Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies

Png, Yi Tian; Vinanica, Natasha; Kamiya, Takahiro; Shimasaki, Noriko; Coustan‐Smith, Elaine; Campana, Dario

doi:10.1182/bloodadvances.2017009928

Cited by 147 publications

(171 citation statements)

References 56 publications

Supporting

Mentioning

170

Contrasting

Order By: Relevance

“…The absence of CD7 ensured fratricide prevention and CD7-directed CAR-T cells showed cytotoxic activity against target antigen-expressing cells [30, 31]. In another approach, a protein expression blocker was used to downregulate CD7 expression by transducing CD7-specific endoplasmic reticulum/Golgi retention peptide-coding plasmids in T cells prior to transient CD7-directed CAR-modification [32]. The phenotype and cytokine profile of CD7-downregulated T cells were comparable to control-transduced T cells.…”

Section: Car-modified Nk Cells Against Leukaemia and Lymphomamentioning

confidence: 99%

“…The phenotype and cytokine profile of CD7-downregulated T cells were comparable to control-transduced T cells. Additionally, CAR-carrying and CD7-downregulated T cells showed potent cytotoxic activity against leukaemic cells in vitro and in xenograft T-ALL mouse models [32]. Eventually, a clinical trial was enrolled in 2016 investigating the safety and toxicity of CD7-directed CAR-NK cells (Table 1).…”

Section: Car-modified Nk Cells Against Leukaemia and Lymphomamentioning

confidence: 99%

See 1 more Smart Citation

CAR-Expressing Natural Killer Cells for Cancer Retargeting

Kloeß

Kretschmer

Stahl

et al. 2019

Transfus Med Hemother

View full text Add to dashboard Cite

Since the approval in 2017 and the outstanding success of Kymriah® and Yescarta®, the number of clinical trials investigating the safety and efficacy of chimeric antigen receptor-modified autologous T cells has been constantly rising. Currently, more than 200 clinical trials are listed on clinicaltrial.gov. In contrast to CAR-T cells, natural killer (NK) cells can be used from allogeneic donors as an “off the shelf product” and provide alternative candidates for cancer retargeting. This review summarises preclinical results of CAR-engineered NK cells using both primary human NK cells and the cell line NK-92, and provides an overview about the first clinical CAR-NK cell studies targeting haematological malignancies and solid tumours, respectively.

show abstract

Section: Car-modified Nk Cells Against Leukaemia and Lymphomamentioning

confidence: 99%

Section: Car-modified Nk Cells Against Leukaemia and Lymphomamentioning

confidence: 99%

CAR-Expressing Natural Killer Cells for Cancer Retargeting

Kloeß

Kretschmer

Stahl

et al. 2019

Transfus Med Hemother

View full text Add to dashboard Cite

show abstract

“…Two clinical trials have been initiated in China studying CD7-CAR-modified T cells for the treatment of CD7-positive malignancies (NCT04033302 and NCT04004637). However, preclinical studies showed significantly reduced expansion of CD7-CAR T cells compared to control T cells, as a result of fratricide [45,49]. Fratricide appears to be observed to a greater extent in CD7-CAR T cells compared to CD5-CAR T cells [45].…”

Section: Cd7mentioning

confidence: 97%

“…Various approaches have been used to overcome these challenges, including CRISPR-Cas9 genome editing to remove the antigen from the CAR T cells [45][46][47], Tet-OFF expression system to limit fratricide during ex vivo expansion [48], protein expression blocker (PEBL) to retain the antigen in the ER/Golgi to prevent cell surface expression [49,50], or using CAR-modified natural killer cells instead of T cells [47,[51][52][53][54]. Additionally, to date, four targets have been investigated as targets for CAR T cell therapy for the treatment of T cell malignancies with limited to no expression in the normal population of T cells, CD30, CD37, TRBC1, and CD1a [55][56][57][58].…”

