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

AbstractAcute myeloid leukemia (AML) is a biologically and clinically heterogeneous disease with a dismal prognosis and limited treatment options. Chimeric antigen receptor (CAR) T cells have achieved unprecedented clinical responses in patients with B cell malignancies but a dismal consequences in AML. In our previous study, we found that interleukin-10 receptor (IL-10R) was overexpressed in most AML cells, and played an important role in promoting the stemness of leukemia cells. In this study, we developed a novel ligand-based CAR-T cell targeting IL-10R, which displayed striking cytotoxicity both in vitro and in vivo against AML cells. Except for monocytes, it had no significant adverse effects on the normal hematopoietic system, including CD34+ hematopoietic stem and progenitor cells (HSPCs). In addition, even though the incorporation of IL-10 in the CAR cassette led to phenotypes change, it had few adverse effects on the survival and biological activity of IL-10 CAR-T cells and did not cause excessive proliferation of leukemia cells. Therefore, we propose IL-10R is a novel promising therapeutic candidate for AML, and IL-10R targeted CAR-T therapy provides a new treatment strategy to improve the prognosis of AML.

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

Blood ◽

10.1182/blood-2013-09-529537 ◽

2014 ◽

Vol 123 (15) ◽

pp. 2343-2354 ◽

Cited By ~ 237

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.

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Gill S, Tasian SK, Ruella M, et al. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor–modified T cells. Blood. 2014;123(15):2343-2354.

Blood ◽

10.1182/blood-2016-10-745448 ◽

2016 ◽

Vol 128 (21) ◽

pp. 2585-2585 ◽

Cited By ~ 1

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Chimeric Antigen Receptor ◽

Myeloid Leukemia ◽

Antigen Receptor ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid

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

Blood ◽

10.1182/blood.v128.22.4058.4058 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4058-4058 ◽

Cited By ~ 3

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

Blood ◽

10.1182/blood-2016-08-736041 ◽

2017 ◽

Vol 129 (17) ◽

pp. 2395-2407 ◽

Cited By ~ 79

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.

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CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia

Leukemia ◽

10.1038/leu.2015.52 ◽

2015 ◽

Vol 29 (8) ◽

pp. 1637-1647 ◽

Cited By ~ 196

Author(s):

S S Kenderian ◽

M Ruella ◽

O Shestova ◽

M Klichinsky ◽

V Aikawa ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Chimeric Antigen Receptor ◽

Myeloid Leukemia ◽

Antigen Receptor ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.695051 ◽

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.

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Can immune therapy cure acute myeloid leukemia?

Cellular Therapy and Transplantation ◽

10.18620/ctt-1866-8836-2020-9-2-8-12 ◽

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.

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