady et al modelled parenchymal fluid mechanics using simulations of intra-tumoral infusions in GBM patients, measuring distributions of traced compounds with MRI and positron emission topography (PET) 58 . From this, they confirmed that convection dominates over effects of diffusion in the context of biological agents or protein-sized molecules delivered by CED despite very small fluid speeds.…”

“…Specifically, expansion of WM was found to significantly raise its hydraulic conductivity, making the tissue less anisotropic. This suggests that shunting of infusions in WM tracts is not primarily due to anisotropy of the neuronal fibers, but rather due to their expandability that permits conductivity to increase dramatically 58 .…”