scholarly journals Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia

Blood ◽  
2017 ◽  
Vol 129 (17) ◽  
pp. 2395-2407 ◽  
Author(s):  
Sarah K. Tasian ◽  
Saad S. Kenderian ◽  
Feng Shen ◽  
Marco Ruella ◽  
Olga Shestova ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Car T Cells ◽  
Key Points ◽  
Car T ◽  
Human Acute Myeloid Leukemia ◽  
Xenograft Models ◽  
Acute Myeloid

Key Points Depletion of CD123-redirected CAR T cells with monoclonal antibodies preserves leukemia remission in human AML xenograft models. AML CAR T-cell depletion enhances feasibility of subsequent allogeneic stem cell transplantation.

scholarly journals Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells

2019 ◽  
Vol 10 (18) ◽  
pp. 4408-4419 ◽  
Author(s):  
Huda Salman ◽  
Kevin G. Pinz ◽  
Masayuki Wada ◽  
Xiao Shuai ◽  
Lulu E. Yan ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Antigen Receptor ◽  
Car T Cells ◽  
Car T ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia

2018 ◽  
Vol 11 (1) ◽  
Author(s):  
Jinghua Wang ◽  
Siyu Chen ◽  
Wei Xiao ◽  
Wende Li ◽  
Liang Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Car T Cells ◽  
Car T ◽  
Acute Myeloid

scholarly journals Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor–modified T cells

Blood ◽  
2014 ◽  
Vol 123 (15) ◽  
pp. 2343-2354 ◽  
Author(s):  
Saar Gill ◽  
Sarah K. Tasian ◽  
Marco Ruella ◽  
Olga Shestova ◽  
Yong Li ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Mouse Models ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Antigen Receptor ◽  
Key Points ◽  
Human Acute Myeloid Leukemia ◽  
Engineered T Cells ◽  
Acute Myeloid

Key Points Targeting of CD123 via CAR-engineered T cells results in rejection of human AML and myeloablation in mouse models.

TCRab Deficient CAR T-Cells Targeting CD123: An Allogeneic Approach of Adoptive Immunotherapy for the Treatment of Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2555-2555 ◽  
Author(s):  
Roman Galetto ◽  
Céline Lebuhotel ◽  
Agnès Gouble ◽  
Nuria Mencia-Trinchant ◽  
Cruz M Nicole ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Surface Expression ◽  
Car T Cells ◽  
Healthy Donors ◽  
Car T ◽  
Acute Myeloid

Abstract The remissions achieved using autologous T-cells expressing chimeric antigen receptors (CARs) in patients with advanced B cell leukemia and lymphomas have encouraged the use of CAR technology to treat different types of cancers by targeting distinct tumor-specific antigens. Since the current autologous approach utilizes CAR T-cells manufactured on a "per patient" basis, we propose an alternative approach based on the use of a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic "off-the-shelf" CAR T-cell-based frozen products. In the present work we have adapted this allogeneic platform to the production of T-cells targeting CD123, the transmembrane alpha chain of the interleukin-3 receptor, which is expressed on tumor cells from the majority of patients with Acute Myeloid Leukemia (AML). Multiple antigen recognition domains were screened in the context of different CAR architectures to identify candidates displaying activity against cells expressing variable levels of the CD123 antigen. The three lead candidates were tested in an orthotopic human AML cell line xenograft mouse model. From the three candidates that displayed comparable activity in vitro, we found two candidates capable of eradicating tumor cells in vivo with high efficiency. Subsequently, Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology was used to inactivate the TCRα constant (TRAC) gene, eliminating the potential for engineered T-cells to mediate Graft versus Host Disease (GvHD). Editing of the TRAC gene can be achieved at high frequencies, and allows efficient amplification of TCR-deficient T-cells that no longer mediate alloreactivity in a xeno-GvHD mouse model. In addition, we show that TCR-deficient T-cells display equivalent in vitro and in vivo activity to non-edited T-cells expressing the same CAR. We have performed an initial evaluation of the expression of CD123 in AML patients and found an average cell surface expression of CD123 was of 67% in leukemic blasts (95% CI 48-82), 71% in CD34+CD38+ cells (95% CI 56-86), and 64% in CD34+CD38- (95% CI 41-87). Importantly, we have found that CD123 surface expression persists in CD34+CD38-CD90- cells after therapy in at least 20% of patients in remission (n=25), thus emphasizing the relevance of the target. Currently, the sensitivity of primary AML cells to CAR T-cells is being tested. Finally, we will also present our large scale manufacturing process of allogeneic CD123 specific T-cells from healthy donors, showing the feasibility for this off-the-shelf T-cell product that could be available for administration to a large number of AML patients. Disclosures Galetto: Cellectis SA: Employment. Lebuhotel:Cellectis SA: Employment. Gouble:Cellectis SA: Employment. Smith:Cellectis: Employment, Patents & Royalties.

