Priming of pancreatic cancer cells with bispecific antibody armed activated T cells sensitizes tumors for enhanced chemoresponsiveness
Autor: | Dana L Schalk, Archana Thakur, Timothy M LaBrie, Johnson Ung, Lawrence G. Lum, Amy Schienschang, Elyse N. Tomaszewski |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
CD3 Complex T-Lymphocytes Immunology pancreatic cancer Chemoresponsiveness Priming (immunology) 03 medical and health sciences 0302 clinical medicine Pancreatic cancer Antibodies Bispecific medicine Immunology and Allergy Humans Cytotoxicity RC254-282 Original Research Cisplatin biology business.industry CD44 Cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC581-607 medicine.disease chemosensitization Gemcitabine Pancreatic Neoplasms 030104 developmental biology Oncology Cell culture 030220 oncology & carcinogenesis biology.protein Cancer research Neoplastic Stem Cells bispecific antibody armed activated T cells Immunologic diseases. Allergy business medicine.drug Research Article |
Zdroj: | Oncoimmunology article-version (VoR) Version of Record OncoImmunology, Vol 10, Iss 1 (2021) |
ISSN: | 2162-402X 2162-4011 |
Popis: | In this study, we investigated the ability of bispecific antibody armed activated T cells to target drug resistant pancreatic cancer cells and whether or not “priming” these resistant cancer cells with bispecific antibody armed activated T cells could enhance subsequent responsiveness to chemotherapeutic drugs. Chemotherapeutic responses for pancreatic cancer are either limited or the tumors develop resistance to chemotherapy regimens. The impetus for this study was the remarkable clinical response seen in our earlier phase I/II clinical trial: a pancreatic cancer patient with drug resistant tumors who showed progression of disease following three infusions of anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) was restarted on the initial low dose of 5-fluorouracil showed complete response, suggesting that BATs infusions may have sensitized patient’s tumor for chemoresponsiveness. In the current study, we tested the hypothesis that BATs can sensitize tumors for chemoresponsiveness. Gemcitabine or cisplatin-resistant MiaPaCa-2 and L3.6 cell lines were effectively targeted by EGFR BATs. Priming of drug sensitive or resistant cells with EGFR BATs followed by retargeting with lower concentrations of 50% inhibitory concentration of gemcitabine or cisplatin showed enhanced cytotoxicity. Gemcitabine or cisplatin-resistant cell lines show an increased proportion of CD44+/CD24+/EpCAM+ cancer stem like cells as well as an increased number of ABC transporter ABCG2 positive cells compared to the parental cell lines. These data suggest that bispecific antibody armed activated T cells can target and kill chemo-resistant tumor cells and also markedly augment subsequent chemotherapeutic responsiveness, possibly by modulating the expression of ABC transporters. |
Databáze: | OpenAIRE |
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