scholarly journals The Role of T Cell Immunotherapy in Acute Myeloid Leukemia

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3376
Author(s):  
Fang Hao ◽  
Christine Sholy ◽  
Chen Wang ◽  
Min Cao ◽  
Xunlei Kang
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Leukemic Cells ◽  
Cytotoxic T Cell ◽  
Cell Phenotype ◽  
T Cell Therapy ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous disease associated with various alterations in T cell phenotype and function leading to an abnormal cell population, ultimately leading to immune exhaustion. However, restoration of T cell function allows for the execution of cytotoxic mechanisms against leukemic cells in AML patients. Therefore, long-term disease control, which requires multiple therapeutic approaches, includes those aimed at the re-establishment of cytotoxic T cell activity. AML treatments that harness the power of T lymphocytes against tumor cells have rapidly evolved over the last 3 to 5 years through various stages of preclinical and clinical development. These include tissue-infiltrated lymphocytes (TILs), bispecific antibodies, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and tumor-specific T cell receptor gene-transduced T (TCR-T) cells. In this review, these T cell-based immunotherapies and the potential of TILs as a novel antileukemic therapy will be discussed.

scholarly journals A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Mohamed-Reda Benmebarek ◽  
Bruno L. Cadilha ◽  
Monika Herrmann ◽  
Stefanie Lesch ◽  
Saskia Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
Tumor Antigens ◽  
Adoptive T Cell Therapy ◽  
Single Chain ◽  
T Cell Therapy ◽  
Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

scholarly journals Checkpoint Blockade in Combination with CD33 Chimeric Antigen Receptor T Cell Therapy and Hypomethylating Agent Against Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1383-1383 ◽  
Author(s):  
Tongyuan Xue ◽  
Marissa Del Real ◽  
Emanuela Marcucci ◽  
Candida Toribio ◽  
Sonia Maryam Setayesh ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
T Cell Therapy ◽  
Programmed Death ◽  
Car T ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The cure rate for primary AML patients is only 35% and decreases with age. Novel and effective immunotherapies for patients with relapsed and/or refractory (r/r) AML remain an urgent unmet need. CD33 is an attractive immunotherapeutic target for myeloid malignancies given its expression on more than 85% of AML patient samples. We therefore set out to design and test CD33 chimeric antigen receptor (CD33CAR) T cells preclinically as a single agent and in combinational therapy. To assess antileukemic responses of CD33CAR T cells in vitro and in vivo, we enriched CD4/CD8 T cells from peripheral blood mononuclear cells (PBMCs) and genetically modified them to express a second-generation CD33CAR. CD33CAR T cells exhibited potent antigen dependent CD107a degranulation, IFN-γ production and killing activities against AML cells in vitro. Using a NOD-SCID-IL2Rgnull (NSG) xenograft model engrafted with MOLM-14-ffluc, a CD33 expressing AML cell line transduced with lentivirus carrying firefly luciferase (ffluc) and enhanced green fluorescent protein (eGFP), 3 million CD33CAR or mock T cells were introduced intravenously. CD33 CAR T cell-treated group displayed 98.2% leukemic regression 4 days post CAR T infusion, and 99.6% reduction on day 31. Bioluminescent imaging (BLI) and Kaplan-Meier analysis demonstrated that CD33CAR T cells significantly decreased leukemic burden and prolonged overall survival compared to mock T cells in vivo. Decitabine, a DNA hypomethylating agent (HMA), is a main therapeutic agent for treating AML. We observed HMA treatment led to increased CD33 expression on MOLM-14 cells in vitro. We hypothesized that decitabine can potentiate CD33CAR T cell-mediated AML killing by increasing CD33 expression. MOLM-14 cells were treated with either decitabine alone, CD33CAR T cells alone, or sequential treatment using various concentrations of decitabine or DMSO followed by CD33CAR or mock T cells in an E:T ratio of 1:100. We determined the target specific killing activities in each group using flow cytometric based analysis 48 and 96 hours later. The decitabine followed by CD33CAR T cells treatment reproducibly resulted in the most robust antileukemic activity with 80.6% MOLM-14 cells killed. In comparison, CD33CAR T cells or decitabine monotherapy resulted in 11.5% and 50.9% killing, respectively. In vivo testing of the combinational effects of decitabine and CD33CAR T cells are underway and will be updated at the meeting. Finally, checkpoint blockade targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) has shown survival benefits, particularly in combination with HMA, for patients with r/r AML (Daver et al. 2019). We observed elevated PD-L1 expression on residual AML blasts that survived the treatment with decitabine in combination with CD33CAR T cells. Therefore, we hypothesized that blockade of PD-1/PD-L1 interaction might further improve the antileukemic effect of CD33CAR T cells against AML cells post antigen induction by decitabine. MOLM-14 cells were treated with decitabine for 2 days and CD33CAR T cells were added in an E:T ratio of 1:75. Anti-PD-1 or IgG4 antibody was added to the culture at various concentrations. The most robust CD33 specific killing was seen in the culture with anti-PD-1 antibody added. Further characterization are underway and will be presented. Taken together, our preclinical findings have demonstrated the potency of the CD33CAR T cell therapy and ways to optimize its efficacy. Our results support clinical translation of CD33CAR T cells for patients with AML. Disclosures Budde: F. Hoffmann-La Roche Ltd: Consultancy.

