CYBERSPACE – At the virtual annual meeting of the American Society of Gene and Cell Therapy, CAR T cells were the subject of both historical overviews and cutting-edge research alike.
In the opening plenary session, CAR T pioneer Michel Sadelain, director of the center for cell engineering at Memorial Sloan Kettering Cancer Center, recalled that the first report of engineered T cells was presented “to basically no interest at all,” considered a scientific curiosity more than a potential underpinning of a major therapeutic advance. The interest has certainly come, along with FDA approvals and an arms’ length of accolades for CAR T pioneer Carl June, director of the Center for Cellular Immunotherapy at the Perelman School of Medicine and the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania.
On Wednesday, June gave the George Stamatoyannopoulos Memorial Lecture, taking his audience on a tour of CAR T that ranged from their first clinical forays as potential anti-HIV therapies through the 2017 approvals of Kymriah (tisagenlecleucel, Novartis AG), which June co-developed, and Yescarta (axicabtagene ciloleucel, Gilead Sciences Inc.) through his team’s most recent feat – the first clinical use of CRISPR-edited T cells, which June and colleagues reported in Science earlier in 2020.
In that paper, June and his colleagues reported on editing T cells of three patients to remove their endogenous T-cell receptors and the checkpoint molecule PD-1, and adding a T-cell receptor that recognized the tumor antigen NY-ESO-1.
The NY-ESO-1 transduced CRISPR 3X edited (NYCE) cells persisted for up to nine months, “suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy,” the authors wrote.
In an accompanying editorial, CRISPR pioneer Jennifer Doudna and co-author Jennifer Hamilton called the results “an important advance in the therapeutic application of gene editing [that] highlight the potential to accelerate development of cell-based therapies.”
Gene editing, especially at multiple locations, could further expand the utility of engineered T cells. There are multiple edits that might improve safety and or efficacy. In his lecture at ASGCT, June highlighted neurotoxicity as possibly amenable to an editing approach.
Along with cytokine release syndrome, cerebral edema has been among the potentially life-threatening complications of CAR T cells. In 2016, Juno Therapeutics abandoned the development of its BCMA-targeting JCAR-015 after five patients in the trial died of cerebral edema.
Multiple explanations have been suggested, and at the ASGCT meeting, the University of Geneva’s Denis Migliorini reported a new possible culprit: the expression of the supposedly B-cell-specific marker CD19 on pericytes, the cells that line the blood-brain barrier.
The team made their discovery by looking at single-cell RNA sequencing data from brain cells. That sequencing, Migliorini said, revealed “a small population” of cells that co-expressed CD19 and CD248, which is a pericyte marker, but did not express other B-cell markers.
The team confirmed their finding by sequencing cells from looking at human tissue from patients undergoing brain surgery, where they found what Migliorini termed fairly “robust” expression of CD19. Subsequent work showed that in animal studies, CD19-targeting CAR T cells with a 28z co-stimulatory domain appeared to cause the most blood-brain barrier disruption.
CD19 expression on pericytes is probably not the only reason that patients suffer cerebral edema. As Massachusetts General Hospital’s Marcela Maus pointed out in the lively virtual Q&A following Migliorini’s presentation, cerebral edema usually resolves within a few days, even as CAR T cells in the same patients can survive for years.
But the syndrome could possibly be reduced by “detargeting” T cells from the brain, June suggested in his overview. The multiple sclerosis drug Gilenya (fingolimod, Novartis AG), for example, works by keeping T cells out of the brain. There are gene editing strategies that could achieve the same effect, June said – “if you had a patient where you were confident [they had] no CNS disease.”