Feasibility and Safety of CD19 Chimeric Antigen Receptor T Cell Treatment for B Cell Lymphoma Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Schubert, Maria‐Luisa; Dietrich, Sascha; Stilgenbauer, Stephan; Schmitt, Anita; Pavel, Petra; Kunz, Alexander; Bondong, Andrea; Wegner, Mandy; Stadtherr, Peter; Jung, Susanne; Ho, Anthony D.; Müller‐Tidow, Carsten; Schmitt, Michael; Dreger, Peter

doi:10.1016/j.bbmt.2020.04.025

Cited by 23 publications

(20 citation statements)

References 25 publications

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“…However, depending on the target population size and total event count, FC-based approaches can be less sensitive. Additionally, cytopenia that occurs frequently after CART treatment [ 1 , 11 , 23 , 24 , 25 ] results in insufficient PBMC numbers to accurately perform FC analysis. Therefore, CART monitoring based on PCR approaches is preferred over FC.…”

Section: Discussionmentioning

confidence: 99%

Assessment of CAR T Cell Frequencies in Axicabtagene Ciloleucel and Tisagenlecleucel Patients Using Duplex Quantitative PCR

Schubert

Kunz

Schmitt

et al. 2020

Cancers

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Chimeric antigen receptor (CAR) T cell (CART) therapy has been established as a treatment option for patients with CD19-positive lymphoid malignancies in both the refractory and the relapsed setting. Displaying significant responses in clinical trials, two second-generation CART products directed against CD19, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), have been approved and integrated into the clinical routine. However, experimental assay for quantitative monitoring of both of these CART products in treated patients in the open domain are lacking. To address this issue, we established and validated a quantitative single copy gene (SCG)-based duplex (DP)-PCR assay (SCG-DP-PCR) to quantify CARTs based on the FMC63 single chain variable fragment (scFv), i.e., axi-cel and tisa-cel. This quantitative PCR (qPCR) approach operates without standard curves or calibrator samples, offers a tool to assess cellular kinetics of FMC63 CARTs and allows direct comparison of CART-copies in axi-cel versus tisa-cel patient samples. For treating physicians, SCG-DP-PCR is an important tool to monitor CARTs and guide clinical decisions regarding CART effects in respective patients.

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Section: Discussionmentioning

confidence: 99%

Assessment of CAR T Cell Frequencies in Axicabtagene Ciloleucel and Tisagenlecleucel Patients Using Duplex Quantitative PCR

Schubert

Kunz

Schmitt

et al. 2020

Cancers

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“…Grade !3 cytopenias are frequent after CAR T-cell therapy 1,15,60,[121][122][123] and grade !3 febrile neutropenia occurred in 31% and 17% of patients treated within the ZUMA-1 14 and JULIET 13 trials, respectively. With CD19-specific CAR T cells, prolonged severe cytopenias beyond 30 days after administration are characteristically observed in approximately 30% of patients treated with axi-cel or tisacel 1,13,14,60 of which most tend to occur in a biphasic pattern.…”

Section: Cytopeniasmentioning

confidence: 99%

“…Late cytopenias after CAR Tcell therapy have been associated with higher amounts of prior chemotherapy, severe CRS and prior hematopoietic cell transplantation (HCT). 32,60,122,123,125 CAR-specific immunobiology, perturbations in the chemokine milieu after CAR T-cell administration and a limited hematopoietic capacity in those patients who have undergone a prior HCT have been proposed as underlying causes. 32,122,123 Treatment of anemia and thrombocytopenia is based on replacement of erythrocytes and platelets.…”

Section: Cytopeniasmentioning

confidence: 99%

“…Granulocyte colony-stimulating factor (G-CSF) is frequently used to treat neutropenia and should be strongly considered in patients with prolonged neutropenia, 40,53,116 although data to formally define whether it can be safely used as standard of care in patients after CAR T-cell treatment or might potentiate the incidence or severity of CRS by activating immune cells are lacking. 80,116,126,127 Anecdotally, persistent cytopenia after CAR T-cell treatment has been resolved by transfusion of autologous 128 or allogeneic 123 stem cell supports. Other toxicities associated with CAR T cells Infusion reaction.…”

Section: Cytopeniasmentioning

confidence: 99%

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Side-effect management of chimeric antigen receptor (CAR) T-cell therapy

et al. 2021

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Chimeric antigen receptor (CAR) T cells directed against the B-cell marker CD19 are currently changing the landscape for treatment of patients with refractory and/or relapsed B-cell malignancies. Due to the nature of CAR T cells as living drugs, they display a unique toxicity profile. As CAR T-cell therapy is extending towards other diseases and being more broadly employed in hematology and oncology, optimal management strategies of side-effects associated with CAR T-cell therapy are of high relevance. Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias constitute challenges in the treatment of patients with CAR T cells. This review summarizes the current understanding of CAR T-cell toxicity and its management.

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“…A deeper analysis of the dataset shows that patients who had received allogeneic bone marrow transplantation several times prior to CAR T cell therapy or whose disease showed extramedullary or neurological involvement had a lower rate of complete remission (CR: 40-50%). Relapse was more common in these patients with the appearance of CD19-negative (e.g., CD22 or myeloid marker positive) "escape" variants (Haso et al 2013;Schubert et al 2020). Anti-CD19 CAR T cells have also been successfully used in chronic B cell (CD19-positive) lymphocytic leukemia (B-CLL) in US cell therapy centers.…”

Section: Car T Cells Against Hematopoietic Tumorsmentioning

confidence: 99%

From antibodies to living drugs: Quo vadis cancer immunotherapy?

2021

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In the last few decades, monoclonal antibodies targeting various receptors and ligands have shown significant advance in cancer therapy. However, still a great percentage of patients experiences tumor relapse despite persistent antigen expression. Immune cell therapy with adoptively transferred modified T cells that express chimeric antigen receptors (CAR) is an engaging option to improve disease outcome. Designer T cells have been applied with remarkable success in the treatment for acute B cell leukemias, yielding unprecedented antitumor activity and significantly improved overall survival. Relying on the success of CAR T cells in leukemias, solid tumors are now emerging potential targets; however, their complexity represents a significant challenge. In preclinical models, CAR T cells recognized and efficiently killed the wide spectrum of tumor xenografts; however, in human clinical trials, limited antitumor efficacy and serious side effects, including cytokine release syndrome, have emerged as potential limitations. The next decade will be an exciting time to further optimize this novel cellular therapeutics to improve effector functions and, at the same time, keep adverse events in check. Moreover, we need to establish whether gene-modified T cells which are yet exclusively used for cancer patients could also be successful in the treatment for other diseases. Here, we provide a concise overview about the transition from monoclonal antibodies to the generation of chimeric antigen receptor T cells. We summarize lessons learned from preclinical models, including our own HER2-positive tumor models, as well as from clinical trials worldwide. We also discuss the challenges we are facing today and outline future prospects.

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Feasibility and Safety of CD19 Chimeric Antigen Receptor T Cell Treatment for B Cell Lymphoma Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Cited by 23 publications

References 25 publications

Assessment of CAR T Cell Frequencies in Axicabtagene Ciloleucel and Tisagenlecleucel Patients Using Duplex Quantitative PCR

Assessment of CAR T Cell Frequencies in Axicabtagene Ciloleucel and Tisagenlecleucel Patients Using Duplex Quantitative PCR

Side-effect management of chimeric antigen receptor (CAR) T-cell therapy

From antibodies to living drugs: Quo vadis cancer immunotherapy?

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