Tweaking cellular composition
Michael Hudecek (Germany) explained why cellular composition of CAR T products matters. “If you take PBMCs, in the end you get a mixed bag of random T cells and that leads to differences in the composition of cells in the infusion product. The problem here is that killer cells and helper cells of course have different effector mechanisms. If you have one patient treated with almost only helper cells and you have another patient where you only have killers, the rapidity with which the tumor will be degraded and the rapidity with which T cells will be activated and the risk of side effects like cytokine release syndrome will be different and that is a problem. Ideally, you want attributes of a traditional pharmaceutical, meaning that it has a defined and predictable pharmacokinetic. This can be achieved by formulating the cell products such that they always contain the same proportions of killer and helper cells, for example.”
Hudecek also showed that the persistence of CAR T cells depends on the T-cell subset from which they were derived, with TCM-derived T cells persisting for extended periods after adoptive transfer. His laboratory took this a step further and embarked on quest to find the perfect CAR T product. They found that CAR T products that were composed of defined subsets (a 1:1 ratio of CD8TCM:CD4TN) displayed enhanced safety and efficacy compared to PBMCs in vivo.
Stanley Riddell (USA) also discussed cell composition of the CAR T product. The CD19-directed Liso-cel product (produced by Juno / Celgene) has a defined cellular composition, with a fixed 1:1 ratio of CD4:CD8. 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.
In the ALL patients, the CAR T cells underwent dose related expansion and rapidly eliminated leukemia cells. This resulted in MRD negative complete remission in 85% of patients and the remission seems durable. CAR T cell expansion and persistence distinguished patients that achieved MRD negative remission and non-responding patients. “Even though we are trying to define the composition of the cells, it’s clear that we’re not necessarily selecting what would be the most optimal cells, that we’ve previously shown have the capacity to proliferate and persist long term. I think that, as the field moves forward, we need to develop reagents that actually allow us to select out these more potent cells,” said Riddell.
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