Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma

Abstract

Tisagenlecleucel is indicated for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL). The tisagenlecleucel chimeric antigen receptor (CAR) contains a murine single-chain variable fragment domain; we examined the effects of humoral and cellular immune responses to tisagenlecleucel on clinical outcomes using 2 validated assays. Data were pooled from the ELIANA (registered at www.clinicaltrials.gov as #NCT02435849) and ENSIGN (#NCT02228096) trials in r/r B-ALL (N = 143) and the JULIET trial (#NCT02445248) in r/r DLBCL (N = 115). Humoral responses were determined by flow cytometric measurement of anti-murine CAR19 (mCAR19) antibodies in serum. Cellular responses were determined using T-cell production of interferon-γ in response to 2 different pools of mCAR19 peptides. Pretreatment anti-mCAR19 antibodies were detected in 81% of patients with r/r B-ALL and 94% of patients with r/r DLBCL. Posttreatment anti-mCAR19 antibodies were higher than patient-specific baseline in 42% of r/r B-ALL and 9% of r/r DLBCL patients. Pretreatment and posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics, including maximum concentration and persistence (r2 < 0.05), clinical response (day-28 response, duration of response, and event-free survival), and safety. T-cell responses were consistent over time, with net responses <1% at baseline and posttreatment time points in a majority of patients and no effect on transgene expansion or persistence or outcomes. Presence of baseline and/or posttreatment anti-mCAR19 antibodies or T-cell responses did not alter the activity of tisagenlecleucel in patients with r/r B-ALL or r/r DLBCL.

© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Preexisting and posttreatment anti-mCAR19 antibodies vs tisagenlecleucel expansion. Tisagenlecleucel expansion (Cmax) in pediatric and young adult patients with r/r B-ALL by preexisting (baseline) (A) and posttreatment (postinfusion) (C) anti-mCAR19 antibodies. Patients in the ELIANA trial are indicated by blue circles, and patients in the ENSIGN trial are indicated by red triangles. Tisagenlecleucel expansion (Cmax) in adult patients with r/r DLBCL by preexisting (baseline) (B) and posttreatment (postinfusion) (D) anti-mCAR19 antibodies. Patients in the JULIET trial are indicated by blue diamonds.

Figure 2.

Pretreatment humoral immunogenicity and maximum fold change in anti-mCAR19 antibodies posttreatment by response category. Baseline anti-mCAR19 antibody levels (A-D) and maximum fold change in posttreatment anti-mCAR19 antibody levels (E-H) (by MFI) by response category. CRi, CR with incomplete blood count recovery; NR, no response; PR, partial response; PD, progressive disease; SD, stable disease.

Figure 3.

Effects of anti-mCAR19 antibodies on duration of response in pediatric and young adult patients with B-ALL. Duration of response among patients who were positive (blue bars) and negative (orange bars) for posttreatment anti-mCAR19 antibodies that increased above baseline levels. Censoring reasons are indicated by the symbols in the legend. Patients in the 90th percentile for anti-mCAR antibody MFI are shown (green circles). HSCT, hematopoietic stem cell transplantation.

Figure 4.

Effects of posttreatment anti-mCAR19 antibodies on tisagenlecleucel persistence in pediatric and young adult patients with r/r B-ALL. Solid red circles represent patients who were positive for posttreatment anti-mCAR19 antibodies. Solid blue triangles represent patients who were negative for posttreatment anti-mCAR19 antibodies. Data are presented as the arithmetic mean ± standard deviation.

Figure 5.

Effects of CD4+ T-cell responses to 2 pools of mCAR19 peptides on tisagenlecleucel transgene expansion and patient outcomes in pediatric and young adult patients with r/r B-ALL. Tisagenlecleucel transgene expansion (A-B) and patient outcomes (C-D). Patients from the ELIANA trial are indicated by blue circles, and patients from the ENSIGN trial are indicated by red triangles. Maximum T-cell responses are grouped by response category. Negative response data represent patients whose posttreatment T-cell responses were lower than their baseline responses. CRi, CR with incomplete blood count recovery; NR, no response.

Figure 6.

Net T-cell responses by scheduled time point. CD4+ and CD8+ net responses to pool-1 peptides in pediatric and young adult patients with r/r B-ALL (A,C) and adult patients with r/r DLBCL (B,D). Patients with sustained CR/CR with incomplete blood count recovery (CRi) or CR/partial response (PR) are indicated by solid color circles and are color-coded by scheduled time point for assessment. Negative net response data represent patients whose posttreatment T-cell responses were lower than the negative control (dimethylsulfoxide DMSO).