DCLK1 Monoclonal Antibody-Based CAR-T Cells as a Novel Treatment Strategy against Human Colorectal Cancers
| Autor: | Robert Berahovich, Kai Ding, Hua Zhou, Lijun Wu, Randal May, Dongfeng Qu, Vita M. Golubovskaya, Courtney W. Houchen, Sripathi M. Sureban, Edwin Bannerman-Menson, Shirley Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class medicine.medical_treatment Monoclonal antibody lcsh:RC254-282 Article 03 medical and health sciences HT29 Cells 0302 clinical medicine tumor stem cells medicine dclk1 Interferon gamma clonogenicity Clonogenic assay Cytotoxicity car-t biology Chemistry Immunotherapy lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Chimeric antigen receptor digestive system diseases 3. Good health 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research immunotherapy Antibody human activities medicine.drug |
| Zdroj: | Cancers, Vol 12, Iss 1, p 54 (2019) Cancers Volume 12 Issue 1 |
| ISSN: | 2072-6694 |
| Popis: | CAR-T (chimeric antigen receptor T cells) immunotherapy is effective in many hematological cancers however, efficacy in solid tumors is disappointing. Doublecortin-like kinase 1 (DCLK1) labels tumor stem cells (TSCs) in genetic mouse models of colorectal cancer (CRC). Here, we describe a novel CAR-T targeting DCLK1 (CBT-511 with our proprietary DCLK1 single-chain antibody variable fragment) as a treatment strategy to eradicate CRC TSCs. The cell surface expression of DCLK1 and cytotoxicity of CBT-511 were assessed in CRC cells (HT29, HCT116, and LoVo). LoVo-derived tumor xenografts in NOD Scid gamma (NSGTM)mice were treated with CBT-511 or mock CAR-T cells. Adherent CRC cells express surface DCLK1 (two-dimensional, 2D). A 4.5-fold increase in surface DCLK1 was observed when HT29 cells were grown as spheroids (three-dimensional, 3D). CBT-511 induced cytotoxicity (2D p < 0.0001), and increased Interferon gamma (IFN-&gamma ) release in CRC cells (2D) compared to mock CAR-T (p < 0.0001). Moreover, an even greater increase in IFN-&gamma release was observed when cells were grown in 3D. CBT-511 reduced tumor growth by approximately 50 percent compared to mock CAR-T. These data suggest that CRC cells with increased clonogenic capacity express increased surface DCLK1. A DCLK1-targeted CAR-T can induce cytotoxicity in vitro and inhibit xenograft growth in vivo. |
| Databáze: | OpenAIRE |
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