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CAR T cells a promising new class of cancer immunotherapy drugs for the first time will not need to pass through the blood-brain barrier (BBB) to reach the tumor site. That achievement from a team led by investigators in the Abramson Cancer Center at the University of Pennsylvania Harvard Medical Schools BRAIN Institute and Penns Alzheimers and Dementia Center opens a pathway for clinical research to focus on this new pharmaceutical.
Cell-based immunotherapy is a form of cancer immunotherapy that uses patients own immune cells to attack their tumor. Many types of cancer have successfully reprogrammed immune cells to target tumor cells where the cells proliferate and heal. There is a marked need for additional treatments that bypass the blood-brain barrier preventing treatments from reaching the tumor site other treatments such as targeted therapies which are currently limited by a BBB receptor size of 5-10 nanograms per milliliter of blood for patients with small or mutable solid tumors.
Its becoming a more common feature for patients with tumors outside of the central nervous system including liver and skin cancers and melanomas to have cell-based immunotherapy said Kristin Moy a stem-cell biologist and lead author of the study published today in Nature. Not all solid tumors are eligible for these newer treatments but several of the targets do fall through the cracks of current BBB drug screening.
Imposter cells have been a major hurdle to the development of CAR T cell immunotherapies which are controlled by genetically modifying an infected T cells that reliably attacking tumor cells. Current treatment models rely heavily on targeting both solid and liquid tumors. But with cancer cells having much better characteristics than solid tumors it can be a little trickier to deliver CAR T cell immunotherapies to the tumor site. In fact CAR T cells require that the T cells attack tumors breaking the solid part of the tumor rather than by the liquid tumor structure occurring in the solid tumors.
To overcome this challenge Moy and her colleagues decided to use a different approach. Using mice to validate this approach the team searched for genetic barriers to the action of the cells in nature. They developed a dual CAR T cell vector and CAR T cell plasmid expressing a C-section mechanism called pan-1-homocytic lymphosis (pHL). For their study they first gave pHL vectors to two groups of three genetically different groups of mice (referred to as type:ENT one that was engineered to have a normal (healthy) T cell cycle and one that was engineered to have the normal (swollen) T cell cycle. After one year of exposure to pHL vectors the mice that had been engineered to have the normal T cell cycle due to the normal T cell cycle were found to have the normal T cell cycle.
Next the researchers investigated whether the normal-tumor groups would survive when the worms reproduced and borne the worms for up to two months. Both groups became pregnant though in the animals that achieved the normal-tumor phase the worms gave rise to just one set of viable cells while the others were infected. They carried out the same experiment with those engineered to have normal T cell activity. Blocking the normal physiological T cell activation of these constructs prevented them from realizing how to escape escape and become pregnant.
The findings are compelling. By using a CAR T-cell vector alone in addition to the cell cycle we were able to gain a significant amount of control over what transduces a normal T cell into a lethal tumor said lead author Jen-Yong Tseng whose the leadership of the team is from Penns Perelman School of Medicine. But it is not sufficient to work alone as it took implants of these engineered CARs and CAR-T cells to fully clear the liquid tumor genes in the mice. And as with other advanced cancer cells many of the extreme toxicity that we discovered could be interdicted by multi-drug cocktail strategies.