iwCLL 2025 | Interim analysis of GIMEMA CLL2020: impact of ibrutinib/venetoclax on CAR T-cell generation in CLL

The GIMEMA CLL2020 study is a collaborative Italian study that is exploring the impact of ibrutinib and venetoclax on the T-cells of treated patients and on the CAR T-cells that are generated from the enrolled patients. The assumption is that achieving a disease response, a good disease response, might somehow positively affect the immune system of CLL patients, which is deteriorated by the disease. We know that in CLL patients there are several immune dysfunctions that appear very early during the disease evolution and then progressively accumulate during the disease history. So the idea is that if we act positively with targeted agents on the immune system, we can obtain more functional and more preserved CAR T-cells. 

So the study is enrolling patients who are undergoing treatment with ibrutinib or venetoclax. Blood samples are collected before treatment starts and then after six months and 12 months of treatment. And we longitudinally monitor the immune system of the patient and we generate anti-CD19 4-1BB CAR T-cells, and look both at the immunophenotypic features and the functional properties of the generated CAR T-cells. 

So, in this interim analysis, we’ll present the data from the first seven patients enrolled for ibrutinib treatment and from the first eight patients who received venetoclax treatment. What we observed is that we can generate the CAR T-cells in 87% of the patients before treatment and 100% of the patients after 6 months and 12 months of treatment. The transduction efficiency was equally good and there was no impact of the type of treatment and of the duration of treatment, as well as the CAR T-cell yield. The treatment had a beneficial impact on the subset differentiation of T-cells. It is known that the presence of less differentiated CAR T-cells can have a positive impact on the in vivo persistence and the functionality of the CAR T-cells. And actually, in our study, what is interesting is that we observe a predominance, after venetoclax treatment, we observe a predominance of less differentiated CAR T-cells compared to the terminally differentiated effector cells, and there is also a positive effect on the expression of inhibitory checkpoint molecules. We observe a nice reduction in some immune checkpoints like the TIM3, PD1 and CTLA4 in the CAR T-cells generated after 12 months of venetoclax treatment compared to the CAR T-cells generated before treatment starts. So overall CAR T-cells can be effectively generated, but they have some hints of not optimal functionality and some abnormalities in the phenotype that can be somehow positively affected by the venetoclax treatment. With longer follow-ups, we will see also the effect of ibrutinib treatment and the longer effect of both targeted agents.

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