Article abstractNature Materials
Published online: 11 January 2009 | doi:10.1038/nmat2357
Infection-mimicking materials to program dendritic cells in situOmar A. Ali1, Nathaniel Huebsch1,2, Lan Cao1, Glenn Dranoff3 & David J. Mooney1,4,5
AbstractCancer vaccines typically depend on cumbersome and expensive manipulation of cells in the laboratory, and subsequent cell transplantation leads to poor lymph-node homing and limited efficacy. We propose that materials mimicking key aspects of bacterial infection may instead be used to directly control immune-cell trafficking and activation in the body. It is demonstrated that polymers can be designed to first release a cytokine to recruit and house host dendritic cells, and subsequently present cancer antigens and danger signals to activate the resident dendritic cells and markedly enhance their homing to lymph nodes. Specific and protective anti-tumour immunity was generated with these materials, as 90% survival was achieved in animals that otherwise die from cancer within 25 days. These materials show promise as cancer vaccines, and more broadly suggest that polymers may be designed to program and control the trafficking of a variety of cell types in the body.
School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02138, USA Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA Wyss Institute for Biologically Inspired Engineering, Cambridge, Massachusetts 02138, USA
Present address: Harvard School of Engineering and Applied Sciences, Harvard University, 29 Oxford St., 319 Pierce Hall, Cambridge, Massachusetts 02138, USA
A polymer device trains immune cells to shrink tumors
One of cancer's cleverest tricks is its ability to hide from the immune system. A new approach to cancer treatment called immunotherapy could spare patients at least some of the grueling battery of chemotherapy treatments by retraining the body's own defenders--the cells of the immune system--to recognize and destroy tumors. Now researchers at Harvard University have developed a simple way to do this inside the body: a polymer implant attracts and trains immune-system cells to go after cancer.
The experimental approach has shown great success in animal studies, increasing the survival rate of mice with a deadly melanoma from 0 to 90 percent. The implant could also be used to treat diseases of the immune system such as arthritis and diabetes, and, potentially, to train other kinds of cells, including stem cells used to repair damage to the body.
The usual methods for cancer immunotherapy are complex and have had little success in clinical trials, says David Mooney, a professor of bioengineering at Harvard who leads the development of the implant. First, immune cells called dendritic cells are removed from a patient's body; then they're exposed to chemical activators and cancer-specific antigens. These cells are then injected back into the patient, where they should, in theory, travel to the lymph nodes and activate another group of cells called T cells, training them to attack a tumor. But dendritic cells are fragile, and while this approach has increased survival in mice, it hasn't caused tumors to shrink in clinical trials with humans.
"When you transplant the cells, virtually all of them die, and you have very little control over what they do when they're reimplanted," says Mooney. So his team took a different approach to the problem, realizing that "perhaps we could do all this inside the body."
Mooney and his research group constructed a polymer that can do inside the body what complex immunotherapies do outside it. They describe the design and performance of an implant for melanoma in the current issue of Nature Materials. The polymer has a history of safe use in humans (in biodegradable sutures, for example). First, it attracts dendritic cells by releasing a kind of chemical signal called a cytokine. Once the cells are there, they take up temporary residence inside spongelike holes within the polymer, allowing time for the cells to become highly active.
The polymer carries two signals that serve to activate dendritic cells. In addition to displaying cancer-specific antigens to train the dendritic cells, it is also covered with fragments of DNA, the sequence of which is typical of bacteria. When cells grab on to these fragments, they become highly activated. "This makes the cells think they're in the midst of infection," Mooney explains. "Frequently, the things you can do to cells are transient--especially in cancer, where tumors prevent the immune system from generating a strong response." This extra irritant was necessary to generate a strong response, the Harvard researchers found.
When implanted just under the skin of mice carrying a deadly form of melanoma, the polymer increased their survival rate to about 90 percent. By contrast, conventional immunotherapies that require treating the cells outside the body are 60 percent effective, says Mooney.作者: 特深沉 时间: 2009-2-1 15:17
Robert Langer, a pioneer in developing drug-delivering polymers and an Institute Professor at MIT, says that Mooney's work is "a really beautiful combination of materials science and cell technology."
