2014年11月27日 讯 /生物谷BIOON/ –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。
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.
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.