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Clinical Trial
. 2022 Nov 8;6(21):5774-5785.
doi: 10.1182/bloodadvances.2022007317.

Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia

Saar Gill  1   2 , Vanessa Vides  3 , Noelle V Frey  1 , Elizabeth O Hexner  1   2 , Susan Metzger  2 , Megan O'Brien  2 , Wei-Ting Hwang  4 , Jennifer L Brogdon  5 , Megan M Davis  2 , Joseph A Fraietta  2   6   7 , Avery L Gaymon  2 , Whitney L Gladney  2 , Simon F Lacey  2 , Anne Lamontagne  2 , Anthony R Mato  1 , Marcela V Maus  8 , J Joseph Melenhorst  2   6   7 , Edward Pequignot  2 , Marco Ruella  1   2 , Maksim Shestov  1   2 , John C Byrd  9 , Stephen J Schuster  1 , Donald L Siegel  2   6 , Bruce L Levine  2   6 , Carl H June  2   6   7 , David L Porter  1
Affiliations
Clinical Trial

Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia

Saar Gill et al. Blood Adv. .

Erratum in

Abstract

In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.

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Conflict of interest statement

Conflict-of-interest disclosure: S.G. declares multiple patents related to CAR T cells; is a scientific founder and has equity in Carisma Therapeutics and Interius Biotherapeutics; and reports grants from Carisma Therapeutics and Interius Biotherapeutics. C.H.J. is a scientific founder and has equity in Tmunity Therapeutics and Capstan Therapeutics; reports grants from Tmunity Therapeutics; and is on the scientific advisory boards of BluesphereBio, Cabaletta, Carisma, Cellares, Celldex, ImmuneSensor, Poseida, Verismo, Viracta Therapeutics, WIRB Copernicus Group, and Ziopharm Oncology. J.L.B. is an employee of Novartis Pharmaceuticals. M.V.M. declares multiple patents related to CAR T cells. M.R. declares multiple patents related to CAR T cells. A.R.M. receives research funding from Abbvie and Pharmacyclics and consults for Pharmacyclics. J.C.B. receives honoraria from Novartis and Pharmacyclics; receives research funding from Pharmacyclics; consults for Novartis and Janssen; and has received travel and accommodation expenses from Janssen, Novartis, and Pharacyclics. S.J.S. receives research funding from Novartis, Pharmacyclics, and Janssen and consults for Novartis and Pharmacyclics.

D.L.P. is a named inventor on CART-19 related technology. B.L.L. is a consultant for Terumo and GSK; served on the Scientific Advisory Board for Akron, Avectas, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, and Vycellix; and is a cofounder and equity holder in Tmunity Therapeutics and Capstan Therapeutics. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight. All remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Screening, enrollment, and follow-up. A total of 20 patients were screened, and all 20 were enrolled. Of the 20 enrolled patients, 1 patient was not infused due to intercurrent lung adenocarcinoma and coincident finding of Richter transformation. Of the 19 patients who were infused, all had received ≥6 months of ibrutinib therapy before apheresis.
Figure 2.
Figure 2.
OS and PFS. (A) Shows OS among all the patients. The median OS was not reached, and the estimated OS probability at 48 months was 84% (90% CI, 63-93%). (B) Shows the OS of patients on first-line ibrutinib compared with those enrolled in the study with relapsed or refractory disease (P = .35, log-rank test). (C) Shows PFS among all the patients. Median PFS was not reached, and the estimated PFS at 48 months was 80% (90% CI, 46-85%). (D) Shows the PFS of patients receiving first-line ibrutinib compared with those enrolled in the study with relapsed or refractory disease (P = .15, log-rank test). Tick marks indicate censored data.
Figure 3.
Figure 3.
Kinetics of response and CAR T-cell expansion. (A) Shows the depth of MRD estimated from deep sequencing of the immunoglobulin loci (left y-axis) and T-cell expansion and persistence quantified by qPCR of the CAR transgene (right y-axis) for individual patients over a 42 month follow-up period. The time of ibrutinib discontinuation, where applicable, is indicated by an arrow. (B) quantifies the presence of CD19+ CD20+ B cells in the blood of individual patients over time as an indicator of CAR-T cell functional persistence. MRD, measurable residual disease; VCN, vector copy numbers per microgram of DNA.
Figure 3.
Figure 3.
Kinetics of response and CAR T-cell expansion. (A) Shows the depth of MRD estimated from deep sequencing of the immunoglobulin loci (left y-axis) and T-cell expansion and persistence quantified by qPCR of the CAR transgene (right y-axis) for individual patients over a 42 month follow-up period. The time of ibrutinib discontinuation, where applicable, is indicated by an arrow. (B) quantifies the presence of CD19+ CD20+ B cells in the blood of individual patients over time as an indicator of CAR-T cell functional persistence. MRD, measurable residual disease; VCN, vector copy numbers per microgram of DNA.
Figure 4.
Figure 4.
Kinetics of cytokine production and association with CRS. (A) Expresses the production of individual cytokines (vertical axis) over time (horizontal axis) from individual patients (unique patient number not shown). Changes in cytokine levels are shown as fold-change from the day −1 baseline on a log2 scale. (B) Shows the correlation of peak cytokine production of selected cytokines out of 30 cytokines tested with CRS severity (using the Penn scale of CRS severity). Pearson correlation with a Bonferroni correction for multiple comparisons. Note that the remaining 26 cytokines tested were not found to be significantly correlated with CRS severity.
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