Understanding the role of CAR design in solid tumor infiltration and intratumoral migration

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Patients with pancreatic ductal adenocarcinoma (PDAC) face a poor prognosis, with only 20% of patients diagnosed with resectable disease, the five-year survival rate is under 10%, and life expectancy for advanced stages is under one year. Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 or BCMA can achieve complete responses in more than 80% of patients with relapsed and refractory acute lymphoblastic leukemia and myeloma. However, attempts to use CAR T cells to target mesothelin (MSLN) for epithelial-derived malignancies like PDAC have shown minimal responses to 2nd-generation chimeric antigen receptor (CAR) T cells. For CAR T cells to be effective in solid tumors, they must overcome physical barriers in the tumor microenvironment (TME), such as leaky or collapsed tumor vasculature and dense extracellular matrix (ECM) from uncontrolled deposition by cancer-associated fibroblasts (CAFs) and other stromal cells. ECM buildup restricts immune cell motility and infiltration, effectively trapping CAR T cells in the stroma, away from tumor nests. These conditions are particularly pronounced in PDAC, where desmoplasia can constitute up to 90% of the tumor mass. CAR design could play a critical role in overcoming these barriers. TCR-CARs and KIR-CARs show enhanced anti-tumor activity in pre-clinical solid tumor models. Unlike traditional 2nd-gen CAR designs, TCR-CARs and KIR-CARs preserve the multichain structure of natural immune receptors, perhaps rescuing T cell adhesion-related function. We hypothesize that KIR-CARs will show enhanced recruitment and migration into tumors, improving solid tumor therapy. By using an adaptable PDAC tumor slice model, this research will compare the infiltration and motility of 2nd-gen, TCR-CAR (TRuC), and KIR-CAR (cKIR/DAP12) T cells for the first time. Lattice light sheet microscopy (LLSM) and multiphoton microscopy will be performed on precision cut tumor slices to analyze 3D tumor infiltration and track T cell migration within tumors, providing insights into how CAR design influences these important functions within tumors. This work aims to reveal mechanisms by which CAR T cells can overcome barriers in solid tumors and improve therapeutic outcomes.

Public health relevance public domain (NIH RePORTER)

NARRATIVE Chimeric interrogate designs will T antigen receptors (CAR) are continuing o evolve, but the field is lacking solid tumor models to their function. The proposed research is an investigation on the influence of different CAR receptor on the tumor infiltration of T cells in the context of pancreatic ductile adenocarcinoma (PDAC). This work be achieved by modeling the tumor microenvironment and using advanced imaging techniques to study CAR cells. t