Accomplishing the entire immunotherapeutic process inside the body using a common polymer is "incredible," adds Peter Polverini, dean of dentistry and a professor of pathology at the University of Michigan, and a specialist in oral cancer. "From the standpoint of efficacy and efficiency, this is a huge advance." For patients, he says, a subcutaneous implant would be "far less burdensome" than doctors removing and reimplanting cells.
Mooney developed the polymer systems with more than melanoma in mind, however. He hopes to develop similar implants for treating other types of cancer, which should simply be a matter of changing the antigen carried by the polymer. But the approach could also be used to treat other kinds of immune disorders. For example, different chemical signals could dampen immune cells' activity in order to prevent transplant rejections and treat autoimmune diseases such as type 1 diabetes and rheumatoid arthritis, which result when the immune system attacks normal tissues. Mooney also hopes that the polymer system can train a different class of cells altogether. Just as fragile dendritic cells seem to respond better to being trained inside the body, this might be a more effective way to recruit and reprogram stem cells.
If proved in people, the cell-training polymers might also bypass some of the regulatory hurdles and expense faced by cell therapies, since devices are more readily approved by the Food and Drug Administration. Indeed, Mooney predicts that the therapy will move quickly through safety tests in large animals (the next step before human trials), and he expects to bring the cancer immunotherapy to clinical trials soon. "All the components are widely used and tested, and shown to be safe," he says.
One thing that remains to be proved, however, is whether the treatment is effective over the long term--whether the body will recognize the cancer cells months and even years later, after the polymer has biodegraded. Most cancer deaths are caused by secondary tumors called metastases that can arise from just a single cell that leaves the primary tumor. The immune system's ability to remember disease-causing agents over the long term is one of the reasons that immunotherapy for cancer seems so promising. Once the cells have been trained to recognize and attack a tumor, the immune system should be prepared to combat cancer recurrence. Mooney says that he's currently working on long-term studies. "Just think what the benefit would be to patients to have their immune system reprogrammed at will to fight disease in a sustained fashion," says Polverini.作者: 春波 时间: 2009-2-2 22:57
特版主翻译一下
拜托作者: 走遍四方 时间: 2009-2-3 09:45
Implant Makes Cells Kill Cancer 植入技术攻杀肿瘤
A polymer device trains immune cells to shrink tumors
一聚合体装置训练免疫细胞攻杀肿瘤
One of cancer's cleverest tricks is its ability to hide from the immune system. A new approach to cancer treatment called immunotherapy could spare patients at least some of the grueling battery of chemotherapy treatments by retraining the body's own defenders--the cells of the immune system--to recognize and destroy tumors. Now researchers at Harvard University have developed a simple way to do this inside the body: a polymer implant attracts and trains immune-system cells to go after cancer.
肿瘤一大厉害在于它的免疫逃避。一种新的叫做免疫疗法的治疗方法使用重新训练机体的卫士---免疫细胞的机制来重新识别癌细胞并摧毁之，无需向传统的化疗那样饱受熬战之苦。如今哈佛大学的研究者们已经研究出一简单方法，那就是在我们的体内植入聚合体来吸收和训练免疫系统细胞去追逃癌细胞。
The experimental approach has shown great success in animal studies, increasing the survival rate of mice with a deadly melanoma from 0 to 90 percent. The implant could also be used to treat diseases of the immune system such as arthritis and diabetes, and, potentially, to train other kinds of cells, including stem cells used to repair damage to the body.动物实验很成功，可将老鼠高致命恶性黑素瘤生存率从0提高到90%。植入方法同样可以用来治疗类风湿关节炎和糖尿病，且有潜在训练诸如干细胞之内的其他机体细胞来达到修复机体损伤的能力。
The usual methods for cancer immunotherapy are complex and have had little success in clinical trials, says David Mooney, a professor of bioengineering at Harvard who leads the development of the implant. First, immune cells called dendritic cells are removed from a patient's body; then they're exposed to chemical activators and cancer-specific antigens. These cells are then injected back into the patient, where they should, in theory, travel to the lymph nodes and activate another group of cells called T cells, training them to attack a tumor. But dendritic cells are fragile, and while this approach has increased survival in mice, it hasn't caused tumors to shrink in clinical trials with humans.