Chimeric antigen receptor T-cell therapy in the treatment of acute myeloid leukemia: Possible challenges

2021 ◽  
Vol 1 (2) ◽  
pp. 86
Author(s):  
TarunKumar Suvvari ◽  
RahulJagdishchandra Mittal ◽  
KanishkK Adhit ◽  
NagaPraneeth Vakkalagadda ◽  
Divya BalaA. M R. Salibindla
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Acute Myeloid

Preclinical Evaluation of CD64 As a Potential Target For CAR-T-cell Therapy For Acute Myeloid Leukemia

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Xiaolei Sun ◽  
Guoling Wang ◽  
Shiyu Zuo ◽  
Qing Niu ◽  
Xiaoli Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
T Cell Therapy ◽  
Preclinical Evaluation ◽  
Potential Target ◽  
Car T Cell Therapy ◽  
Car T ◽  
Acute Myeloid

Targeting of a B7-1 (CD80) immunoglobulin G fusion protein to acute myeloid leukemia blasts increases their costimulatory activity for autologous remission T cells

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 3138-3145 ◽  
Author(s):  
Michael Notter ◽  
Tim Willinger ◽  
Ulrike Erben ◽  
Eckhard Thiel
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Fusion Protein ◽  
Immunoglobulin G ◽  
Myeloid Leukemia ◽  
Costimulatory Molecule ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Acute Myeloid

Abstract Transfection of tumor cells with the gene encoding the costimulatory molecule B7-1 (CD80), the ligand for CD28 and cytotoxic T lymphocye antigen-4 on T cells, has been shown to result in potent T-cell–mediated antitumor immunity. As an alternative approach, this study analyzed the costimulatory capacity of a human B7-1 immunoglobulin G (IgG) fusion protein targeted to the cell membrane of human acute myeloid leukemia (AML) blasts. Flow cytometric analysis revealed a low constitutive expression of B7-1 on human AML blasts (on average, 3.0 ± 4.3%; n = 50). In contrast, the expression of B7-2 (CD86) was highly heterogeneous and higher in AML blasts of French-American-British classification types M4 and M5 (P < .0001). The B7-1 IgG fusion protein used in this study efficiently costimulated the proliferation of resting and preactivated T cells when immobilized on plastic. After preincubation with B7-1 IgG, specific binding of the fusion protein to the high-affinity Fcγreceptor I (CD64) on leukemic cells was demonstrated and was found to increase the proliferation of both allogeneic and autologous T cells in costimulation experiments. Furthermore, targeting of B7-1 IgG to the tumor membrane resulted in increased proliferation of autologous remission T cells and had the potential to generate an enhanced redirected cytotoxic T-cell response against autologous AML blasts. In summary, the targeting of B7-1 IgG fusion protein described in this study represents a strategy alternative to gene therapy to restore the expression of the costimulatory molecule B7-1 on human AML blasts, thereby enhancing their immunogenicity for autologous T cells. This new approach may have implications for T-cell–mediated immunotherapy in AML.

scholarly journals PS974 MODELING NKG2D-BASED CAR-T CELL THERAPY IN ANIMALS WITH ACUTE MYELOID LEUKEMIA

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 439
Author(s):  
M. Fontaine ◽  
E. Breman ◽  
B. Demoulin ◽  
S. Bornschein ◽  
J. Bolsée ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Acute Myeloid

scholarly journals STAT3 Inhibition Enables TLR9-Driven Differentiation of Cbfb/Myh11 acute Myeloid Leukemia Cells to Antigen-Presenting Cell Phenotype In Vivo

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4070-4070
Author(s):  
Marcin Kortylewski ◽  
Priyanka Duttagupta ◽  
Yu-Lin SU ◽  
Tomasz Adamus ◽  
Guido Marcucci
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemic Cells ◽  
Pharmacological Intervention ◽  
Cell Phenotype ◽  
Atp Production ◽  
Antigen Presenting ◽  
Stat3 Inhibition ◽  
Acute Myeloid

Abstract STAT3 transcription factor is persistently activated in cancer cells and in diverse tumor-associated immune cells being an important oncogene and an essential immune checkpoint regulator. It is a highly desirable but challenging therapeutic target for pharmacological intervention. We previously demonstrated that ligand for the intracellular receptor TLR9 (CpG oligonucleotide) allows for the uptake and cytoplasmic delivery of decoy oligodeoxynucleotides (dODNs) to inhibit transcriptional activity of STAT3 in a variety of human and mouse acute myeloid leukemia (AML) cells. Here, we demonstrate that CpG-STAT3dODN injected intravenously to mice engrafted with Cbfb/MYH11 AML, dramatically altered leukemic cell morphology, by reducing nucleus-cytoplasm ratio and increasing mitochondria size, and also resulting in metabolic shift from glycolysis to oxidative phosphorylation, resulting in increased mitochondrial ATP production. The transcriptional profiling of AML cells isolated from spleens of mice treated using CpG-STAT3dODN vs control CpG-scrODN or PBS, revealed the increased expression of genes regulating myeloid cell differentiation (Irf8, Cebpa, Gadd45a) and antigen-presentation (B2m, CIIta, IL-12a, Ifng), with decrease of leukemia-related regulators Runx1and Run1t1. Thein vivodifferentiation of leukemic cells was confirmed using flow cytometry by detecting appearance of the population of AML-derived CD11b+/MHCII+/CD86+myeloid cells after CpG-STAT3dODN but not control treatments. Furthermore, we confirmed that the differentiated AML cells have immunogenic effects, which drive expansion of Th1 effector T cell responses in Cbfb/MYH11 as well as C1498 AML models. Overall, our studies suggest that STAT3-inhibition can unleash immune-stimulatory potential downstream of TLR9 signaling transforming AMLcells into antigen-presenting cells. These findings support development of CpG-STAT3dODN strategy as a new bi-functional agent for AML immunotherapy. This project described was supported by the National Cancer Institute of the National Institutes of Health under award number R01CA213131 to M.K. Disclosures Kortylewski: N/A: Patents & Royalties: I am an inventor on the US patent 9,976,147.

Sign in / Sign up

Export Citation Format

Share Document