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Nature:恶性膀胱癌的新型抗体疗法

标签:膀胱癌 疗法
摘要 : 近日,刊登在国际著名杂志Nature上的两篇研究报告中,来自伦敦王后大学的科学家通过研究开发了一种治疗膀胱癌的新型疗法,在过去30年里治疗膀胱癌并无有效的疗法,本文研究中研究人员检测了一种名为MPDL3280A的抗体可以有效阻断PD-L1蛋白,该蛋白被认为可以帮助癌细胞逃脱免疫系统的监视。

 

近日,刊登在国际著名杂志Nature上的两篇研究报告中,来自伦敦王后大学的科学家通过研究开发了一种治疗膀胱癌的新型疗法,在过去30年里治疗膀胱癌并无有效的疗法,本文研究中研究人员检测了一种名为MPDL3280A的抗体可以有效阻断PD-L1蛋白,该蛋白被认为可以帮助癌细胞逃脱免疫系统的监视。

文章中,研究人员对68名恶性膀胱癌患者进行了第一阶段的多中心临床研究,这些患者对其它疗法比如化疗均无反应,试验中研究人员给予患者抗体MPDL3280A,同时对患者进行蛋白PD-L1的检测,发现有30名患者PD-L1检测阳性。

在6周的治疗结束后,43%的PD-L1阳性患者机体中的肿瘤萎缩了,在接下来的12周里肿瘤受抑制的患者的比率上升到了52%;对其中两名患者(7%)进行放射线影像检测发现在患者机体中并无癌症迹象存在,而在PD-L1阴性的患者中,11%的患者对MPDL3280A疗法产生了明显的反应。

肿瘤学家Tom Powles表示,本文研究为有效改善恶性膀胱癌的新型疗法提供了很大的帮助,很多年以来化疗方法被认为是首选的抗癌疗法,但其对膀胱癌的预后较差,而且很多病人的疾病难以用化疗来进行治疗。本文研究不仅揭示了抗体MPDL3280A对肿瘤的明显抑制作用,而且研究者可以通过扫描特殊蛋白PD-L1来对患者进行靶向作用。

膀胱癌是英国第七大最常见的癌症,被诊断的个体中有10%的患者都是恶性膀胱癌,患者确诊后平均寿命仅为12-18个月,由于化疗方法有限因此往往并不会给患者的生存期带来明显改善,本文中MPDL3280A抗体的开发或为开发新型的膀胱癌疗法提供希望和帮助。

原文摘要:

Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

Roy S. Herbst, Jean-Charles Soria, Marcin Kowanetz, Gregg D. Fine, Omid Hamid, Michael S. Gordon, Jeffery A. Sosman, David F. McDermott, John D. Powderly, Scott N. Gettinger, Holbrook E. K. Kohrt, Leora Horn, Donald P. Lawrence, Sandra Rost, Maya Leabman, Yuanyuan Xiao, Ahmad Mokatrin, Hartmut Koeppen, Priti S. Hegde, Ira Mellman, Daniel S. Chen & F. Stephen Hodi

The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system1, 2, 3, 4. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment5. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the ‘cancer immunity cycle’ by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing6, 7, 8, 9, 10. The PD-L1–PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections11. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.(doi:10.1038/nature14011

MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer

Thomas Powles, Joseph Paul Eder, Gregg D. Fine, Fadi S. Braiteh, Yohann Loriot, Cristina Cruz, Joaquim Bellmunt, Howard A. Burris, Daniel P. Petrylak, Siew-leng Teng, Xiaodong Shen, Zachary Boyd, Priti S. Hegde, Daniel S. Chen & Nicholas J. Vogelzang

There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor1, 2. One hallmark of UBC is the presence of high rates of somatic mutations3, 4, 5. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens6. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment7, 8. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80)9. Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC—the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.(doi:10.1038/nature13904

来源: Nature 浏览次数:49

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