Surmounting the obstacles that impede effective CAR T cell trafficking to solid tumors

Abstract

Innovative immunotherapies based on immune checkpoint targeting antibodies and engineered T cells are transforming the way we approach cancer treatment. However, although these T cell centered strategies result in marked and durable responses in patients across many different tumor types, they provide therapeutic efficacy only in a proportion of patients. A major challenge of immuno-oncology is thereby to identify mechanisms responsible for resistance to cancer immunotherapy in order to overcome them via adapted strategies that will ultimately improve intrinsic efficacy and response rates. Here, we focus on the barriers that restrain the trafficking of chimeric antigen receptor (CAR)-expressing T cells to solid tumors. Upon infusion, CAR T cells need to home into malignant sites, navigate within complex tumor environments, form productive interactions with cancer cells, deliver their cytotoxic activities, and finally persist. We review the accumulating evidence that the microenvironment of solid tumors contains multiple obstacles that hinder CAR T cells in the dynamic steps underlying their trafficking. We focus on how these hurdles may in part account for the failure of CAR T cell clinical trials in human carcinomas. Given the engineered nature of CAR T cells and possibilities to modify the tumor environment, there are ample opportunities to augment CAR T cell ability to efficiently find and combat tumors. We present some of these strategies, which represent a dynamic field of research with high potential for clinical applicability.

Keywords: T cell trafficking; cancer immunotherapy; chimeric antigen receptor engineering; extracellular matrix; motility; tumor microenvironment.