Next generation CAR T cells: Carl June
CAR T pioneer Carl June (USA) explained that CAR persistence and proliferation correlates with treatment response. “The failure of CAR T cells to expand explains failure in most cases,” he said. June discussed how his research group is exploring inhibition or disruption of the Tet2 enzyme (involved in stem cell renewal) as a route to enhance proliferation and thus improve CAR T cell therapy in elderly patients.
June also summarized the results of clinical trials with CD19-directed CAR T cell therapy in ALL and CLL patients. The CLL response rates were much lower than in ALL patients, with 21-29% complete remission rates. Adding Ibrutinib to the CAR T therapy appears to result in increased safety and substantially better efficacy in CLL patients. “So, the summary of this is that it is feasible; it is actually better tolerated than the CAR alone,” said June. In AML, he discussed CD33-directed CAR T, including a trial with dual engineered CD33 CAR T cells and CD33-deleted hematopoietic stem cells.
Other topics addressed by June include pediatric ALL, toxicities of Car T cell therapy, mechanisms of resistance to CD19 CAR T, combing CAR T and BiTEs, and pharmacology & pharmacodynamics of the therapy. “Importantly, autologous CAR T cells are inherently safe. We now have more than 1700 years of patient safety data on the patients and not a single case of transformed T cells. So, they can persist long-term, but the rate of transformation is much less than it is if you give patients chemotherapy.”
June also discussed genome editing tools. He presented the NYCE trial, which uses CRISPR/Cas9 to knock out genes in T cells, with the aim to generate checkpoint resistant T cells. “Checkpoint blockade causes autoimmunity in all organs and I think potentially therapy with CAR T cells and T cell receptor engineered cells will as well,” he said. June’s laboratory is testing if removing the endogenous T cell receptor will reduce autoimmunity and epitope spreading after adoptive transfer.
Professor June’s keynote lecture can be found here: