scholarly journals Novel Immune Cell-Based Therapies to Eradicate High-Risk Acute Myeloid Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Roberto Limongello ◽  
Andrea Marra ◽  
Antonella Mancusi ◽  
Samanta Bonato ◽  
Eni Hoxha ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Genetic Risk ◽  
Myeloid Leukemia ◽  
Immune Cell ◽  
Car T Cells ◽  
Wide Range ◽  
Car T ◽  
Acute Myeloid

Adverse genetic risk acute myeloid leukemia (AML) includes a wide range of clinical-pathological entities with extremely poor outcomes; thus, novel therapeutic approaches are needed. Promising results achieved by engineered chimeric antigen receptor (CAR) T cells in other blood neoplasms have paved the way for the development of immune cell-based therapies for adverse genetic risk AML. Among these, adoptive cell immunotherapies with single/multiple CAR-T cells, CAR-natural killer (NK) cells, cytokine-induced killer cells (CIK), and NK cells are subjects of ongoing clinical trials. On the other hand, allogeneic hematopoietic stem cell transplantation (allo-HSCT) still represents the only curative option for adverse genetic risk AML patients. Unfortunately, high relapse rates (above 50%) and associated dismal outcomes (reported survival ~10–20%) even question the role of current allo-HSCT protocols and emphasize the urgency of adopting novel effective transplant strategies. We have recently demonstrated that haploidentical allo-HSCT combined with regulatory and conventional T cells adoptive immunotherapy (Treg-Tcon haplo-HSCT) is able to overcome disease-intrinsic chemoresistance, prevent leukemia-relapse, and improve survival of adverse genetic risk AML patients. In this Perspective, we briefly review the recent advancements with immune cell-based strategies against adverse genetic risk AML and discuss how such approaches could favorably impact on patients’ outcomes.

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 Can immune therapy cure acute myeloid leukemia?

2020 ◽  
Vol 9 (2) ◽  
pp. 8-12
Author(s):  
Robert P. Gale
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Immune Therapy ◽  
Hla Antigens ◽  
Gemtuzumab Ozogamicin ◽  
Car T Cells ◽  
Car T ◽  
Acute Myeloid

There is considerable progress in immune therapy of diverse cancers. In haematology these advances are mostly limited to lymphoid cancers. Effective therapies include monoclonal antibodies and chimeric antigen receptor (CAR)-T-cells to lymphoid lineage-antigens such as CD19, CD20 and B-cell maturation antigen (BCMA). Gemtuzumab ozogamicin (Myelotarg®) is the only FDA-approved immune-based therapy for acute myeloid leukemia (AML). Several clinical trials of antibodies to CD38 and CD123 are reported with unimpressive efficacy and safety concerns. Reasons are higher daily production rates of myeloid cells and unacceptable collateral damage to normal haematopoietic cells because of imperfect specificity for AML cells. Potential targets of anti-AML immune therapy are (1) HLA antigens; (2) minor histocompatibility antigens; (3) leukemia-associated antigens; and (4) leukemia-specific antigens. Data supporting an effective allogeneic anti-AML effect come from studies in recipients of haematopoietic cell transplants with graft-versus-host disease (GvHD) and recipients of donor lymphocyte infusions (DLI). A special problem is a relative paucity of neo-antigens in AML compared with solid cancers because of a low cumulative mutation frequency. Cell immune therapy trials are in progress including CAR-T-cells, CAR-NK-cells and allogeneic NK-cells. Approaches using synthetic biology are being developed. Presently, except for gemtuzumab ozogamicin there are no convincing data of efficacy of immune therapy in AML.

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

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 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.

scholarly journals Harnessing T Cells to Target Pediatric Acute Myeloid Leukemia: CARs, BiTEs, and Beyond

Children ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. 14
Author(s):  
Rebecca Epperly ◽  
Stephen Gottschalk ◽  
Mireya Paulina Velasquez
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Targeted Therapies ◽  
Myeloid Leukemia ◽  
Immune Therapy ◽  
Bispecific Antibodies ◽  
Car T Cells ◽  
Car T ◽  
Acute Myeloid

Outcomes for pediatric patients with acute myeloid leukemia (AML) remain poor, highlighting the need for improved targeted therapies. Building on the success of CD19-directed immune therapy for acute lymphocytic leukemia (ALL), efforts are ongoing to develop similar strategies for AML. Identifying target antigens for AML is challenging because of the high expression overlap in hematopoietic cells and normal tissues. Despite this, CD123 and CD33 antigen targeted therapies, among others, have emerged as promising candidates. In this review we focus on AML-specific T cell engaging bispecific antibodies and chimeric antigen receptor (CAR) T cells. We review antigens being explored for T cell-based immunotherapy in AML, describe the landscape of clinical trials upcoming for bispecific antibodies and CAR T cells, and highlight strategies to overcome additional challenges facing translation of T cell-based immunotherapy for AML.

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