Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, Virginia, USA.
Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, Michigan, USA.
Oncoimmunology. 2021 Jun 1;10(1):1930883. doi: 10.1080/2162402X.2021.1930883.
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 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.
在这项研究中，我们研究了双特异性抗体武装激活 T 细胞靶向耐药胰腺癌细胞的能力，以及用双特异性抗体武装激活 T 细胞“预刺激”这些耐药癌细胞是否能增强对化疗药物的后续反应。化疗对胰腺癌的反应要么有限，要么肿瘤对化疗方案产生耐药性。这项研究的动力来自我们早期的 I/II 期临床试验中观察到的显著临床反应：一名患有耐药肿瘤的胰腺癌患者在接受三次抗 CD3 x 抗 EGFR 双特异性抗体武装激活 T 细胞（EGFR BATs）输注后疾病进展，重新开始最初的低剂量 显示完全缓解，这表明 BATs 输注可能使患者的肿瘤对化疗敏感。在目前的研究中，我们检验了 BATs 可以使肿瘤对化疗敏感的假设。EGFR BATs 可以有效地靶向吉西他滨或顺铂耐药的 MiaPaCa-2 和 L3.6 细胞系。用 EGFR BATs 对敏感或耐药细胞进行预刺激，然后用较低浓度的 50%抑制浓度的吉西他滨或顺铂进行重新靶向，显示出增强的细胞毒性。与亲本细胞系相比，吉西他滨或顺铂耐药细胞系显示出增加比例的 CD44/CD24/EpCAM 癌症干细胞样细胞，以及增加数量的 ABC 转运蛋白 ABCG2 阳性细胞。这些数据表明，双特异性抗体武装激活 T 细胞可以靶向和杀死化疗耐药的肿瘤细胞，并显著增强随后的化疗反应性，可能是通过调节 ABC 转运蛋白的表达。
Zotero 插件
