A homing system targets therapeutic T cells to brain cancer

• Published in: Nature (London) Vol. 561; no. 7723; pp. 331 - 337
• Main Authors: Samaha, Heba, Pignata, Antonella, Fousek, Kristen, Ren, Jun, Lam, Fong W., Stossi, Fabio, Dubrulle, Julien, Salsman, Vita S., Krishnan, Shanmugarajan, Hong, Sung-Ha, Baker, Matthew L., Shree, Ankita, Gad, Ahmed Z., Shum, Thomas, Fukumura, Dai, Byrd, Tiara T., Mukherjee, Malini, Marrelli, Sean P., Orange, Jordan S., Joseph, Sujith K., Sorensen, Poul H., Taylor, Michael D., Hegde, Meenakshi, Mamonkin, Maksim, Jain, Rakesh K., El-Naggar, Shahenda, Ahmed, Nabil
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Nature Publishing Group
• Subjects: 13/51; 13/62; 13/95; 42; 42/34; 42/62; 631/250/2161; 631/67/580; 692/308/2778; 692/699/67/1922; 96; 96/106; 96/31; Adhesion; Anticancer properties; Brain; Brain cancer; Brain diseases; Brain tumors; Cancer; Cancer treatment; Care and treatment; CD6 antigen; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cytotoxicity; Endothelial cells; Endothelium; Extravasation; Homing; Humanities and Social Sciences; Immunotherapy; Intercellular adhesion molecule 1; Intravenous administration; Kinases; Leukocytes; Lymphocytes; Lymphocytes T; Medical schools; multidisciplinary; Multiple sclerosis; Science; Science (multidisciplinary); Sensitizing; Stem cell research; T cells; Tumors; FlowJo Data Analysis Software; Human Brain Microvascular Endothelial Cells (HBMECs); ALCAM Expression; Cancer Endothelium; Activated Leukocyte Cell Adhesion Molecule (ALCAM)
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-018-0499-y

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. Therapeutic T cells bearing ligands engineered to optimize adhesion and transmigration through the blood–brain barrier can be targeted to brain tumours.