2015年3月2日讯 /生物谷BIOON/ -- Provenge (sipuleucel-T)，普罗文奇，第一个在美国被批准用于治疗目的的肿瘤疫苗，开创了癌症免疫治疗的新时代，已经上市销售快5年。2月23日，加拿大拉瓦尔的Valeant公司宣布以四亿多美元的价格将Provenge买断，原制造商丹德里昂公司（Dendreon Corporation）宣告破产。
Provenge疫苗是利用患者自身的免疫系统与恶性肿瘤抗争，它由载有重组前列腺酸性磷酸酶(PAP)抗原的肿瘤患者自身的神经元树突细胞(免疫系统抗原的递呈细胞)构成。PAP蛋白表达于绝大多数的前列腺肿瘤细胞，也表达于正常的前列腺组织中，只是以极低的水平存在于其他正常组织中。在治疗性肿瘤疫苗Provenge中，PAP抗原融合于作为佐剂的一种免疫刺激细胞因子——粒细胞一巨噬细胞集落刺激因子(GM.CSF)，树突细胞则将PAP蛋白消化为多肽而呈现于其表面，当其被重新回输入患者体内后，可被免疫系统T细胞识别，而接触过该抗原后的T细胞能找到并杀灭表达PAP抗原的癌细胞。
2010年，位于华盛顿西雅图的Dendreon公司旗下的前列腺癌疫苗Provenge经FDA批准投放市场，赚足了医药界的眼球。诺华细胞和基因疗法事业部头目Usman Azam高度评价：“Dendreon有高明的预知能力和长远的眼光”，尽管现在Dendreon已不复存在。“不要认为Dendreon是个失败案例，它只是为后来者铺平了道路。”
Valeant是出了名的收购狂，以往关注的都是简单药品或是已经确立市场地位的产品。而这次买入Provenge却让人摸不着头脑。Valeant对Provenge信心满满，发言人说他们知道如何降低成本以及如何将Provenge推广到市场上，至少两年内就能回本。
Dendreon的荣辱之路
90年代早期，斯坦福大学的免疫学家Edgar Engleman在患有淋巴瘤的小鼠身上做了实验，开创性地发明了肿瘤免疫技术。随后，他与同僚Samuel Strober组建团队，就这一领域继续深入研究。
当他们意识到可以成立公司，吸引投资者入资时，实际上临床数据远远不够，也不清楚到底需要多长时间才能将其用于人类肿瘤的治疗，当时世界上还没有一家公司将该疗法做成产品，也没有哪个疗法这么个体化，医疗过程想当复杂、繁琐。但庆幸的是，他们获得了资金注入，凭借的就是这个具有前瞻性的创意，而不是潜在的商业价值。
1992年，Dendreon公司成立。2010年，产品Provenge获得FDA批准。耗时近20年！
2010年后，公司营业状况却每况愈下，陷入财政困难。原因归结于保险公司并没有将该药加到理赔药品清单上，这直接导致了医生不敢为患者开药，销量低迷，公司收入远远低于早期估算。直到最近，Dendreon连基本的运营也困难重重。
Engleman在谈及公司的失败时，表示最初的一些决策可能是错的，比如没有冷冻活化的免疫细胞，这使得产品工序更负责，成本更高；另一方面，他们最初动物实验的靶标是淋巴瘤，实验数据很有说服力，但移植到人体时，选择了前列腺癌，因为如果输入的免疫细胞攻击了正常的前列腺组织，人不会发生死亡，这就降低了服药的风险，而且前列腺癌的市场需求更大。Dendreon确实能延长晚期前列腺癌患者的寿命，但平均值仅仅4个月。Dendreon售价也较高，这也造成了它的渐渐失利。
Engleman以及他的合伙人并没有因此熄灭创业的热情，而是将目光锁定在器官移植领域，希望发明一种技术降低宿主的器官排斥反应。他们的临床实验已经进行了十年之久，数据也很乐观，估计融资是没有问题，“相信比Dendreon进展快很多。”他的合伙人Strober如是说。
英文原文：
Therapeutic cancer vaccine survives biotech bust
Pharmaceutical company rescues landmark prostate-cancer treatment， Provenge.
Therapeutic cancer vaccines harness the patient's own immune system to fight tumours. The first therapeutic cancer vaccine to be approved in the United States will stay on the market despite the financial collapse of the trailblazing biotechnology company that developed it. The vaccine， Provenge (sipuleucel-T)， was purchased on 23 February by Valeant Pharmaceuticals of Laval， Canada， which paid US$415 million for the prostate-cancer treatment and other assets of the bankrupt Dendreon Corporation.
