Improving CAR T persistence
CAR persistence and proliferation correlates with treatment response. CAR T cell therapy may fail if the CAR T cells do not engraft and persist. “The failure of CAR T cells to expand explains failure in most cases,” said CAR T pioneer Carl June. Therefore, scientists are developing strategies to promote persistence of CAR T cells in the patient’s body. For instance,
- Claire Roddie (UK) presented ‘CATCARs’ that were developed by scientists at UCL. In CATCARs, the CD19-binding motif is CAT instead of the gold standard FMC63. CAT has a lower binding affinity and more physiological binding kinetics than FMC63. Two trials (CARPALL in pediatric patients and ALLCAR19 in adults) are currently testing if CAT CARs result in better engraftment & persistence and reduced toxicity.
- The choice of costimulatory domain in the CAR T molecule affects persistence, with 4-1BB and OX40 showing better persistence than CD28 (mentioned by Claire Roddie, Carl June, Peihua Lu, and others).
- Carl June (USA) showed that his group is exploring inhibition or disruption of the Tet2 enzyme (involved in stem cell renewal) as a route to improve CAR T cell therapy in elderly patients.
- Mohamad Mohty mentioned that combining CAR T cells with immune checkpoint inhibitors may improve the duration of the response.
- Stanley Riddell (USA) presented the molecular mechanisms that may underlie the superior persistence that is observed with 4-1BB CARs compared to CD28 CARs. The latter have more effective function and expand more rapidly, but they have a propensity to exhaust. Riddell’s group introduced mutations in the Lck binding domain of CD28, toning down the signaling of these receptors. These mutated CD28 appears to be more effective.
- CAR T pioneer Michel Sadelain (USA) discussed several approaches to prevent exhaustion of CAR T cells that are explored in his laboratory (see 'Next wave of CAR T cells: Michel Sadelain').
Visit the EHA Learning Center to view webcasts related to this topic: