Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents

Sharifzadeh, Zahra; Rahbarizadeh, Fatemeh; Shokrgozar, Mohammad Ali; Ahmadvand, Davoud; Mahboudi, Fereidoun; Jamnani, Fatemeh Rahimi; Moghimi, S. Moein

doi:10.1016/j.canlet.2012.08.010

Cited by 62 publications

(44 citation statements)

References 43 publications

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“…Because the scFvs used to date in the clinic have almost all consisted of both heavy and light chain‐derived antigen binding domains and are often derived from murine monoclonal antibodies, there is considered to be a significant risk of anti‐idiotype or anti‐mouse antibodies, either of which can block function. Single domain scFvs have therefore also been used to prepare CARs . Their smaller ectodomain may render them less immunogenic, although this may come with the cost of lower affinity/specificity.…”

Section: Design Of the Chimeric Antigen Receptormentioning

confidence: 99%

Design and development of therapies using chimeric antigen receptor‐expressing T cells

Dotti

Gottschalk

Savoldo

et al. 2013

Immunological Reviews

429

348

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Summary Investigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non-protein antigens) with the persistence, trafficking and effector functions of a T-cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CART cells. Our review then describes our own and other investigators’ work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR-T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained.

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Section: Design Of the Chimeric Antigen Receptormentioning

confidence: 99%

Design and development of therapies using chimeric antigen receptor‐expressing T cells

Dotti

Gottschalk

Savoldo

et al. 2013

Immunological Reviews

429

348

View full text Add to dashboard Cite

show abstract

“…(Sharifzadeh et al 2013), folate-binding protein and MUC16 for the treatment of ovarian cancer (Chekmasova et al 2010, Hwu et al 1993, and the diasialoganglioside GD2 for the treatment of neuroblastoma (Rossig et al 2002). Studies have shown various CARs containing receptor polypeptide ligands linked to intracellular domains such as an integrinbinding peptide (anti-avb6), a polypeptide against vascular endothelial growth factor receptor (anti-VEGFR2), heregulin (anti-Her3/4 receptor), or interleukin (IL)-13 mutein (anti-IL13 receptor-a) (Kahlon et al 2004, Muniappan et al 2000, Niederman et al 2002, Pameijer et al 2007.…”

Section: Car Specificitymentioning

confidence: 99%

CAR-modified T-cell therapy for cancer: an updated review

Haji-Fatahaliha

Hosseini

Akbarian

et al. 2015

Artificial Cells, Nanomedicine, and Biotechnology

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The use of chimeric antigen receptor (CAR)-modified T cells is a promising approach for cancer immunotherapy. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in T-cell activation subsequent to antigen binding. Optimal tumor removal through CAR-modified T cells requires suitable target antigen selection, co-stimulatory signaling domain, and the ability of CAR T cells to traffic, persist, and retain antitumor function after adoptive transfer. There are several elements which can improve antitumor function of CAR T cells, including signaling, conditioning chemotherapy and irradiation, tumor burden of the disease, T-cell phenotype, and supplementary cytokine usage. This review outlines four generations of CAR. The pre-clinical and clinical studies showed that this technique has a great potential for treatment of solid and hematological malignancies. The main purpose of the current review is to focus on the pre-clinical and clinical developments of CAR-based immunotherapy.

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“…For example, the anti-TAG-72 antibody was used as a radioimmunotherapeutic agent to treat ovarian cancer (37). Moreover, several nanoparticles conjugated with the anti-TAG-72 antibody were also used as targeting agents for radioimmunotherapy and tumor imaging (13, 38). The CC49 mAb recognizes the sialyl-Tn and sialyl-T epitopes, which are disaccharide carbohydrate antigens present on TAG-72.…”

Section: Discussionmentioning

confidence: 99%

A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio

Chien

Chang

Lee

et al. 2017

Molecular Cancer Therapeutics

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Altered expression of the Fas ligand (FasL)/Fas ratio exhibits a direct impact on the prognosis of cancer patients, and its impairment in cancer cells may lead to apoptosis resistance. Thus, the development of effective therapies targeting the FasL/Fas system may play an important role in the flght against cancer. In this study, we evaluated whether a fusion protein (hcc49scFv-FasL) comprising of the cytotoxicity domain of the FasL fused to a humanized antibody (CC49) against tumor-associated glycoprotein 72, which is expressed on oral squamous cell carcinoma (OSCC), can selectively kill OSCC cells with different FasL/Fas ratios. In clinical samples, the significantly low FasL and high Fas transcripts were observed in tumors compared with normal tissues. A lower FasL/Fas ratio was correlated with a worse prognosis of OSCC patients and higher proliferative and invasive abilities of OSCC cells. The hcc49scFv-FasL showed a selective cytotoxic effect on OSCC cells (Cal-27 and SAS) but not on normal oral keratinocytes cells (HOK) through apoptosis induction. Moreover, SAS cells harboring a lower FasL/Fas ratio than Cal-27 were more sensitive to the cytotoxic effect of hcc49scFv-FasL. Unlike wild-type FasL, hcc49scFv-FasL was not cleaved by matrix metalloproteinases and did not induce nonapoptotic signaling in SAS cells. In vivo, we found that hcc49scFv-FasL drastically reduced the formation of lymph node metastasis and decreased primary tumor growth in SAS orthotopic and subcutaneous xenograft tumor models. Collectively, our data indicate that a tumor-targeting antibody fused to the FasL can be a powerful tool for OSCC treatment, especially in populations with a low FasL/Fas ratio.

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Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents

Cited by 62 publications

References 43 publications

Design and development of therapies using chimeric antigen receptor‐expressing T cells

Design and development of therapies using chimeric antigen receptor‐expressing T cells

CAR-modified T-cell therapy for cancer: an updated review

A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio

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