Targeting the extra domain A of fibronectin for cancer therapy with CAR-T cells

• DOI: 10.1136/jitc-2021-004479
• Publication Date: 2022-08-25T15:26:07Z
• Authors: Celia Martín-Otal; Aritz Lasarte-Cia; Diego Serrano; Noelia Casares; Enrique Conde; Flor Navarro; Inés Sánchez-Moreno; Marta Gorraiz; Patricia Sarrión; Alfonso Calvo; Carlos E De Andrea; José Echeveste; Amaia Vilas; Juan Roberto Rodr...; Jesús San Miguel; Felipe Prosper; Sandra Hervas-Stubbs; Juan Jose Lasarte; Teresa Lozano
• Keywords: Jurkat cells; Tumor Antigen

Background One of the main difficulties adoptive cell therapies with chimeric antigen receptor (CAR)-T cells in solid tumors is identification specific target antigens. The tumor microenvironment can present suitable antigens for CAR design, even though they are not expressed by cells. We have generated a splice variant extra domain A (EDA) fibronectin, which highly stroma many types but healthy tissues. Methods EDA expression was explored RNA-seq data from different human and immunohistochemistry paraffin-embedded biopsies. Murine anti-EDA CAR-T were prepared using recombinant retro/lentiviruses, respectively. functionality measured vitro response to stimulation. antitumor activity vivo C57BL/6 mice challenged PM299L-EDA hepatocarcinoma line, 129Sv mice-bearing F9 teratocarcinoma NSG injected line PLC. Results recognized killed EDA-expressing lines rejected immunocompetent mice. Notably, showed an effect EDA-negative when or basement membrane endothelial express EDA. Thus, administration delayed growth F9. treatment exerted antiangiogenic significantly reduced gene signatures associated epithelial-mesenchymal transition, collagen synthesis, extracellular matrix organization as well IL-6-STAT5 KRAS pathways. Importantly, version CAR, that includes 41BB CD3ζ endodomains, strong PLC, expresses vasculature. exhibited tropism tissue no toxicity observed bearing Conclusions These results suggest targeting tumor-specific fibronectin feasible offers therapeutic option applicable cancer.