领导这样技术开发的哈佛大学生物工程学教授David Mooney声称：通常的免疫疗法复杂且临床效果不好。首先将数突状细胞（一种免疫细胞）从机体取出，再将他们暴露在化学催化剂及癌细胞特性抗原之下，然后将他们重新输入到机体，理论上，这些重新输入到机体的树突状细胞应该能到到达淋巴结，并在淋巴结出作用于另一种免疫细胞-T细胞，并训练T细胞如何攻击癌细胞。但是树突状细胞很脆弱，虽然在老鼠身上能明显提高生存率，但在人类身上的临床实验却不见肿瘤的缩小。
"When you transplant the cells, virtually all of them die, and you have very little control over what they do when they're reimplanted," says Mooney. So his team took a different approach to the problem, realizing that "perhaps we could do all this inside the body."
Mooney说这是因为当你重新植入树突状细胞时，事实上其中大部分已经死亡，且很难控制到底重新输入的树突状细胞在机体干什么，基于此，他的团队采用另外方法来解决这个问题，也就是意识到或许可以在机体内完成这些。
Mooney and his research group constructed a polymer that can do inside the body what complex immunotherapies do outside it. They describe the design and performance of an implant for melanoma in the current issue of Nature Materials. The polymer has a history of safe use in humans (in biodegradable sutures, for example). First, it attracts dendritic cells by releasing a kind of chemical signal called a cytokine. Once the cells are there, they take up temporary residence inside spongelike holes within the polymer, allowing time for the cells to become highly active.
Mooney和他的研发团队构建了一聚合体，它能在体内完成传统免疫疗法在体外完成的工作。他们在Nature Material（自然材料）上阐述了针对黑素瘤的植入法设计性能。此聚合体在人类历史上曾安全使用过，比如能生物降解的医学缝合。此聚合体通过释放一种叫做cytokine（细胞浆）的物质来吸聚树突状细胞。一旦树突状细胞被吸聚过来，它们将在聚合体中的海绵状小孔内短暂驻留至强活性状态。
The polymer carries two signals that serve to activate dendritic cells. In addition to displaying cancer-specific antigens to train the dendritic cells, it is also covered with fragments of DNA, the sequence of which is typical of bacteria. When cells grab on to these fragments, they become highly activated. "This makes the cells think they're in the midst of infection," Mooney explains. "Frequently, the things you can do to cells are transient--especially in cancer, where tumors prevent the immune system from generating a strong response." This extra irritant was necessary to generate a strong response, the Harvard researchers found.
此聚合体载有2上信号来作用树突状细胞。其一是加载癌细胞特性抗原来训练树突状细胞。其二是典型细菌的DNA片段，当细胞接触到这些片段是将会高度活性。Mooney解释说，这是因为细胞会认为它们处于感染状态。在肿瘤逃避免疫机制中这类强烈反应状态很短暂，因此哈佛研究者们发现额外的刺激很必要拉加强细胞的强烈反应。
When implanted just under the skin of mice carrying a deadly form of melanoma, the polymer increased their survival rate to about 90 percent. By contrast, conventional immunotherapies that require treating the cells outside the body are 60 percent effective, says Mooney.
Mooney声称，当植入聚合体应用到老鼠黑素瘤时，生存率增至90%，而传统的体外免疫疗法仅仅60%有效。
Robert Langer, a pioneer in developing drug-delivering polymers and an Institute Professor at MIT, says that Mooney's work is "a really beautiful combination of materials science and cell technology."
MIT（麻省理工学院）教授Robert Langer，一位药物给送聚合体研发先驱，声称Mooney团队的成果是材料科学和细胞技术的完美结合。
Accomplishing the entire immunotherapeutic process inside the body using a common polymer is "incredible," adds Peter Polverini, dean of dentistry and a professor of pathology at the University of Michigan, and a specialist in oral cancer. "From the standpoint of efficacy and efficiency, this is a huge advance." For patients, he says, a subcutaneous implant would be "far less burdensome" than doctors removing and reimplanting cells.
