[ad_1]
A multi-institutional international team led by researchers at Baylor College of Medicine has come up with a new strategy to overcome one of the key barriers to treating brain cancer: access to the tumor.
Under the influence of cancer, the blood-brain barrier diverts immune T cells that try to enter the brain to fight the tumor. The new discovery, published in the journal
Nature
, decodes the molecular cause of this immune release mechanism and designs T cells with a first-class molecule called Homing System, which allows T cells to cross the blood-brain barrier of impermeable cancer to effectively fight tumors.
"T cell immunotherapy is a promising emerging area in clinical trials on cancer and other diseases," said Dr. Nabil Ahmed, senior author and associate professor of pediatrics at the Cell Therapy Center and Genetics of Baylor College of Medicine. "However, the effective return of therapeutic T cells to the target site remains a major limiting factor, particularly for brain tumors."
In this study, Heba Samaha, principal investigator of Children's Cancer Hospital Egypt-57357 and the research team described a previously unknown "escape mechanism" for cancer cells to divert T cells from brain tumors. They genetically modified the T cells to give them the molecular keys they needed to overcome these obstacles and cross this barricade into the tumor.
To understand what prevented T cells from crossing the blood-brain barrier, Ahmed and his colleagues looked at diseases in which T cells have access to the brain, especially multiple sclerosis.
"We thought that if we could understand how T cells in multiple sclerosis were able to infiltrate the brain, we could probably design therapeutic T cells to cross the blood-brain barrier and infiltrate brain tumors at very high density," he said. said Ahmed. He is also a member of the Dan L Duncan's Comprehensive Cancer Center of Baylor and the Children's Cancer and Hematology Centers of Texas Texas Children's Hospital.
A healthy blood-brain barrier has some characteristics that help protect the brain by preventing a number of cells and molecules from accessing it. In diseases such as multiple sclerosis, the blood-brain barrier changes and, therefore, the immune cells mediating the disease gain preferential access and cause the disease by destroying the protective lining of the nerves.
On the other hand, in the case of brain cancer, the study team discovered that, in order to escape the death of the tumor, the blood-brain barrier blocked access to specialized T cells in the destruction of the tumor. Specifically, Samaha and colleagues investigated changes in the cancer-associated blood-brain barrier that limit T-cell access to the tumor and developed a strategy to overcome them.
Homing T cells on brain tumors
In multiple sclerosis, access to the blood-brain barrier follows a sophisticated and well-coordinated process. First, T cells engage ALCAM, an adhesion molecule overexpressed on the surface of the endothelium of the blood-brain barrier, loosely connecting the T-cell to the T-cell. Endothelium in what is called the primary adhesion wave. The crossover requires that the T cells detect a "secondary adhesion wave" created by more ubiquitous molecules, primarily ICAM-1 and VCAM-1, to reach the "tight" adhesion threshold necessary to capture the T cells of the bloodstream.
"When we examined the blood-brain barrier in brain cancer, we found that, similarly to multiple sclerosis, the endothelium-associated cancer also overexpressed ALCAM, but that it was not the same. it reduced ICAM1 and eliminated VCAM1. This has probably helped to escape the immune recognition of the tumor by diverting T cells from the tumor, "Samaha said.
As a result, the researchers felt that if they could enhance T-cell binding to ALCAM by reconfiguring its natural binding protein on T cells, CD6, they could create enough contact between T cells and the endothelium for stalemate of the brain barrier.
"The redesigned CD6 molecule works as a" reference system ". It enhances T-cell binding to ALCAM on the endothelium and also enhances the sensitivity of T cells to reduced levels of ICAM1 on blood vessels associated with cancer, "said Ahmed. "As a result, the endothelial cell interaction of T-cell cancer allowed the capture of circulating T cells and their passage through the endothelium to robustly infiltrate glioblastoma and medulloblastoma, the brain cancers more common in adults and children. "
To test whether improved access would allow Homing System-T cells to better fight brain cancer, researchers have equipped these T cells with chimeric antigen receptors (CARs), molecules that can guide T cells to specific cancers. They administered intravenously these Homing-modified T cells and CAR to mice with established human glioblastoma and measured tumor growth.
"The results have been very encouraging," said Samaha. "We observed that T cells with the Homing system and CAR significantly reduced tumors in all treated animals. In contrast, T cells without the Homing system were misdirected on the tumor and thus only transiently slow tumor growth. More importantly, Homing System-T cells were strictly directed to the tumor sites, but not the normal brain or other normal body tissues.
"Next, we will test the Homing System platform as part of clinical trials and simultaneously design next-generation Homing System molecules for targeted delivery of therapeutic or diagnostic cells to other diseases," he said. said Ahmed. "We anticipate that the Homing System platform could be a gateway to brain pathologies, including inflammation and cancer."
Source link
