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. 2022 Nov 30;2(11):1520-1531.
doi: 10.1158/2767-9764.CRC-22-0175. eCollection 2022 Nov.

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

Sandra Dupouy  1 , Ibtissam Marchiq  2 , Thibaud Derippe  1   3 , Maria Almena-Carrasco  1 , Agnieszka Jozwik  4 , Sylvain Fouliard  1 , Yasmina Adimy  1 , Julia Geronimi  1 , Charlotte Graham  4 , Nitin Jain  5 , Marcela V Maus  6 , Mohamad Mohty  7 , Nicolas Boissel  8 , Takanori Teshima  9 , Koji Kato  10 , Reuben Benjamin  4   11 , Svetlana Balandraud  1
Affiliations

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

Sandra Dupouy et al. Cancer Res Commun. .

Abstract

Background: UCART19 is an "off-the-shelf" genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells.

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 (C max) and exposure (AUCTlast) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR+ T cells did not 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 IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC0-28.

Conclusions: UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection.

Significance: First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population.

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Conflict of interest statement

S. Dupouy reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. I. Marchiq reports other from Allogene Therapeutics during the conduct of the study; and I. Marchiq is an employee of Servier. T. Derippe reports grants from Servier during the conduct of the study; grants from Servier outside the submitted work. M. Almena-Carrasco reports personal fees from Servier Laboratoires and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier Laboratoires outside the submitted work. S. Fouliard reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. J. Geronimi reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. C. Graham reports grants from Servier during the conduct of the study. N. Jain reports grants, personal fees, and non-financial support from Servier during the conduct of the study; grants, personal fees, and non-financial support from Cellectis, Precision Biosciences, Abbvie, Genentech, Loxo Oncology, Fate Therapeutics; grants from Takeda outside the submitted work. M.V. Maus reports other from 2Seventy Bio outside the submitted work; in addition, M.V. Maus has a patent to Patents in CAR T cells for multiple indications pending; and M.V. Maus is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab) and University of Pennsylvania (some licensed to Novartis). M.V. Maus holds Equity in 2SeventyBio, Century Therapeutics, Neximmune, Oncternal, and TCR2 and has served as a consultant for multiple companies involved in cell therapies; board of directors: 2Seventy Bio; M.V. Maus is a consultant for: Adaptimmune, Agenus, Allogene, Arcellx, Astellas, AstraZeneca, Atara, Bayer, BMS, Cabaletta Bio (SAB), Cellectis (SAB), CRISPR therapeutics, Genocea, In8bio (SAB), Intellia, GSK, Kite Pharma, Micromedicine/BendBio, Neximmune, Novartis, Oncternal, Sanofi, TCR2 (SAB), Tmunity, and WindMIL (SAB); M.V. Maus has had Grant/Research support : CRISPR therapeutics, Kite Pharma, Servier, Novartis; speaker's bureau: none. M. Mohty reports grants and personal fees from Jazz, Janssen, Sanofi; personal fees from Amgen, Takeda, Pfizer, Adaptive, Novartis, Astellas, GSK, Oncopeptides, and BMS outside the submitted work. N. Boissel reports personal fees from SERVIER during the conduct of the study; grants and personal fees from AMGEN; personal fees from Pfizer, Gilead, and Novartis outside the submitted work. T. Teshima reports grants from Sanofi, Chugai, Astellas, Teijin Pharma, Fuji Pharma, Nippon Shinyaku; personal fees from Merck Sharp & Dohme, Pfizer, Bristol-Myers Squibb; grants and personal fees from Kyowa Kirin; non-financial support from Janssen; grants, personal fees, and non-financial support from Novartis, and personal fees from Takeda outside the submitted work. K. Kato reports grants from Kyowa-Kirin, Novartis, Chugai, Takeda, AbbVie, Eisai, Janssen, Bristol-Myers Squibb, Ono, and Daiichi Sankyo during the conduct of the study. R. Benjamin reports grants from Servier and Allogene during the conduct of the study. No disclosures were reported by the other authors.

