In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. This study was conducted to test strategies for enhancing efficacy. The researchers adapted the KrasLSL-G12D/+;p53f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1.ACT using autologous T cells modified by gene transfer to express a chimeric antigen receptor (CAR) specific for the CD19 molecule present on both normal B cells and B cell malignancies has shown remarkable success in leukemia and lymphoma (Kochenderfer and Rosenberg. Understanding which barriers interfere most with T cell efficacy in vivo and developing strategies to overcome these obstacles are necessary to achieve reproducible antitumor activity with CAR-T cells. The researchers sought to develop a model that faithfully mimics tumor development and the tumor microenvironment (TME) found in human malignancies to guide clinical strategies for improving the efficacy of T cells in solid tumors. An alternative to transplantable models is to induce malignant transformation in normal cells in situ by introducing defined genetic events. ROR1 is being investigated in a clinical trial as a target for CAR-T cells due to its high expression in a subset of non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC).
As a conclusion, the results showed that robust CAR-T cell expansion in the peripheral blood of three treated patients without toxicity to normal tissues. A tumor biopsy obtained post-treatment from one patient showed few infiltrating ROR1 CAR-T cells by flow cytometry, indicating that CAR-T cells failed to accumulate or persist in ROR1+ tumors.