A homing system targets therapeutic T cells to brain cancer

Heba Samaha, Antonella Pignata, Kristen Fousek, Jun Ren, Fong W. Lam, Fabio Stossi, Julien Dubrulle, Vita S. Salsman, Shanmugarajan Krishnan, Sung-Ha Hong, Matthew L. Baker, Ankita Shree, Ahmed Z. Gad, Thomas Shum, Dai Fukumura, Tiara T. Byrd, Malini Mukherjee, Sean P. Marrelli, Jordan S. Orange, Sujith K. Joseph, Poul H. Sorensen, Michael D. Taylor, Meenakshi Hegde, Maksim Mamonkin, Rakesh K. Jain, Shahenda El-Naggar and Nabil Ahmed ()
Additional contact information
Heba Samaha: Children’s Cancer Hospital Egypt-57357
Antonella Pignata: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine
Kristen Fousek: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine
Jun Ren: Massachusetts General Hospital, Harvard Medical School
Fong W. Lam: Baylor College of Medicine
Fabio Stossi: Baylor College of Medicine
Julien Dubrulle: Baylor College of Medicine
Vita S. Salsman: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine
Shanmugarajan Krishnan: Massachusetts General Hospital, Harvard Medical School
Sung-Ha Hong: McGovern Medical School at UT Health
Matthew L. Baker: Baylor College of Medicine
Ankita Shree: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine
Ahmed Z. Gad: Children’s Cancer Hospital Egypt-57357
Thomas Shum: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine
Dai Fukumura: Massachusetts General Hospital, Harvard Medical School
Tiara T. Byrd: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine
Malini Mukherjee: Texas Children’s Hospital
Sean P. Marrelli: McGovern Medical School at UT Health
Jordan S. Orange: Baylor College of Medicine
Sujith K. Joseph: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine
Poul H. Sorensen: University of British Columbia
Michael D. Taylor: Laboratory Medicine and Pathobiology, and of Medical Biophysics, University of Toronto, Toronto
Meenakshi Hegde: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine
Maksim Mamonkin: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine
Rakesh K. Jain: Massachusetts General Hospital, Harvard Medical School
Shahenda El-Naggar: Children’s Cancer Hospital Egypt-57357
Nabil Ahmed: Texas Children’s Hospital, Houston Methodist Hospital and Baylor College of Medicine

Nature, 2018, vol. 561, issue 7723, 331-337

Abstract: Abstract 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.

Keywords: Activated Leukocyte Cell Adhesion Molecule (ALCAM); Cancer Endothelium; ALCAM Expression; Human Brain Microvascular Endothelial Cells (HBMECs); FlowJo Data Analysis Software (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (1)

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DOI: 10.1038/s41586-018-0499-y

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