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 cellsReport as inadecuate




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 - Download this document for free, or read online. Document in PDF available to download.

Journal of Hematology and Oncology

, 8:108

First Online: 06 October 2015Received: 06 July 2015Accepted: 28 September 2015DOI: 10.1186-s13045-015-0205-6

Cite this article as: Fan, D., Li, W., Yang, Y. et al. J Hematol Oncol 2015 8: 108. doi:10.1186-s13045-015-0205-6

Abstract

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.

KeywordsBi-specific antibody Diabody Anti-CD3 Anti-CD19 Disulfide crosslinks B-ALL Cancer immunotherapy AbbreviationsAPCAllophycocyanin

Ara-CCytarabine

B-ALLB-acute lymphoblastic leukemia

BiTEBi-specific T cell engager

bsAbsBi-specific antibodies

CARTChimeric antigen receptor–modified T cells

CRSCytokine release syndrome

ds-diabodyDisulfide-stabilized format

FACSFluorescence-activated cell sorting

PBMCsPeripheral blood mononuclear cells

TAATumor-associated antigen

Dongmei Fan and Wei Li contributed equally to this work.

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Author: Dongmei Fan - Wei Li - Yuqi Yang - Xiaolong Zhang - Qing Zhang - Yan Yan - Ming Yang - Jianxiang Wang - Dongsheng Xiong

Source: https://link.springer.com/







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