Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia

Abstract

Purpose: UCART19 is an “off-the-shelf” genome-edited anti-CD19 CAR-T cell product, manufactured from unrelated healthy donor cells. Patients and Methods: UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology. Results: Responder patients (12/25) had higher UCART19 expansion (Cmax) and exposure (AUCTlast) than non-responders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR+ T cells didn’t exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected interleukin-7 and UCART19 kinetics, while negatively correlating with host T-lymphocyte AUC0-28. Conclusions: UCART19 expansion is a driver of response in adult R/R B-ALL patients. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on interleukin-7 and host-versus-graft rejection.

Mechanistic Modeling of the Interplay Between Host Immune System, IL-7 and UCART19 Allogeneic CAR-T Cells in Adult B-cell Acute Lymphoblastic Leukemia

“…This section first provides key information regarding the clinical trial protocol and bioanalytical assays previously described in several publications (6,33). The model construction is then described in detail, including the generation of the assumptions, their mathematical translations into a set of ordinary equations, and an overview of the global model building strategy.…”

“…All sets, except two, also received alemtuzumab, either as a flat dose (40 mg, n = 8, or 60 mg, n = 5) or a body weight–adjusted dose (1 mg/kg, n = 11), split into five doses administered from day −7 to day −3. Further details are available in an associated publication ( 33 ). The CALM study was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonization, and Good Clinical Practice Guidelines and was approved by Institutional Review Boards/Ethics Committees.…”

“…Prior to the modeling process, an exploratory analysis was performed through visualization of time profiles of variables and correlation between covariates and derived descriptive parameters. Detailed results are described in an associated publication ( 33 ).…”

“…Many studies suggest that increasing these cytokines is the real purpose of lymphodepletion prior to CAR-T therapy (12)(13)(14)(15). IL-15 was not added into the final model because exploratory analysis showed an absence of correlation with UCART19 expansion (33), which is in contrast to prior studies (13,46).…”

“…UCART19 is an allogeneic CAR-T cell product (32) developed against relapsed/refractory (R/R) CD19+ B-cell ALL. This therapy was tested during CALM and PALL phase I clinical trials (6,33). Briefly, three patterns of UCART19 PK profiles were observed: 1) an expansion followed by long persistence, 2) an expansion followed by a sharp decline after the 𝐶 , and 3) an absence of observed expansion (Fig.…”