Cytosine Arabinoside Promotes Cytotoxic Effect of T Cells on Leukemia Cells Mediated by Bispecific Antibody

Li, Wei; Fan, Daiming; Yang, Moon-Sik; Yan, Yan; Shi, Ruizan; Cheng, Jin; Li, Zhenzhen; Zhang, MengNan; Wang, Jianxiang; Xiong, Dongsheng

doi:10.1089/hum.2013.051

Cited by 6 publications

(5 citation statements)

References 35 publications

(29 reference statements)

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“…However, increasing evidence indicates that such ligands can be displayed on malignant myeloid or lymphoid cells in patients with active leukemia before treatment initiation and/or be induced by various stimuli such as cytokines, histone deacetylase inhibitors, DNA methyltransferase inhibitors and conventional chemotherapeutics. 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 Consistent with this, we observed significantly increased expression of T-cell ligands after 24–48 h culture of several of the primary AML cells in the presence of interferon-γ ( Supplementary Figure 2 ). As several checkpoint inhibitors (for example, antibodies blocking CTLA-4 or PD-1) are currently undergoing testing as a means to restore anti-tumor immune responses in human trials, 18 , 40 it is conceivable that the clinical potential of such combination strategies could be exploited in the near future.…”

Section: Discussionsupporting

confidence: 84%

T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330

Laszlo

Gudgeon

Harrington

et al. 2015

Blood Cancer Journal

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Preclinical and emerging clinical studies demonstrate that bispecific T-cell engaging (BiTE) antibody constructs can potently lyse targeted tumor cells, but the determinants for their activity remain incompletely understood. Using human acute myeloid leukemia (AML) cell lines engineered to overexpress individual T-cell ligands, we found that expression of the inhibitory ligands, PD-L1 and PD-L2, reduced the cytolytic activity of the BiTE antibody construct targeting CD33, AMG 330; conversely, expression of the activating ligands, CD80 and CD86, augmented the cytotoxic activity of AMG 330. Consistent with these findings, treatment with an activating antibody directed at the co-stimulatory T-cell receptor, CD28, significantly increased AMG 330-induced cytotoxicity in human AML cell lines. Using specimens from 12 patients with newly diagnosed or relapsed/refractory AML, we found that activation of CD28 also increased the activity of AMG 330 in primary human AML cells (P=0.023). Together, our findings indicate that T-cell ligands and co-receptors modulate the anti-tumor activity of the CD33/CD3 BiTE antibody construct, AMG 330. These findings suggest that such ligands/co-receptors could serve as biomarkers of response and that co-treatment strategies with pharmacological modulators of T-cell receptor signaling could be utilized to further enhance the activity of this targeted therapeutic.

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Section: Discussionsupporting

confidence: 84%

T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330

Laszlo

Gudgeon

Harrington

et al. 2015

Blood Cancer Journal

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“…We coated magnetic microbeads with anti-CD19 idiotype antibodies to cross-link the anti-CD19 CAR. This approach avoided the introduction of target cell proteins and RNA that confound analyses of signaling and did not add additional signals to the CAR T cells through other costimulatory interactions such as by integrin and CD28 activation (42). Furthermore, such beads have been used by our group and others to study CAR signaling and its effects on T cell expansion, metabolism, and differentiation (12,43,44).…”

Section: -1bb Costimulation Enhances Ex Vivo Car T Cell Expansion Relative To Cd28 Costimulation and Is Associated With Improved T Cell Smentioning

confidence: 99%

4-1BB costimulation promotes CAR T cell survival through noncanonical NF-κB signaling

