Augmenting the efficacy of prostate cancer-directed CAR T cell therapy by combining immune-editing, chemotherapy and androgen receptor blockade
通过结合免疫编辑、化疗和雄激素受体阻断来增强针对前列腺癌的 CAR T 细胞疗法的疗效
基本信息
- 批准号:520640763
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:
- 资助国家:德国
- 起止时间:
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Prostate cancer (PC) is the second most common cancer in men worldwide. Whereas primary tumors can often be successfully managed, new therapeutic options are urgently needed for advanced, thus far incurable stages of the disease. In recent years, immunotherapy became a new cornerstone in the treatment of cancer, including monoclonal antibodies that target immune checkpoint receptors and chimeric antigen receptor (CAR) T cells that target tumor-associated antigens. We recently demonstrated that our prostate-specific membrane antigen (PSMA)-targeting CAR T cells were able to eradicate human PC in a xenografted mouse model after local application, and, after systemic application, to inhibit tumor growth when combined with docetaxel (DTX) chemotherapy. Our preliminary data show that DTX or enzalutamide treatment increased CCL2 and CCL22 expression in PC cells, and that CAR T cells co-expressing the chemokine receptors CCR2 and CCR4 showed enhanced migration towards CCL2 and CCL22, respectively. We thus hypothesize that equipping CAR T cells with chemokine receptors will improve both their migration to CCL2/CCL22 secreting tumor cells as well as their ability to kill PSMA-expressing tumor cells after DTX or enzalutamide treatment. The objectives of our project are (i) to characterize the anti-tumor efficacy of gene-edited CCR2/CCR4-expressing PSMA-targeting CAR T cells alone and in combination with DTX and/or enzalutamide in vitro, and (ii) to validate the antitumor efficacy of CCR2/CCR4-expressing CAR T cells in mice xenografted orthotopically with metastasizing human PC cells upon non-ablative DTX and/or enzalutamide therapy. We believe that the results will expand our knowledge of immuno-oncological features of PC and pave the way for clinical trials.
前列腺癌(PC)是全球男性第二大常见癌症。虽然原发性肿瘤通常可以成功管理,但对于晚期,迄今为止无法治愈的疾病阶段,迫切需要新的治疗选择。近年来,免疫疗法成为癌症治疗的新基石,包括靶向免疫检查点受体的单克隆抗体和靶向肿瘤相关抗原的嵌合抗原受体(CAR)T细胞。我们最近证明,我们的前列腺特异性膜抗原(PSMA)靶向CAR T细胞能够在局部应用后在异种移植小鼠模型中根除人PC,并且在全身应用后,当与多西他赛(DTX)化疗组合时抑制肿瘤生长。我们的初步数据显示,DTX或恩杂鲁胺处理增加了PC细胞中的CCL 2和CCL 22表达,并且共表达趋化因子受体CCR 2和CCR 4的CAR T细胞分别显示出向CCL 2和CCL 22的迁移增强。因此,我们假设为CAR T细胞配备趋化因子受体将改善它们向分泌CCL 2/CCL 22的肿瘤细胞的迁移以及它们在DTX或恩杂鲁胺治疗后杀死表达PSMA的肿瘤细胞的能力。我们的项目的目的是(i)在体外表征基因编辑的表达CCR 2/CCR 4的靶向PSMA的CAR T细胞单独和与DTX和/或恩杂鲁胺组合的抗肿瘤功效,和(ii)在非消融性DTX和/或恩杂鲁胺治疗后,验证表达CCR 2/CCR 4的CAR T细胞在与转移性人PC细胞原位异种移植的小鼠中的抗肿瘤功效。我们相信,这些结果将扩大我们对PC免疫肿瘤学特征的了解,并为临床试验铺平道路。
项目成果
期刊论文数量(0)
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Professor Dr. Toni Cathomen其他文献
Professor Dr. Toni Cathomen的其他文献
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{{ truncateString('Professor Dr. Toni Cathomen', 18)}}的其他基金
Therapeutic gene targeting in human CD34+ cells.
人类 CD34+ 细胞的治疗性基因靶向。
- 批准号:
22811570 - 财政年份:2006
- 资助金额:
-- - 项目类别:
Priority Programmes
Targeted gene correction mediated by recombinant adeno-associated virus and DNA double strand breaks
重组腺相关病毒介导的靶向基因校正和DNA双链断裂
- 批准号:
5421152 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Research Grants
Gene editing as a novel therapeutic strategy in Fanconi anemia
基因编辑作为范可尼贫血的新型治疗策略
- 批准号:
460683728 - 财政年份:
- 资助金额:
-- - 项目类别:
Research Grants
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