CAR-T cell therapies infused into brain shrink tumors in two glioblastoma studiesRyan CrossSenior Science Correspondent
Two groups of researchers say that experimental CAR-T cell therapies have shrunk tumors in a matter of days in patients with recurrent glioblastoma, a deadly brain cancer, who got a single infusion of the engineered cells directly into their heads earlier this year.Both teams treated patients whose cancer came back despite previous treatments like chemotherapy, radiation and surgery, and many had multiple tumors scattered throughout their brains. The interim results from the two ongoing Phase I studies for just three patients each were presented Sunday at the Society for NeuroOncology’s annual meeting in Vancouver.Donald O’RourkeIn interviews with Endpoints News, researchers from the University of Pennsylvania and the Mass General Cancer Center stressed that more data are needed. But in glioblastoma, which has an average survival time of roughly 15 months after initial diagnosis, the researchers were shocked to see the treatments reduce tumors just one to three days after infusions this summer and fall. The engineered immune cells are keeping cancer at bay in most patients thus far.“I’ve seen everything. And this is the best stuff I’ve seen in my career,” said Donald O’Rourke, a neurosurgeon at the University of Pennsylvania who has treated glioblastoma patients for 25 years. “These are the kind of patients that wouldn’t be expected to stabilize.”advertisementadvertisementThe three patients in the UPenn study were on their third recurrence and had multiple tumors throughout their brains. All three patients are still alive, and two are stable roughly five and three months post-treatment. Two of the three patients in the Mass General study are still stable, one for four months so far. The third patient’s cancer has resurged.“The effects are dramatic and very rapid. And it’s something that we really don’t see in any form of treatment,” said Bryan Choi, a neurosurgeon at Mass General Cancer Center in Boston. “But it’s too early to tell what the durability of this treatment will be. And that is one of the most important questions.”An eye on safetyThe UPenn treatment was previously licensed to Tmunity Therapeutics, a biotech co-founded by CAR-T pioneer and UPenn researcher Carl June. Kite, the cell therapy subsidiary of Gilead Sciences, announced plans to acquire Tmunity at the end of last year, following a reorganization of the startup in 2021 when neurotoxicity from a previous CAR-T therapy killed patients. The deal closed in February.Bryan ChoiO’Rourke said patients in the new UPenn study experienced temporary neurological side effects known as TIAN for tumor inflammation-associated neurotoxicity, which is when inflammation in the brain can cause problems with speech or movement. Choi said his team also saw a “fairly robust” inflammatory syndrome a few days after infusion.But both groups said the symptoms resolved within a few days to a week, and both reported using the immunosuppressive drug anakinra to manage the symptoms. Neither team reported any dose-limiting toxicities in the trials.O’Rourke said there are about 20 patients in the queue who have had their T cells collected after an initial glioblastoma diagnosis and treatment. When the cancer recurs, as it almost always does in glioblastoma, they will get the cell therapy.The Mass General study could enroll roughly 20 people, too, and Choi hopes to eventually give patients the treatments even earlier — when their tumors are first detected.A two-pronged approachCommercial cell therapies for blood cancers all use a single chimeric antigen receptor, or CAR, to target a protein on the surface of blood cells to destroy them. However, scientists believe that a more sophisticated approach may be required for killing solid tumors, which are often a hodgepodge of mutant cells that make it difficult to hit them all with a single CAR.“No two cells in a brain tumor are alike,” Choi said. “So you have to find a way to battle that.”Marcela MausEach group designed their therapies to land a one-two punch against brain cancer. UPenn’s cells include two CAR molecules that target EGFR and IL13Ra2, proteins with strong links to glioblastoma, with the goal of hitting a broader swathe of the tumor.Mass General’s cell therapy, designed by Choi and researcher Marcela Maus, uses a CAR to take aim at a common mutant form of EGFR called EGFRvIII, using it as a homing beacon to attract the engineered cells to attack the cancer.Once there, the cells release a bispecific antibody that targets regular EGFR, recruiting immune cells to pile on to the rest of the tumor. Choi hopes this approach will “circumvent” potential toxicity by targeting EGFR more directly since the protein is found throughout the body.The team used a kind of bispecific antibody that Amgen calls a BiTE for bispecific T cell engager. But Choi and Maus said they got a cease-and-desist letter from Amgen to stop using the trademarked term after testing the approach in mice. They’ve since taken to calling the drug a T cell engaging antibody molecule, or TEAM
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