Adoptive immunotherapy of acute myeloid leukemia (AML) with allogenic CAR t-cells targeting CD123.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 3041-3041
Author(s):  
Roman Galetto ◽  
Celine Lebuhotel ◽  
Patricia Francon ◽  
Agnes Gouble ◽  
Julianne Smith
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Adoptive Immunotherapy ◽  
Myeloid Leukemia ◽  
Car T Cells ◽  
Car T ◽  
Acute Myeloid

scholarly journals Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor–expressing T cells

Blood ◽  
2015 ◽  
Vol 125 (22) ◽  
pp. 3466-3476 ◽  
Author(s):  
Rachel C. Lynn ◽  
Mathilde Poussin ◽  
Anna Kalota ◽  
Yang Feng ◽  
Philip S. Low ◽  
...  
Keyword(s):  
T Cells ◽  
Myeloid Leukemia ◽  
Folate Receptor ◽  
Car T Cells ◽  
Key Points ◽  
Car T ◽  
Receptor Upregulation ◽  
Acute Myeloid

Key PointsHuman FRβ-specific CAR T cells target AML in vitro and in vivo without toxicity against healthy bone marrow HSCs. Combination with ATRA-mediated receptor upregulation may augment FRβ-directed CAR therapy of AML.

scholarly journals Chimeric Antigen Receptor-Modified T Cells for the Treatment of Acute Myeloid Leukemia Expressing CD33

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4058-4058 ◽  
Author(s):  
Degang Song ◽  
Michael H. Swartz ◽  
Steve G. Biesecker ◽  
Fernando Borda ◽  
Rutul R. Shah ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Relapsed acute myeloid leukemia (AML) is an aggressive disease with very poor outcomes. Redirection of T-cell specificity via chimeric antigen receptor (CAR) has shown promising anti-tumor activity in clinical trials, particularly for B cell linage malignancies. CD33 is a transmembrane protein expressed on normal and malignant myeloid-derived cells as well (as on subsets of activated T cells and NK cells). Since this protein is commonly expressed on AML cells, we sought to evaluate the efficacy of targeting AML with CD33-specific CAR-T cells. We generated a lentiviral construct to co-express CD33-specific CAR and a kill switch based on a tag derived from the epidermal growth factor receptor. The latter allows for the conditional elimination of CAR-T cells in vivo. Following transduction of primary T cells, we confirmed CAR and kill switch co-expression by flow cytometry and western blot analyses. Elimination of genetically modified T cells was demonstrated using the clinically-available antibody, cetuximab. CD33 CAR-T cells demonstrated specific cytotoxicity to CD33+ target cell lines. CD33 CAR-T cells were also activated to produce IFNg, TNF, and IL-2 cytokines in response to CD33+ target cells. Furthermore, adoptive transfer of CD33 CAR-T in immunocompromised (NSG) mice bearing established CD33+(CD19neg) AML (MOLM-13) tumor resulted in reduction of tumor burden and improvement of overall survival, compared to control mice receiving CD19 CAR-T cells or no immunotherapy (Figure). Sampling of blood demonstrated the persistence of the CD33 CAR-T cells with no detection of AML (MOLM-13) tumor cells. These pre-clinical data demonstrate the effectiveness of CD33 CAR-T cells in targeting CD33+ AML tumor cells and provide a rationale for future clinical evaluation in AML patients with unmet medical need. Disclosures Song: Intrexon Corporation: Employment, Equity Ownership. Swartz:Intrexon Corporation: Employment, Equity Ownership. Biesecker:Intrexon Corporation: Employment, Equity Ownership. Borda:Intrexon Corporation: Employment. Shah:Intrexon Corporation: Employment, Equity Ownership. Wierda:Genentech: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding. Cooper:MD Anderson Cancer Center: Employment; Intrexon: Equity Ownership; Sangamo BioSciences: Patents & Royalties; Targazyme,Inc.,: Equity Ownership; City of Hope: Patents & Royalties; ZIOPHARM Oncology: Employment, Equity Ownership, Patents & Royalties; Miltenyi Biotec: Honoraria; Immatics: Equity Ownership. Chan:Intrexon Corporation: Employment, Equity Ownership.

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