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Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia
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 t...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035397/ https://www.ncbi.nlm.nih.gov/pubmed/36970059 http://dx.doi.org/10.1158/2767-9764.CRC-22-0175 |
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author | Dupouy, Sandra Marchiq, Ibtissam Derippe, Thibaud Almena-Carrasco, Maria Jozwik, Agnieszka Fouliard, Sylvain Adimy, Yasmina Geronimi, Julia Graham, Charlotte Jain, Nitin Maus, Marcela V. Mohty, Mohamad Boissel, Nicolas Teshima, Takanori Kato, Koji Benjamin, Reuben Balandraud, Svetlana |
author_facet | Dupouy, Sandra Marchiq, Ibtissam Derippe, Thibaud Almena-Carrasco, Maria Jozwik, Agnieszka Fouliard, Sylvain Adimy, Yasmina Geronimi, Julia Graham, Charlotte Jain, Nitin Maus, Marcela V. Mohty, Mohamad Boissel, Nicolas Teshima, Takanori Kato, Koji Benjamin, Reuben Balandraud, Svetlana |
author_sort | Dupouy, Sandra |
collection | PubMed |
description | 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 (AUCT(last)) 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 AUC(0-28). 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. |
format | Online Article Text |
id | pubmed-10035397 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-100353972023-03-24 Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia Dupouy, Sandra Marchiq, Ibtissam Derippe, Thibaud Almena-Carrasco, Maria Jozwik, Agnieszka Fouliard, Sylvain Adimy, Yasmina Geronimi, Julia Graham, Charlotte Jain, Nitin Maus, Marcela V. Mohty, Mohamad Boissel, Nicolas Teshima, Takanori Kato, Koji Benjamin, Reuben Balandraud, Svetlana Cancer Res Commun Research Article 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 (AUCT(last)) 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 AUC(0-28). 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. American Association for Cancer Research 2022-11-30 /pmc/articles/PMC10035397/ /pubmed/36970059 http://dx.doi.org/10.1158/2767-9764.CRC-22-0175 Text en © 2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. |
spellingShingle | Research Article Dupouy, Sandra Marchiq, Ibtissam Derippe, Thibaud Almena-Carrasco, Maria Jozwik, Agnieszka Fouliard, Sylvain Adimy, Yasmina Geronimi, Julia Graham, Charlotte Jain, Nitin Maus, Marcela V. Mohty, Mohamad Boissel, Nicolas Teshima, Takanori Kato, Koji Benjamin, Reuben Balandraud, Svetlana Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia |
title | Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia |
title_full | Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia |
title_fullStr | Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia |
title_full_unstemmed | Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia |
title_short | Clinical Pharmacology and Determinants of Response to UCART19, an Allogeneic Anti-CD19 CAR-T Cell Product, in Adult B-cell Acute Lymphoblastic Leukemia |
title_sort | clinical pharmacology and determinants of response to ucart19, an allogeneic anti-cd19 car-t cell product, in adult b-cell acute lymphoblastic leukemia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035397/ https://www.ncbi.nlm.nih.gov/pubmed/36970059 http://dx.doi.org/10.1158/2767-9764.CRC-22-0175 |
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