Figures

FIGURE 1
FIGURE 1
UCART19 cellular kinetics and correlation with clinical response. A, Graphical representation of UCART19 kinetic profile in PB of patients with B-ALL in the CALM study. B, Individual UCART19 kinetic profiles of adult patients with B-ALL by best overall response (BOR). C, From left to right: UCART19 AUC0-28 (AUC between day 0 and day 28 after CAR-T infusion), AUCTlast (AUC from day 0 until the last observed quantifiable level of CAR transgene) and Cmax (maximum peak expansion) according to response status. Statistical comparison was performed using a Wilcoxon test. BLQ, below the limit of quantification; NR, nonresponder; R, responder.
FIGURE 2
FIGURE 2
Impact of T-cell donor and product characteristics on UCART19 cellular kinetics. Peak (Cmax; A) and persistence (AUCTlast; B) of UCART19 expansion related to donors are represented. Graphs show mean ± SD values of transgene levels by VCN analysis (copies/μL). Number of patients having received a batch from the same donor (n) are shown. Correlation between peak (C) and persistence (D) of UCART19 expansion related to the CD4:CD8 ratio of CAR+ cells in the drug substance (DS) is analyzed. DS characterization is performed by multiparametric flow cytometry at D19 of manufacturing. E, Persistence of UCART19 (AUCTlast) depending on memory subsets composition of the GMP batches is evaluated. Statistical comparison was performed using a Wilcoxon test for A and B and a Spearman correlation for C–E. [Tn, naïve T cells and Tscm, stem cell memory T cells (CD62L+ CD45RA+); Tcm, central memory T cells (CD62L+ CD45RA−); Tem, effector memory T cells (CD62L− CD45RA−); Teff, effector T cells (CD62L− CD45RA+)].
FIGURE 3
FIGURE 3
Impact of lymphodepletion and alemtuzumab on UCART19 cellular kinetics. A, Total lymphocytes before and after (at the day of UCART19 infusion) lymphodepletion. B, Relationship between alemtuzumab total exposure and UCART19 expansion status. C, Positive correlation between alemtuzumab and UCART19 exposure. D, Correlation between UCART19 and IL7 Cmax. E, Relationship between IL7 Cmax and alemtuzumab doses. F, Relationship between IL7 Cmax and UCART19 expansion status. Statistical comparison was performed using a Wilcoxon test for B, E, and F and a Spearman correlation for D.
FIGURE 4
FIGURE 4
Interplay between alemtuzumab, IL7, host immune system and UCART19 kinetics. Individual host T profiles up to day 60, highlighted by expansion status (A), relationship between alemtuzumab total exposure and host T early AUC (AUC0-28; B), higher host T early exposures are correlated with the absence of observable UCART19 expansion (C), IL7 exposure AUC28 and host T early exposure AUC0-28 are strongly correlated (D). Individual host NK profiles up to day 60, highlighted by expansion status (E), relationship between alemtuzumab total exposure and host NK early AUC (AUC0-28; F), absence of correlation between host NK early exposures and UCART19 expansion (G), absence of correlation between IL7 exposure AUC28 and host NK early exposure AUC0-28 (H). Statistical comparison was performed using a Wilcoxon test for C and G and a Spearman correlation for B, D, F, and H.
FIGURE 5
FIGURE 5
Influence of HLA allele mismatching between unrelated UCART19 T-cell donors and recipients on UCART19 kinetics. Level of HLA matching (expressed as a percentage of overall matching) represented according to the UCART19 expansion status (A) or, clinical response status (B). Comparison is based on eight alleles (red dots) or 10 alleles (black dots) depending on local practices for HLA allele typing assessment. Relationship between HLA matching level and UCART19 Cmax (C) or, AUCTlast (D). Statistical comparison was performed using a Wilcoxon test for A and B and a Spearman correlation for C and D.
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