A new strategy to overcome one of the main obstacles in the treatment of brain cancer — access to the tumor - has been developed by an international team led by researchers at Baylor College of Medicine.
Under the influence of cancer, the blood-brain barrier diverts immune T cells that attempt to enter the brain to fight the tumor. This new discovery decodes the molecular cause of this immune escape mechanism and engineers T cells with a first-in-class molecule called Homing System that enables the T cells to cross the impervious cancer blood-brain barrier to effectively fight tumors.
“T cell immunotherapy is an emerging field that has shown promise in clinical trials for cancer and other conditions. However, effective homing of therapeutic T cells on the target site remains a major limiting factor, especially for brain tumors,"
said senior author Dr. Nabil Ahmed, associate professor of pediatrics at the Center for Cell and Gene Therapy at Baylor College of Medicine.
Infiltrating Brain Tumors
Heba Samaha, the lead researcher, and the study team described a previously unknown ‘escape mechanism’ used by cancer cells to divert T cells from brain tumors. They accordingly genetically-engineered T cells to give them the molecular keys they needed to overcome this obstacles and cross this barricade into the tumor.
To understand what was preventing the T cells from crossing the blood-brain barrier, Ahmed and his colleagues looked into diseases in which T cells are granted access into the brain, specifically multiple sclerosis.
“We reasoned that if we could understand how T cells in multiple sclerosis succeeded at infiltrating the brain, then we could probably engineer therapeutic T cells to cross the cancer blood-brain barrier and infiltrate brain tumors in very high density,"
said Ahmed, who also is a member of the Dan L Duncan Comprehensive Cancer Center at Baylor and the Texas Children’s Cancer and Hematology Centers at Texas Children’s Hospital.
A healthy blood-brain barrier has certain characteristics that allow it to protect the brain by preventing a number of cells and molecules from getting access to it. In diseases such as multiple sclerosis, the blood-brain barrier changes and, consequently, disease-mediating immune cells are granted preferential access and cause the disease by destroying the protective covering of nerves.
In contrast, in brain cancer the study team found that, to evade the tumor’s demise, the blood-brain barrier blocks access to T cells that specialize in destroying the tumor. Specifically, Samaha and her colleagues investigated the changes in the cancer-associated blood-brain barrier that limit the T cells' access to the tumor and developed a strategy to overcome them.
Homing T Cells
In multiple sclerosis, access through the blood-brain barrier follows a sophisticated well-concerted process.
First, T cells engage ALCAM, an adhesion molecule overexpressed on the surface of the endothelium of the blood-brain barrier, loosely tethering the T cell to the endothelium in what is referred to as the “primary adhesion wave.” After binding ALCAM, successful crossing requires that T cells sense a “secondary adhesion wave” created by more ubiquitous molecules, predominantly ICAM-1 and VCAM-1, to reach the ‘tight’ adhesion threshold needed to capture T cells from the bloodstream.
“When we looked at the blood-brain barrier in brain cancer we found that, in a way similar to multiple sclerosis, the cancer-associated endothelium also overexpressed ALCAM, but by contrast, it reduced ICAM1 and eliminated VCAM1. This likely contributed to the tumor’s escape from immune recognition by diverting T cells from the tumor,"
Consequently, the researchers reasoned that if they could strengthen the binding of T cells to ALCAM by re-engineering its natural binding protein on T cells, CD6, they might be able to create enough contact between T cells and the endothelium to overcome the blood-brain barrier impasse.
“The re-engineered CD6 molecule works like a ‘homing system.’ It strengthened T cell binding to ALCAM on the endothelium and also enhanced T cell sensitivity to the reduced levels of ICAM1 on the blood vessels associated with cancer. As a result, the T cell-cancer endothelium cell interaction mediated the capture of circulating T cells and their crossing across the endothelium to robustly infiltrate glioblastoma and medulloblastoma, the most common brain cancers in adults and children, respectively,"
To test whether having improved access would enable Homing System-T cells to better fight brain cancer, the researchers equipped these T cells with chimeric antigen receptor (CAR), molecules that can direct the killing capacity of T cells toward specific cancers. They administered these Homing System- and CAR-modified T cells intravenously to mice carrying established human glioblastoma and measured tumor growth.
“The results were very encouraging. We observed that T cells with both the Homing System and CAR substantially shrunk tumors in all treated animals. In contrast, T cells without the Homing System homed poorly on the tumor and thus only transiently slowed down tumor growth. Rather importantly, Homing System-T cells were strictly directed to tumor sites, but not normal brain or other normal body tissues,"
“Next, we will test the Homing System platform in clinical trials and simultaneously engineer next-generation Homing System molecules for the targeted delivery of therapeutic or diagnostic cells to other diseases. We anticipate that the Homing System platform could be a gateway into brain pathologies, including both inflammation and 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 & Nabil Ahmed A homing system targets therapeutic T cells to brain cancer Nature 05 September 2018
Image: Human brain cancer stem cells treated with graphene, SEM. Credit: Izzat Suffian, Pedro Costa, Stephen Pollard, David McCarthy & Khuloud T. Al-Jamal. CC BY