肿瘤细胞治疗研究
英文原题：Coadministration with bendamustine restores the antitumor activity of obinutuzumab in obinutuzumab-resistant tumors.
Coadministration with bendamustine restores the antitumor activity of obinutuzumab in obinutuzumab-resistant tumors.
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在 obinutuzumab 再治疗中联合使用 bendamustine 可能对 obinutuzumab 耐药肿瘤有效。
糖工程化人源化抗CD20抗体obinutuzumab适用于既往未经治疗或复发/难治性CD20阳性滤泡性淋巴瘤（FL）。然而，对于既往接受过含obinutuzumab治疗的复发/难治性FL，obinutuzumab再治疗的有效性尚不明确。为解决这一问题，我们在由人非霍奇金淋巴瘤异种移植模型建立的obinutuzumab耐药肿瘤中，研究了obinutuzumab联合bendamustine的抗肿瘤活性。
通过反复给予obinutuzumab，从SU-DHL-4异种移植模型中建立了obinutuzumab耐药肿瘤（SU-DHL-4-OR-18-8）。在第1、8和15天给予obinutuzumab和/或在第1和2天给予bendamustine后，基于肿瘤体积评估抗肿瘤活性。通过免疫组织化学和流式细胞术评估瘤内自然杀伤（NK）细胞/巨噬细胞。
在SU-DHL-4-OR-18-8异种移植瘤中，obinutuzumab治疗后第4天，瘤内NK细胞/巨噬细胞较亲本肿瘤显著减少。内质网应激感受器phospho-IRE1也降低。在SU-DHL-4-OR-18-8肿瘤中，bendamustine治疗在第4天增加phospho-IRE1，在第10天增加瘤内NK细胞/巨噬细胞。与各单药相比，obinutuzumab联合bendamustine在第29天显著增加抗肿瘤活性，并在第10天增加趋化因子CCL6表达。
The glycoengineered, humanized anti-CD20 antibody obinutuzumab is indicated for previously untreated or relapsed/refractory CD20-positive follicular lymphoma (FL). However, the effectiveness of obinutuzumab retreatment in relapsed/refractory FL after prior obinutuzumab-containing therapy is unclear. To address this issue, we investigated the antitumor activity of obinutuzumab plus bendamustine in obinutuzumab-resistant tumors established from a human non-Hodgkin lymphoma xenograft model.
Obinutuzumab-resistant tumors (SU-DHL-4-OR-18-8) were established from an SU-DHL-4 xenograft model by repeated administration of obinutuzumab. Antitumor activity was evaluated based on tumor volume after treatment with obinutuzumab on Day 1, 8, and 15 and/or bendamustine on Day 1 and 2. Intratumoral natural killer (NK) cells/macrophages were evaluated by immunohistochemistry and flow cytometry.
In SU-DHL-4-OR-18-8 xenografted tumors, intratumoral NK cells/macrophages after obinutuzumab treatment were significantly decreased compared with parent tumors on Day 4. The endoplasmic reticulum stress sensor phospho-IRE1 was also decreased. In SU-DHL-4-OR-18-8 tumors, bendamustine treatment increased phospho-IRE1 on Day 4 and intratumor NK cells/macrophages on Day 10. Obinutuzumab combined with bendamustine significantly increased antitumor activity compared with each single agent on Day 29, with an increase in chemoattractant CCL6 expression on Day 10.
Coadministration of bendamustine in obinutuzumab retreatment may be effective against obinutuzumab-resistant tumors.
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