CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes.
A new study analyzed data from 44 patients with R/R B-cell malignancies (ALL, n=14; CLL, n=9; NHL, n=21) who received CART2 on a phase 1/2 trial at our institution. Despite a CART2 dose increase in 82% of patients, a low incidence of severe toxicity was observed after CART2 (grade ≥3 CRS, 9%; grade ≥3 neurotoxicity, 11%). After CART2, CR was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively.
Addition of fludarabine to cyclophosphamide-based lymphodepletion before CART1 and an increase in the CART2 dose compared to CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. Furthermore, a durabule CAR T-cell persistence was observed after CART2 in patients who received Cy-Flu lymphodepletion before CART1 and a higher CART2 compared to CART1 cell dose.
The identification of two modifiable pre-treatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions. These results will possibly have implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.
Gauthier J, Bezerra ED, Hirayama AV et al. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B cell malignancies. Blood. 2020 Sep23;blood.2020006770. doi: 10.1182/blood.2020006770.