Microengineered transplantation of human solid tumors for in vitro studies of CAR T immunotherapy

Treatment of solid malignancies using chimeric antigen receptor (CAR) T
cells remains a significant challenge, but current efforts to advance this
therapy are challenged by our limited capacity to probe and understand
cancer-immune interactions in human solid tumors. Here, we present a
microengineered platform for in vitro modeling of malignant solid tumors
during CAR T therapy. This system makes it possible to vascularize human
tumor explants and perfuse them with blood-borne immune cells in a
controlled manner. We first present a microphysiological model of human
lung adenocarcinomas infused with CAR-T cells and show how this system can
be used to simulate, visualize, and interrogate tumor-directed trafficking
and effector function of CAR T cells. We then demonstrate the
proof-of-principle of testing a chemokine-directed CAR T cell engineering
strategy in a model of malignant pleural mesothelioma and validating our
in vitro assessment using a matching in vivo mouse model. Finally, we
describe a potential therapeutic target discovered by single-cell RNA
sequencing that can be pharmacologically modulated to increase the
efficacy of CAR T cells for lung adenocarcinoma, for which we also present
specific biomarkers identified by global metabolomics analysis. We believe
that the bioengineering principle demonstrated here will make important
contributions to developing new capabilities for preclinical studies of
adoptive cell therapies for cancer and other complex diseases.