Samaha et al. designed a brain tumor homing system (HS) by engineering T cells to express a multimerized version of the D3 domain of the ALCAM-binding CD6 exodomain together with CD6 transmembrane and signaling endodomains. In a two-step process, HS T cells bind to ALCAM, which is overexpressed on brain tumor endothelial cells, sensitizing the T cells to the downregulated levels of ICAM1 in tumor endothelium and allowing for infiltration of T cells into the tumor. In mice, HER2-targeting CAR 5HS T cells selectively infiltrated the GBM tumor, induced tumor regression, and increased survival compared with HER2 CAR T cells and normal T cells.
Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.
Author Info: (1) Children's Cancer Hospital Egypt-57357, Cairo, Egypt. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Ho
Author Info: (1) Children's Cancer Hospital Egypt-57357, Cairo, Egypt. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. (2) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. (3) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. (4) Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (5) Baylor College of Medicine, Houston, TX, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Center for Translational Research on Inflammatory Diseases at the Michael E DeBakey Veterans Affairs Medical Center, Houston, Texas, USA. (6) Baylor College of Medicine, Houston, TX, USA. Integrated Microscopy Core, Advanced Technology Cores, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. (7) Baylor College of Medicine, Houston, TX, USA. Integrated Microscopy Core, Advanced Technology Cores, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. (8) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. (9) Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (10) Department of Neurology, McGovern Medical School at UT Health, Houston, TX, USA. (11) Baylor College of Medicine, Houston, TX, USA. National Center for Macromolecular Imaging, Baylor College of Medicine, Houston, TX, USA. (12) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. (13) Children's Cancer Hospital Egypt-57357, Cairo, Egypt. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. (14) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. (15) Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (16) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. (17) Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. Center for Human Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. (18) Department of Neurology, McGovern Medical School at UT Health, Houston, TX, USA. (19) Baylor College of Medicine, Houston, TX, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Center for Human Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. (20) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. (21) Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. (22) Developmental and Stem Cell Biology Program, The Arthur and Sonia Labatt Brain Tumour Research Centre, Division of Neurosurgery, Departments of Surgery, Laboratory Medicine and Pathobiology, and of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. (23) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. Houston Methodist Hospital, Houston, TX, USA. Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. (24) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. Texas Children's Hospital, Houston, TX, USA. Baylor College of Medicine, Houston, TX, USA. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA. (25) Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (26) Children's Cancer Hospital Egypt-57357, Cairo, Egypt. (27) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu. Texas Children's Hospital, Houston, TX, USA. nahmed@bcm.edu. Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu. Houston Methodist Hospital, Houston, TX, USA. nahmed@bcm.edu. Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA. nahmed@bcm.edu.
