Tvt CAR7: Phase 1 Clinical Trial of Base-Edited "Universal” CAR7 T Cells for Paediatric Relapsed/Refractory T-ALL

Chiesa, Robert; Georgiadis, Christos; Ottaviano, Giorgio; Syed, Farhatullah; Braybrook, Toni; Etuk, Annie; Zhan, Hong; Gkazi, Soragia Athina; Preece, Roland; Adams, Stuart; Thomas, Rebecca; Awuah, Agnes; Gilmour, Kimberly; Mhaldien, Lana; Chu, Jan; Pinner, Danielle; Kubat, Agnieszka; Veys, Paul; Rao, Kanchan; Lucchini, Giovanna; O’Connor, David; Vora, Ajay; Qasim, Waseem

doi:10.1182/blood-2022-169114

Cited by 11 publications

(12 citation statements)

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“…An alternative genome editing technology, base editing, does not generate DNA double-stranded breaks (DSBs) and may induce less genomic damage to the T cells. Base-edited allo-CAR T cells were used to treat refractory T-cell leukemia (T-ALL) ( 101 , 102 ). However, in this trial, B2M was not deleted and therefore HLA class I complex is still intact in allo-CAR T cells ( 101 ).…”

Section: Major Challenges To Overcome For Car T Cell Therapymentioning

confidence: 99%

“…Base-edited allo-CAR T cells were used to treat refractory T-cell leukemia (T-ALL) ( 101 , 102 ). However, in this trial, B2M was not deleted and therefore HLA class I complex is still intact in allo-CAR T cells ( 101 ). In addition, TALEN-mediate gene editing is also used to disrupt endogenous TRAC and B2M loci to generate immune-evasive universal CAR T cell therapy ( 103 ).…”

Section: Major Challenges To Overcome For Car T Cell Therapymentioning

confidence: 99%

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From bench to bedside: the history and progress of CAR T cell therapy

et al. 2023

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Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.

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Section: Major Challenges To Overcome For Car T Cell Therapymentioning

confidence: 99%

Section: Major Challenges To Overcome For Car T Cell Therapymentioning

confidence: 99%

From bench to bedside: the history and progress of CAR T cell therapy

et al. 2023

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“…The abstract 2001 reported a targeted base- editing (BE) technology that can mediate precise C → U → T conversion using CRISPR guided cytidine deamination [ 4 ] (Table 1 ). The BE-edited allogeneic CAR T cells have disruptions of TCR, CD7 and CD52 (BE-CAR7).…”

Section: Cd7 Targeted Car T Cells By Genome Editingmentioning

confidence: 99%

“…The BE-edited allogeneic CAR T cells have disruptions of TCR, CD7 and CD52 (BE-CAR7). Early data from the clinical trial, TvT CAR7 study, were reported at ASH2022 [ 4 ]. This phase I study was planned for children with relapsed /refractory (R/R) CD7 + T-ALL.…”

Section: Cd7 Targeted Car T Cells By Genome Editingmentioning

confidence: 99%

CAR T cell therapy for T cell leukemia and lymphoma: latest updates from 2022 ASH Annual Meeting

2023

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Due to the concern of fratricide, clinical development of CAR T cells for the therapy of T cell malignancies lags behind that for B cell malignancies. Attempts are being made to revise T cell biomarkers so that the re-engineered CAR T cells can target T cell malignancies. CD3 and CD7 are the two pan-T cell surface biomarkers that have been either knocked out or knocked down through genome base- editing technology or by protein expression blockers so that the re-engineered T cells can target T cells without fratricide. We summarized several latest reports on the CAR T cells for the therapy of T cell leukemia /lymphoma from the 2022 ASH Annual Meeting, with latest updates on clinical trials of TvT CAR7, RD-13-01, and CD7 CART.

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“…For this therapy, named BE CAR-7, T cells were collected from healthy donors to make allogeneic CAR-T cells for later infusion into patients with relapsed/refractory T cell acute lymphoid leukemia. After collecting the donor T cells, the base editor designed to modify three genes ( TRBC , CD52 , CD7 ) was delivered via electroporation, followed by delivery of a chimeric antigen receptor with a lentiviral vector [ 151 , 152 ]. While no peer-reviewed studies have been reported about the outcomes for this trial, news reports have hinted at promising results by reporting which showed that the first patient enrolled in this trial is leukemia free six months after she received the edited CAR-T cells and a second bone marrow transplant [ 153 ].…”

Section: Base Editingmentioning

confidence: 99%

CRISPR-Cas System: The Current and Emerging Translational Landscape

Bhokisham

Laudermilch

Traeger

et al. 2023

Cells

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CRISPR-Cas technology has rapidly changed life science research and human medicine. The ability to add, remove, or edit human DNA sequences has transformative potential for treating congenital and acquired human diseases. The timely maturation of the cell and gene therapy ecosystem and its seamless integration with CRISPR-Cas technologies has enabled the development of therapies that could potentially cure not only monogenic diseases such as sickle cell anemia and muscular dystrophy, but also complex heterogenous diseases such as cancer and diabetes. Here, we review the current landscape of clinical trials involving the use of various CRISPR-Cas systems as therapeutics for human diseases, discuss challenges, and explore new CRISPR-Cas-based tools such as base editing, prime editing, CRISPR-based transcriptional regulation, CRISPR-based epigenome editing, and RNA editing, each promising new functionality and broadening therapeutic potential. Finally, we discuss how the CRISPR-Cas system is being used to understand the biology of human diseases through the generation of large animal disease models used for preclinical testing of emerging therapeutics.

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Tvt CAR7: Phase 1 Clinical Trial of Base-Edited "Universal” CAR7 T Cells for Paediatric Relapsed/Refractory T-ALL

Cited by 11 publications

References 0 publications

From bench to bedside: the history and progress of CAR T cell therapy

From bench to bedside: the history and progress of CAR T cell therapy

CAR T cell therapy for T cell leukemia and lymphoma: latest updates from 2022 ASH Annual Meeting

CRISPR-Cas System: The Current and Emerging Translational Landscape

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