Michigan大学牙科主任，病理学教授，口腔癌专家Peter Polverini称，采用以普通的聚合体来完成所用的免疫疗法过程真是好得难以置信。从功效和效率的角度来说，皮下植入比起取出且重新输入免疫细胞对病人轻松很多。
Mooney developed the polymer systems with more than melanoma in mind, however. He hopes to develop similar implants for treating other types of cancer, which should simply be a matter of changing the antigen carried by the polymer. But the approach could also be used to treat other kinds of immune disorders. For example, different chemical signals could dampen immune cells' activity in order to prevent transplant rejections and treat autoimmune diseases such as type 1 diabetes and rheumatoid arthritis, which result when the immune system attacks normal tissues. Mooney also hopes that the polymer system can train a different class of cells altogether. Just as fragile dendritic cells seem to respond better to being trained inside the body, this might be a more effective way to recruit and reprogram stem cells.
然而，Mooney开发的聚合体装置远非针对黑素瘤。同样可以通过更改肿瘤特性抗原开发针对其他种类癌症的植入，而且还可以用于其他免疫紊乱疾病的治疗。比如不同的化学信号可以削弱免疫细胞的活性来达到预防器官移植排异反应和治疗自身免疫疾病比如1型糖尿病和类风湿关节炎，因为在这类疾病中免疫细胞会攻击正常组织。
Mooney希望该聚合体能够选练更多类别的细胞。就像在体内训练树突状细胞能够使脆弱的树突状细胞反映更好一样，如果该装置能够训练干细胞将会更有效果。
If proved in people, the cell-training polymers might also bypass some of the regulatory hurdles and expense faced by cell therapies, since devices are more readily approved by the Food and Drug Administration. Indeed, Mooney predicts that the therapy will move quickly through safety tests in large animals (the next step before human trials), and he expects to bring the cancer immunotherapy to clinical trials soon. "All the components are widely used and tested, and shown to be safe," he says.
如果人体实验，该细胞训练聚合体能够绕过一些细胞疗法的规章制度和花费问题，将很容易被FDA批准。Mooney预计将很快通过人体试验前的大规模动物安全实验并期望尽快进入癌症免疫疗法临床试验，因为所有成分都是广泛使用过和测试过的且是安全的。
One thing that remains to be proved, however, is whether the treatment is effective over the long term--whether the body will recognize the cancer cells months and even years later, after the polymer has biodegraded. Most cancer deaths are caused by secondary tumors called metastases that can arise from just a single cell that leaves the primary tumor. The immune system's ability to remember disease-causing agents over the long term is one of the reasons that immunotherapy for cancer seems so promising. Once the cells have been trained to recognize and attack a tumor, the immune system should be prepared to combat cancer recurrence. Mooney says that he's currently working on long-term studies. "Just think what the benefit would be to patients to have their immune system reprogrammed at will to fight disease in a sustained fashion," says Polverini.
仍有一事需待证实，是否该疗法疗效持久，是否该聚合体生物降解后数月，甚至数年，机体仍能识别癌细胞。因为许多病人死于二次肿瘤（癌细胞转移），而二次肿瘤的形成只仅仅需要原发肿瘤中的一个癌细胞的转移就可以了。免疫疗法希望巨大的一大优越在于免疫系统能够持久记住引发疾病的物质。一旦免疫细胞被训练住识别癌细胞并攻击爱细胞，免疫系统就应该准备好了针对癌细胞复发的再次战斗。Mooney称他的团队正致力于长期的研究。作者: 走遍四方 时间: 2009-2-3 10:53
以下内容是关键所在。。
Frequently, the things you can do to cells are transient--especially in cancer, where tumors prevent the immune system from generating a strong response." This extra irritant was necessary to generate a strong response, the Harvard researchers found.
Mooney解释说，这是因为细胞会认为它们处于感染状态。在肿瘤逃避免疫机制中这类强烈反应状态很短暂，因此哈佛研究者们发现额外的刺激很必要拉加强细胞的强烈反应。作者: marsq 时间: 2009-2-3 14:35
就像看科幻.
