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Building on their research showing that a new form of exciting cancer immunotherapy has activity in patients with glioblastoma, the most common and deadliest form of brain cancer, researchers at Mbadachusetts General Hospital (MGH) have created a new method that could enhance the still effective immune therapy of brain tumors and extend its use against other types of solid tumors. Their study is published in the journal Nature Biotechnology.
The treatment, known as CAR T (chimeric antigen receptor) therapy, involves genetically collecting and modifying the patient's immunosuppressed T cells to recognize specific targets (antigens) on the surface of the tumors, then to return them to the patient. Two CAR T products have been approved by the FDA for the treatment of non-Hodgkin's lymphoma and acute lymphoblastic leukemia, respectively cancers of the lymphatic system and blood.
But solid tumors such as glioblastoma are notoriously difficult to treat with conventional anticancer drugs because most of these drugs contain molecules too big to cross the blood-brain barrier, and immunotherapy poses its own problems in this area. field, says lead investigator Marcela V Maus, MD, PhD, director of cellular immunotherapy at MGH Cancer Center.
"We had previously made CAR T cells for glioblastoma, and one of the challenges of glioblastoma is that not all tumor cells express the target that a T cell can reach," says Maus. , badistant professor of medicine at Harvard. School of Medicine (HMS).
The target target was Epidermal Growth Factor Receptor Variant III (EGFRvIII), a mutant cancer-causing protein, present on the surface of many, but not all, glioblastomas.
Thus, to enhance the effectiveness of CAR T cells, they decided to target a second antigen, the natural or "wild type" of EGFR. But as EGFR is present in many cells of the body, protein-targeting drugs can cause serious side effects. To overcome this toxicity problem, Maus and his colleagues developed a CAR T cell that can be introduced into the cerebrospinal fluid at the base of the brain. When it enters the brain, CAR T then secretes a second type of immunotherapy, called a bi-specific T-lymphocyte revealer, or "BiTE". BiTEs are antibodies that direct killer T cells from cells to a specific target, which is somewhat similar to a head-on mechanism on an "intelligent bomb".
Although they are smaller than the antibody-based drugs, the BiTEs are still too bulky to cross the blood-brain barrier if they are administered intravenously. Therefore, the construction of the BiTE secreting CAR T protein may have a local tumor effect by targeting the second antigen, one way to overcome this tumor heterogeneity and to be able to target two things at once. on the other side of the blood-brain barrier and in small amounts, it does not cause any toxicity to other organs, "explains Maus.
When they tested them on human glioblastoma models, they found that modified TCRs secreting BiTE removed about 80% of the tumors.
The technique is also promising for the treatment of other solid tumors, says lead author Bryan D. Choi, MD, of the Department of Neurosurgery at the US General Hospital.
Researchers say the biggest hurdle they still face in their efforts to integrate research into clinical trials in humans is financial support.
Reference: Bryan D. Choi, et al. CAR-T cells secreting BiTEs bypbad the escape of antigen without detectable toxicity. Nature Biotechnology (2019) DOI: https://doi.org/10.1038/s41587-019-0192-1
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