The now-defunct Dendreon， of Seattle， Washington， made history in 2010 by showing that complex treatments made fresh for each patient could win regulatory approval， and could be expanded beyond the realm of specialized academic hospitals. Industry took note： today， experimental cancer therapies that spur patients' immune cells to attack tumours are among the hottest properties in biotechnology.
“Dendreon had vision and foresight，” says Usman Azam， head of cell and gene therapies at Novartis， a Swiss pharmaceutical company that has purchased one of Dendreon’s manufacturing plants to fuel its own cell-therapy efforts. “Don’t view Dendreon as a failure： it paved the way.”
But although Dendreon created the market for cell therapies， it ultimately could not survive in it.
Primed for attack
Provenge is made by harvesting a patient’s dendritic cells and then mixing them with a protein that is particularly abundant in prostate tumours. After being primed by that process to recognize and attack the tumour， the cells are infused back into the patient.
The technique was pioneered in the early 1990s by Edgar Engleman， an immunologist at Stanford University in California， who had seen promising results in animal studies of a different cancer， lymphoma. Engleman teamed up with fellow Stanford immunologist Samuel Strober to work out ways to make the process more efficient.
When the two pitched their idea for a company to investors， they had little clinical data and were too optimistic about how fast the treatment could reach patients， says Strober. The company was an enormous gamble： harnessing the immune system to fight cancer was still a controversial idea， and no other company had marketed a therapy so personalized and labour-intensive. “But at that time it was a little different from now，” says Strober. “Companies were getting funded on the basis of promise， rather than actually looking at their capacity for early commercial success.”
Engleman and Strober founded Dendreon in 1992； the US Food and Drug Administration approved Provenge in 2010.
Short-lived victory
The approval was celebrated as an important proof of concept by researchers working to develop cancer vaccines and other treatments that stimulate immune responses to the disease. But Dendreon， already strained by the long wait for approval， soon ran into financial difficulty.
Confusion over how payment for Provenge would be reimbursed by insurance companies left many doctors in the United States hesitant to use it， says Corey Davis， an analyst at Canaccord Genuity， an investment bank based in Toronto， Canada. When revenues came in far below the company’s initial estimates， Dendreon failed to adjust its operations accordingly， Valeant chief J. Michael Pearson told investors on 23 February.
Provenge is， at first glance， an odd purchase for Valeant， a company known for acquiring relatively simple， established products — for example， it controls 10% of the US contact-lens market. But Valeant saw an opportunity to cut costs and improve how the vaccine is marketed to doctors， and thinks it can make back its investment in less than two years， says Davis.
The vaccine’s rescue is a relief to Engleman， who had feared that Provenge might disappear along with Dendreon. As the company struggled financially， the scientists who founded it watched helplessly from the sidelines. “This was our baby，” says Engleman. “It was extraordinarily frustrating. There was nothing we could do.”
Early choices
In retrospect， Engleman says， some early scientific choices may have exacerbated Dendreon’s struggle. The company decided not to develop ways to freeze the stimulated immune cells， he notes， which could have simplified the procedure and lowered its cost.
And both scientists lament the choice of prostate cancer as the inaugural disease target of the technology. Although the early lymphoma data had been very promising， recalls Engleman， the company decided to switch to a more common cancer with a bigger potential market. And prostate cancer had another advantage： people can live without a prostate， which helped to calm fears (since proved unfounded) about what would happen if the primed immune cells attacked healthy tissue.
But the results in prostate cancer were not as dazzling as Engleman had hoped on the basis of his animal results in lymphoma. Dendreon did extend survival in some people with advanced prostate cancer， but by a median of only four months1. This week， the UK National Institute for Health and Care Excellence advised that at more than ￡47，000 (US$73，000) per course of treatment， Provenge is too expensive to justify its use by the National Health Service.
The Dendreon experience has not dampened Engleman’s enthusiasm for entrepreneurship. He and Strober， along with other collaborators， have teamed up on a company that aims to develop a technique to reduce the likelihood that recipients of transplanted organs will develop an immune response to the new tissue.
They are again on the hunt for funding， but this time the team is backed by more than a decade of clinical-trial data that backs the method. “We’re thinking that this one will progress a lot faster than the Dendreon thing，” says Strober.