et al. 2020

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Clinical response to chimeric antigen receptor (CAR) T cell therapy is correlated with CAR T cell persistence, especially for CAR T cells that target CD19+ hematologic malignancies. 4-1BB–costimulated CAR (BBζ) T cells exhibit longer persistence after adoptive transfer than do CD28-costimulated CAR (28ζ) T cells. 4-1BB signaling improves T cell persistence even in the context of 28ζ CAR activation, which indicates distinct prosurvival signals mediated by the 4-1BB cytoplasmic domain. To specifically study signal transduction by CARs, we developed a cell-free, ligand-based activation and ex vivo culture system for CD19-specific CAR T cells. We observed greater ex vivo survival and subsequent expansion of BBζ CAR T cells when compared to 28ζ CAR T cells. We showed that only BBζ CARs activated noncanonical nuclear factor κB (ncNF-κB) signaling in T cells basally and that the anti-CD19 BBζ CAR further enhanced ncNF-κB signaling after ligand engagement. Reducing ncNF-κB signaling reduced the expansion and survival of anti-CD19 BBζ T cells and was associated with a substantial increase in the abundance of the most pro-apoptotic isoforms of Bim. Although our findings do not exclude the importance of other signaling differences between BBζ and 28ζ CARs, they demonstrate the necessary and nonredundant role of ncNF-κB signaling in promoting the survival of BBζ CAR T cells, which likely underlies the engraftment persistence observed with this CAR design.

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“…In the present study, Ara-C up-regulated CD80 expression on the CD19+ human leukemia cell-line Nalm-6. A combination of the diabody plus Ara-C induced greater CTL activity against Nalm-6 cells both in vitro and in vivo [ 34 ]. Ara-C, which is one component of the most widely used regimens for treating ALL, was used in this study at a low dose.…”

Section: Introductionmentioning

confidence: 99%

Redirection of CD4+ and CD8+ T lymphocytes via an anti-CD3 × anti-CD19 bi-specific antibody combined with cytosine arabinoside and the efficient lysis of patient-derived B-ALL cells

Fan

Yang

et al. 2015

J Hematol Oncol

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BackgroundB-acute lymphoblastic leukemia (B-ALL) is derived from B cell progenitors. Recently, the development of appropriate combinations of chemotherapy and immunotherapy represents a promising approach for eliminating cancer. We previously constructed an anti-CD3 × anti-CD19 bi-specific antibody in a diabody configuration and its disulfide-stabilized format (ds-diabody). The combination of the diabody or ds-diabody and Ara-C was highly effective in enhancing the cytotoxicity of T cells against the CD19+ human leukemia cell-line, Nalm-6, both in vitro and in vivo. This study verified whether B-ALL patient-derived cells were sensitive to the diabody or ds-diabody and low-dosage Ara-C combination.MethodsThis study aimed to detect the B7 family members B7.1 (CD80) and B7.2 (CD86) that were expressed in B-ALL patient-derived cells pre-treated by Ara-C (0.25 μM) and to determine the targeted killing ability of T cell subtypes induced by the diabody or ds-diabody combination with Ara-C both in vitro and in vivo. We also determined the levels of the cytokines that were released by activated CD4+ or CD8+ T cells during therapy.ResultLow-dose Ara-C enhanced CD80 and CD86 expression in nearly 50 % of specimens of B-ALL patient-derived cells. A combination of diabody or ds-diabody and Ara-C enhanced T cell against B-ALL cells in vitro and in vivo. Both CD8+ and CD4+ T cells were potently activated. Expression of CD25 and CD69 was augmented equally by CD4+ or CD8+ T cells. However, CD8+ T cells made the major contribution by redirecting target cell lysis in a granzyme B and perforin-dependent mechanism. CD4+ T cells played an important immunomodulatory role by secreting IL2. Consequently, IL3, IL6, TNFα, and IFNγ were also released by CD4+ or CD8+ T cells following diabody-mediated T cell activation.ConclusionT cell therapy induced by diabody or ds-diabody combined with low dose of Ara-C was effective against cancer cell-lines and in clinical trials. In vivo, the ds-diabody was more efficient than its parent diabody due to its enhanced stability.

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Cytosine Arabinoside Promotes Cytotoxic Effect of T Cells on Leukemia Cells Mediated by Bispecific Antibody

Cited by 6 publications

References 35 publications

T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330

T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330

4-1BB costimulation promotes CAR T cell survival through noncanonical NF-κB signaling

Redirection of CD4+ and CD8+ T lymphocytes via an anti-CD3 × anti-CD19 bi-specific antibody combined with cytosine arabinoside and the efficient lysis of patient-derived B-ALL cells

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