研究证实,尽早使用胸腺肽α1,将带来显著获益

2018-10-19 19:14来源:本站作者:admin

  胸腺肽α-1(Tα1)是一种经典的免疫治疗药物,可以增强先天性和适应性免疫反应。基于以往研究,达卡巴嗪(DTIC)和Tα1联合治疗能够使患者进一步获得生存期的延长和更长时间的疾病稳定期。那么,在已经获得长期生存的转移性黑色素瘤(MM)患者中,Tα1治疗后序贯接受抗细胞毒性T淋巴细胞抗原-4(CTLA-4)药物治疗是否仍具有潜在的协同作用?日前,《Expert Opinion on Biological Therapy》杂志上发表了意大利Sienna医学院免疫与肿瘤中心Riccardo Danielli教授团队的相关研究结果。

  对于该项研究结果,乔治华盛顿大学医学院生物化学与分子医学系Allan L. Goldstein教授进行了精彩点评。

  研究简介背景

  免疫检查点抑制剂(imAbs),如以ipilimumab(IPI)为代表的细胞毒性T淋巴细胞抗原-4(CTLA-4)能够提高转移性黑色素瘤(MM)的总生存期(OS)。长期随访下的OS逐渐成为MM的终点事件。一项转移性黑色素瘤II期临床研究及一项EAP项目中,Tα1联合DTIC显示出抗肿瘤效果。本研究回顾分析了使用Tα1治疗MM患者的长期随访数据,以明确在接受imAbs治疗的患者中Tα1所起到的作用。

  ‍方法‍

  对Ⅱ期临床试验(试验号:NCT00911443)和EAP项目中使用Tα1治疗的黑色素瘤患者数据收集后,分析Tα1治疗后序贯接受抗CTLA-4药物治疗患者的中位OS。此外,研究还探索了Tα1治疗后序贯IPI治疗对长期生存患者的影响。

  ‍结果

  在使用Tα1治疗的61例患者中‍,21例患者序贯接受抗CTLA-4治疗。结果显示,序贯接受抗CTLA-4治疗的中位OS 57.8个月,未序贯接受CTLA-4治疗的中位OS 7.4个月。对于所有95例接受IPI治疗的患者,使用Tα1进行预处理能够显著延长患者长期OS(38.4个月对8.0个月,P=0.03),患者的2年、3年、4年、5年生存率均显著升高(图)。

‍结论

  这是关于Tα1治疗患者长期随访的首份报告。该研究表明患者使用Tα1和IPI的序贯治疗,能够获得OS的显著延长,该结果表明Tα1与IPI具有协同作用。

  Abstract

  Immune checkpoint blockade antibodies (imAbs), such as the anti Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) ipilimumab (IPI) raised overall survival (OS) in metastatic melanoma (MM). Further, long-term OS is a crucial endpoint in MM. Thymosin alpha-1 (Tα1) with dacarbazine (DTIC) showed activity in a phase II trial and a compassionate use program (EAP). We report on long-term follow-up of patients treated with Tα1 to investigate the preconditioning role of Tα1 in imAbs-treated patients.

  Methods

  Records of patients with melanoma treated with Tα1 within a phase II trial and EAP program were reviewed comparing median OS among patients that sequentially received anti-CTLA-4 imAb and Tα1. Further, the effect of Tα1 on IPI long-term survivor patients was investigated.

  Results

  Among patients treated with Tα1, 21/61 patients received sequentially even anti CTLA-4 imAbs. Median OS at the data cut-off was 57.8 and 7.4 months in patients treated sequentially with anti-CTLA-4 imAbs or not, respectively. Moreover, pretreatment with Tα1 in all (95) IPI-evaluable patients confirmed a significant increase in long-term OS.

  Conclusion

  This is the first report on long-term follow-up of Tα1-treated patients. Moreover, an advantage in OS in patients sequentially treated with Tα1 and IPI was seen that suggests a synergistic effect.

  Allan L. Goldstein教授点评

  来自意大利Sienna医学院免疫与肿瘤中心的Riccardo教授及研究团队首次研究并报道Tα1联合IPI治疗MM患者,能够产生协同作用提高疗效,显著提高患者的OS(Expert Opinion on Biological Therapy 2018, Vol 18, No. s1, 77-83)。

  近年来,imAbs在肿瘤治疗中发展迅猛。IPI等imAbs专门作用于CTLA-4——一种位于T细胞上的蛋白质,如同一种“关闭开关”,可以防止T细胞特异性攻击癌细胞。有研究表明,IPI及其他imAbs有助于延长晚期黑色素瘤、肺癌、肾癌及膀胱癌患者的生存期。

