Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies

Abstract

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. We 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, we observed a low incidence of severe toxicity 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. We observed durable CAR T-cell persistence 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, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia

“…Clinical trials have precisely reported little to no success of reinfusions [15,16,63], which could also be related to the lack of lymphodepleting chemotherapy and/or the role of regulatory T-cells. A recent study identified the factors associated with complete response after second infusions [64]. These are mainly a higher dose, as reported here, and lymphodepleting chemotherapy before the first dose.…”

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

“…The extent of the role of ADA in this setting will need to be ascertained in a larger cohort of patients in the future. Previously, a large study evaluating CD19targeted CAR T-cell therapy in B-cell malignincies showed that addition of fludarabine to cyclophosphamide-based lymphodepletion before the first infusion and an increased dose in the second infusion compared to the first infusion would increase the response rate 16 , both of which were followed in the currect study.…”

Bench‐to‐bedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokinetic‐pharmacodynamic model: A case study with anti‐BCMA CAR‐T

“…These clinical observations provide further validity of adopting a systems approach while developing translational PK-PD relationships for CAR-T cells. 31 Some other factors that could impact the cellular kinetics and efficacy of CAR-T cells include (i) product characteristics such as CAR-T cell subsets (CD4/CD8 ratios 27,32,33 ), phenotypes (T scm , T cm , T em , and T e 28,34 ), and exhaustion markers (PD-1, LAG-3, TIM-3 28,34 ) in patient apheresate and preinfusion products; (ii) presence of immunosuppressive immune cells and soluble factors 35 ; (iii) presence or absence of lymphodepletion 28,29,36,37 ; and (iv) resistance mechanisms leading to antigen escape. 29 These factors are further discussed in the Supporting Information.…”