Improving outcomes: Stanley Riddell
Speaking at double speed, CAR T pioneer Stanley Riddell (USA) took the audience through the research of his laboratory at the Fred Hutchinson Cancer Research Center. Among other things, his group studies the molecular mechanisms of CAR T cell receptor signaling because this may facilitate designing more effective CARs (see 'Improving CAR T persistence').
Riddell discussed clinical work on CD19-directed CAR T cells in ALL, NHL, and CLL. He presented factors that predict event free survival and overall survival in ALL patients, including adding fludarabine to lymphodepletion prior to treatment. In relapsed or refractory NHL, patients with ‘indolent’ histology respond very well to CAR T cell therapy, suggesting an influence of the tumor microenvironment. Therefore, the researchers aim to study the tumor microenvironment and T cells pre and post therapy. Riddell presented data from a phase 1/2 clinical trial sponsored by Juno, in which 200 adult patients with relapsed or refractory CD19+ B cell malignancies (ALL, NHL, and CLL) have been treated with Liso-cel (see 'Tweaking cellular composition'). Riddell also presented a trial with BCMA CAR T cells in very advanced MM patients (see 'Combinatorial therapy').
Riddell concluded that there are several challenges ahead:
- optimal cell compositions and manufacturing platforms are yet to be determined,
- CAR design can be markedly improved, tuning signaling and sensitivity,
- need for multivalent targeting to prevent antigen loss/escape,
- need to understand mechanisms of adaptive resistance and design rationale combinations to improve complete remission rates (NHL) and durability,
- need to consider moving CAR T cells earlier in the disease course.
Watch and listen to Professor Riddell’s presentation on the EHA Learning Center: