UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial

Boucaud, Floriane; Balandraud, Svetlana; Gianella‐Borradori, Athos; Binlich, Florence; Marchiq, Ibtissam; Dupouy, Sandra; Almena-Carrasco, Maria; Pannaux, Matthieu; Fouliard, Sylvain; Benjamin, Reuben; Graham, Charlotte; Jóźwik, Agnieszka; Yallop, Deborah; Bonganay, Laarni; Catt, Lorraine; Chappell, Jackie; Cheung, Gary; Chu, Vicky; Cuthill, Kirsty; Devereux, S; Dunlop, Alan; Ellard, Rose; Farzeneh, Farzin; Folarin, Najeem; Giemza, Elka; Kassam, Shireen; Kazmi, Majid; Kühnl, Andrea; Lewis, Jen; Liskova, M.Yu.; Mason, Alice; Metaxa, Victoria; Mufti, Ghulam J.; Munro, Helena; Pagliuca, Antonio; Patten, Piers; Potter, Victoria; Rice, Carmel; Saleem, Adeel; Sanderson, Robin; Stewart, Orla; Jabbour, Elias; Jain, Nitin; Jones, Emily; Kantarjian, Hagop; Kebriaei, Partow; Konopleva, Marina; McGee, Kara; Wierda, William G.; Brown, Jami; Casey, Kevin; Frigault, Matthew J.; Hock, Hanno; Mathews, Richard; Maus, Marcela V.; McKeown, Meaghan A; Spitzer, Thomas R.; Toncheva, Vesselina; Azoulay, Élie; Boissel, Nicolas; Caillat‐Zucman, Sophie; Celli-Lebras, Karine; Clappier, Emmanuelle; Itzykson, Raphaël; Larghero, Jérôme; Lengliné, Etienne; Madelaine, Isabelle; Meunier, Martine; Rabian, Florence; Raffoux, Emmanuel; Tremorin, Marie-Thérèse; Bonnin, Agnès; Brissot, Éolia; Daguenel-Nguyen, Anne; Duléry, Rémy; Ledraa, Tounes; Malard, Florent; Mediavilla, Clemence; Mohty, Mohamad; Vekhoff, Anne; Teshima, Takanori; Kato, Koji

doi:10.1016/s2352-3026(22)00245-9

Cited by 65 publications

(38 citation statements)

References 18 publications

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“…We have previously reported that alemtuzumab-containing lymphodepletion appears to be required for UCART19 expansion (14,15). To confirm these results, we explored the relationship between alemtuzumab doses and UCART19 expansion across the three DLs of UCART19 (Supplementary Table S4).…”

Section: Impact Of Lymphodepletion and Alemtuzumab On Ucart19 Cellula...mentioning

confidence: 65%

“…We previously showed that UCART19, an allogeneic genome-edited anti-CD19 CAR-T cell therapy, could be safely administered and achieved anti-leukemic activity in pediatric and adult patients with R/R B-ALL enrolled in two multicenter phase I studies (14,15).…”

Section: Discussionmentioning

confidence: 99%

“…Elimination of TRAC prevents GvHD, while the CD52 gene knock-out protects donor cells from early rejection through alemtuzumab, a powerful anti-CD52 peripheral lymphodepleting agent (13). We recently demonstrated the feasibility of administering UCART19 to adult and pediatric patients diagnosed with R/R B-ALL (14,15). UCART19 induced preliminary antileukemic activity in these heavily pre-treated populations and exhibited a manageable safety profile with minimal GvHD and moderate cytokine release syndromes (CRS).…”

Section: Introductionmentioning

confidence: 99%

“…We have previously reported preliminary UCART19 PK results with a peak expansion similar to autologous CAR-T cells, around 14 days post-UCART19 administration, and a variable persistence following a fludarabine/cyclophosphamide-based lymphodepletion regimen with or without alemtuzumab (14,15). The current work goes deeper into the cellular kinetics and factors impacting expansion, persistence, and response of this genome-edited allogeneic anti-CD19 CAR-T cell therapy administered to 25 non-HLA matched adult patients with R/R B-ALL as part of the CALM clinical trial.…”

Section: Introductionmentioning

confidence: 99%

“…Nine GMP batches originating from 6 different donors were administered. Study design (Supplementary Fig.S1), study primary objectives and key inclusion and exclusion criteria were previously detailed by Benjamin et al(15). Characteristics of the patient population and overall results are described in Supplementary Materials and Methods.…”

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confidence: 99%

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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

Dupouy

Marchiq

Derippe

et al. 2022

Cancer Research Communications

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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.

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Section: Impact Of Lymphodepletion and Alemtuzumab On Ucart19 Cellula...mentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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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

Dupouy

Marchiq

Derippe

et al. 2022

Cancer Research Communications

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CAR T Cells and T-Cell Therapies for Cancer

Brudno,

Maus,

Hinrichs

2024

JAMA

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ImportanceChimeric antigen receptor (CAR) T cells are T lymphocytes that are genetically engineered to express a synthetic receptor that recognizes a tumor cell surface antigen and causes the T cell to kill the tumor cell. CAR T treatments improve overall survival for patients with large B-cell lymphoma and progression-free survival for patients with multiple myeloma.ObservationsSix CAR T-cell products are approved by the US Food and Drug Administration (FDA) for 6 hematologic malignancies: B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, and multiple myeloma. Compared with standard chemotherapy followed by stem cell transplant, CAR T cells improved 4-year overall survival in patients with large B-cell lymphoma (54.6% vs 46.0%). Patients with pediatric acute lymphoblastic leukemia achieved durable remission after CAR T-cell therapy. At 3-year follow-up, 48% of patients were alive and relapse free. In people with multiple myeloma treated previously with 1 to 4 types of non–CAR T-cell therapy, CAR T-cell therapy prolonged treatment-free remissions compared with standard treatments (in 1 trial, CAR T-cell therapy was associated with progression-free survival of 13.3 months compared with 4.4 months with standard therapy). CAR T-cell therapy is associated with reversible acute toxicities, such as cytokine release syndrome in approximately 40% to 95% of patients, and neurologic disorders in approximately 15% to 65%. New CAR T-cell therapies in development aim to increase efficacy, decrease adverse effects, and treat other types of cancer. No CAR T-cell therapies are FDA approved for solid tumors, but recently, 2 other T lymphocyte–based treatments gained approvals: 1 for melanoma and 1 for synovial cell sarcoma. Additional cellular therapies have attained responses for certain solid tumors, including pediatric neuroblastoma, synovial cell sarcoma, melanoma, and human papillomavirus–associated cancers. A common adverse effect occurring with these T lymphocyte–based therapies is capillary leak syndrome, which is characterized by fluid retention, pulmonary edema, and kidney dysfunction.Conclusions and RelevanceCAR T-cell therapy is an FDA-approved therapy that has improved progression-free survival for multiple myeloma, improved overall survival for large B-cell lymphoma, and attained high rates of cancer remission for other hematologic malignancies such as acute lymphoblastic leukemia, follicular lymphoma, and mantle cell lymphoma. Recently approved T lymphocyte–based therapies demonstrated the potential for improved outcomes in solid tumor malignancies.

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Advances in research on factors affecting chimeric antigen receptor T‐cell efficacy

Zhou,

Zhu,

Xiao

2024

Cancer Medicine

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Chimeric antigen receptor T‐cell (CAR‐T) therapy is becoming an effective technique for the treatment of patients with relapsed/refractory hematologic malignancies. After analyzing patients with tumor progression and sustained remission after CAR‐T cell therapy, many factors were found to be associated with the efficacy of CAR‐T therapy. This paper reviews the factors affecting the effect of CAR‐T such as tumor characteristics, tumor microenvironment and immune function of patients, CAR‐T cell structure, construction method and in vivo expansion values, lymphodepletion chemotherapy, and previous treatment, and provides a preliminary outlook on the corresponding therapeutic strategies.

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UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial

Cited by 65 publications

References 18 publications

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

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

CAR T Cells and T-Cell Therapies for Cancer

Advances in research on factors affecting chimeric antigen receptor T‐cell efficacy

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