  本研究进一步显示,除已经被证实的可激活化疗、放疗和手术后肿瘤患者的先天性免疫和适应性免疫反应外,Tα1还可协同IPI进一步延长患者的生存期。该研究还发现,随访95例接受IPI治疗的患者,曾经接受Tα1治疗的患者其3年、4年和5年生存期相较未曾接受Tα1治疗的患者显著增加。

  作者还建议,评估Tα1-IPI协同作用的最好方法是在晚期黑色素瘤患者中观察患者的“长期总体生存终点”。但很遗憾,该研究采用了回顾性数据分析,期待针对该研究结果开展前瞻性Ⅲ/Ⅳ期黑色素瘤患者采用Tα1-IPI序贯治疗的研究以进一步证实其疗效。如果该研究结果被证实,将极大提升Tα1联合IPI,甚至整个imAbs家族的信心。

  Allan L. Goldstein

  Dr. Goldstein is Emeritus Professor in the Department of Biochemistry and Molecular Medicine at The George Washington University School of Medicine in Washington, DC. He Chaired the Department from 1978 until March 2009. He is an authority on the thymus gland and the workings of the immune system, and co-discoverer (with Abraham White) of the Thymosins, a family of hormone-like peptides isolated from the thymus gland. Thymosina1(TA1) a molecule with immune enhancing properties, was the first of the Thymosins to enter clinical trials. It has been approved in China and 35 other countries, and has shown great promise in the treatment of severe sepsis, cancer, and a number of other diseases including   the potential treatment of cystic fibrosis. Most recentlyTA1 has been found to synergize with Ipilimumab(IPI) ,a check-point inhibitor & further extend the survival of Stage III/IV melanoma patients previously treated successfully with TA1 melanoma patients Thymosinβ4 (Tβ4), the second of the Thymosins to reach the clinic, has been shown to accelerate wound healing and the remodeling of injured tissues.  Early Phase-II trials have been completed in patients with pressure and venostasis ulcers. Two Phase-III trials in  with dry eye and neurotrophic keratopathy have been completed in the US with promising results. A new Phase 3 trial in dry eye with 700 patients will begin in the fourth quarter of 2018An injectable form of Tb4 has been developed for internal indications such as myocardial infarction, stroke, multiple sclerosis, brain trauma and peripheral neuropathy. Dr. Goldstein’s research has helped define the role of biological response modifiers in health and disease, and has led to the discovery of important new links between the immune system, the neuroendocrine system and the brain.

  He received his B.S. degree from Wagner College in 1959 and his M.S. and Ph.D. degrees from Rutgers University in 1964. He served on the faculties of the Albert Einstein College of Medicine from 1964 to 1972, and The University of Texas Medical Branch in Galveston from 1972 through 1978. Dr. Goldstein was the co-founder and first President and Scientific Director of The Institute for Advanced Studies in Aging and Geriatric Medicine (IASIA). He has also served as a member of the Board of Trustees of the Albert Sabin Vaccine Institute, as well as the Board of Directors of The George Washington University Cardiovascular Institute. He currently serves as the Chairman of the Board and Chief Scientific Advisor for RegeneRx Biopharmaceuticals, a public company developing novel wound healing and remodeling therapeutics.

  Dr. Goldstein is the author of more than 445 scientific articles in professional journals, the inventor on over 25 U.S. and overseas patents, and the editor of several books in the fields of biochemistry, biomedicine, immunology and neuroscience. He is the recipient of several awards including the Career Scientist Award of the Health Research Council, City of New York; the Van Dyke Memorial Award in Pharmacology from the College of Physicians and Surgeons of Columbia University, a citation from the U.S. Department of Health, Education and Welfare “in recognition and appreciation of outstanding work in helping to establish a national program of ‘Biological Response Modifiers’”; a Doctor of Science Degree (Honoris Causa), Wagner College; the Decoration of the Order “Vasco Nunez De Balboa,” in the rank of Commander, Panama’s highest national honor for “contributions directed to the preservation of human life in the world”; the Distinguished Researcher Award of The George Washington University School of Medicine, and the “Chevalier des PalmesAcademiques,” for his scientific contributions to France.

  Over the years, Dr. Goldstein’s laboratory has been a center for the training of graduate, medical, and postdoctoral students, many of whom are now continuing and expanding his studies on the role of the thymus in health and disease. Dr. Goldstein has also been a pioneer in medical education having developed a unique series of distance education programs presented for the Internet, called “Frontiers in Medicine.” This series of lectures and National Town Forums by leading scientists focused on research at the cutting edge. The broadcasts, which were presented “live” from The George Washington University, began in 1997 and were a first for continuing medical education on the Internet.

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