Section: Translating Car T Cell Therapy For Treatment Of T Cell Maligmentioning

confidence: 99%

“…As a result, fratricide was observed only transiently, allowing the CD5-CAR T cells to expand. These cells had significant Genome editing of target antigen [45][46][47] Targeting antigens with limited expression on T cells (e.g., CD30, CD37, TRBC1, CD1a) [55][56][57][58] Tet-OFF expression system [48] Protein expression blockers (PEBLs) [49] Using NK cells or NK-92 cells [47,[51][52][53][54]60] T cell aplasia Targeting antigens with limited expression on T cells (e.g., CD30, CD37, TRBC1, CD1a) [55][56][57][58] mRNA electroporation…”

Section: Cd5mentioning

confidence: 99%

See 1 more Smart Citation

Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions

2019

View full text Add to dashboard Cite

Chimeric antigen receptor (CAR) T cell therapy has been successful in treating B cell malignancies in clinical trials; however, fewer studies have evaluated CAR T cell therapy for the treatment of T cell malignancies. There are many challenges in translating this therapy for T cell disease, including fratricide, T cell aplasia, and product contamination. To the best of our knowledge, no tumor-specific antigen has been identified with universal expression on cancerous T cells, hindering CAR T cell therapy for these malignancies. Numerous approaches have been assessed to address each of these challenges, such as (i) disrupting target antigen expression on CARmodified T cells, (ii) targeting antigens with limited expression on T cells, and (iii) using third party donor cells that are either non-alloreactive or have been genome edited at the T cell receptor α constant (TRAC) locus. In this review, we discuss CAR approaches that have been explored both in preclinical and clinical studies targeting T cell antigens, as well as examine other potential strategies that can be used to successfully translate this therapy for T cell disease.

show abstract

CD38‐Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells

et al. 2023

View full text Add to dashboard Cite

The robust and stable expression of CD38 in T‐cell acute lymphoblastic leukemia (T‐ALL) blasts makes CD38 chimeric antigen receptor (CAR)‐T/natural killer (NK) a potential therapy for T‐ALL. However, CD38 expression in normal T/NK cells causes fratricide of CD38 CAR‐T/NK cells. Here a “2‐in‐1” gene editing strategy is developed to generate fratricide‐resistant locus‐specific CAR‐T/NK cells. CD38‐specific CAR is integrated into the disrupted CD38 locus by CRISPR/Cas9, and CAR is placed under the control of either endogenous CD38 promoter (CD38KO/KI) or exogenous EF1α promoter (CD38KO/KIEF1α). CD38 knockout reduces fratricide and allows the expansion of CAR‐T cells. Meanwhile, CD38KO/KIEF1α results in higher CAR expression than CD38KO/KI in both CAR‐T and CAR‐NK cells. In a mouse T‐ALL model, CD38KO/KIEF1α CAR‐T cells eradicate tumors better than CD38KO/KI CAR‐T cells. Surprisingly, CD38KO/KI CAR‐NK cells show superior tumor control than CD38KO/KIEF1α CAR‐NK cells. Further investigation reveals that endogenous regulatory elements in NK cells lead to higher expression of CD38 CAR than in T cells, and the expression levels of CAR affect the therapeutic outcome of CAR‐T and CAR‐NK cells differently. Therefore, these results support the efficacy of CD38 CAR‐T/NK against T‐ALL and demonstrate that the “2‐in‐1” strategy can resolve fratricide and enhance tumor eradication, paving the way for clinical translation.

show abstract

Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies

Abstract: Key Points Blockade of CD7 expression with a novel method, combined with a second-generation CAR, results in highly potent anti-CD7 CAR T cells. This practical strategy provides a new treatment option for patients with high-risk T-cell malignancies, including ETP-ALL.

Cited by 147 publications

References 56 publications

CAR-Expressing Natural Killer Cells for Cancer Retargeting

CAR-Expressing Natural Killer Cells for Cancer Retargeting

Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions

CD38‐Specific CAR Integrated into CD38 Locus Driven by Different Promoters Causes Distinct Antitumor Activities of T and NK Cells

Contact Info

Product

Resources

About