Prospects for future tumor immunotherapy: the era of immune normalization therapy has come
October 10, 2018 Source: Web of Science Author: Ye Bu
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];Over the past 100 years, efforts have been made to enhance immune activation mechanisms that are used by humans to destroy invaders, including tumor cells.
But over the past decade, researchers have found that this "immune-enhancing" strategy often fails to achieve objective relief and has frequent immune-related adverse events (irAEs).
On October 4th, Yale University School of Medicine Professor Ping Ping published an article entitled "A Paradigm Shift of Cancer Immunotherapy: From Enhancement to Normalization" on Cell, expounding the history, current status and methods of tumor immunotherapy. And put forward the concept of "immunization normalization" which has a guiding role in future tumor immunotherapy.
Immune-enhancing therapy
The general idea of ​​immunoenhancing therapy is to activate and enhance the immune response. However, cancer can develop various mechanisms to evade specific and non-specific immune attacks. These strategies are collectively referred to as "immune escape mechanisms." There is ample evidence that this immune escape mechanism typically leads to localized immunosuppression, preventing T cell attack in the tumor microenvironment (TME).
Dong Zengjun, secretary general of the Precision Medicine and Companion Diagnostics Committee of the Chinese Society of Bioengineering, told the Journal of the Chinese Journal of Science and Technology that it is undeniable that immunoenhancement therapy has an objective role in relieving tumors, and the FDA has approved treatment for some tumors - most It is a natural immunogenic tumor such as melanoma and renal cell carcinoma. However, in most cases, these strategies also push the immune system to super-physiological levels, which in turn increases the risk of immune-related adverse events (irAEs). In other words, the drawbacks of immune-enhanced therapy are reflected in the results of several clinical trials, and the article may be more directly expressed.
The study analyzed the FDA's approval of four immunoenhancing therapies and concluded that the general experience with immunoenhanced therapies using tumors is that irAEs caused by extensive activation of the immune system are more frequent than objective anti-tumor remissions, and poor response/toxicity ratio limits The use of most therapies, to date, these drugs do not have a wide range of indications.
More unfortunately, most of the mechanisms discovered in the past to control tumor immune escape, even if they are not identical, are often similar to the mechanisms that control self-tolerance, making it difficult to develop a mechanism that can produce resistance. Tumor response can also avoid treatment of irAEs.
Anti-PD therapy or both strategies
Despite this, researchers have not abandoned the strategy of using anti-tumor immune response to treat cancer. In the past decade, tumor immunotherapy (anti-PD therapy) against the B7-H1 / PD-1 pathway has achieved a higher objective response rate in patients.
In FDA-approved immunotherapy, studies have found that anti-PD therapy is the first treatment in cancer patients with more objective tumor remission than serious immune-related adverse events, suggesting that it is possible to improve efficacy without increasing toxicity. of.
The goal of anti-PD therapy is to correct the immune mechanism of defects and return the immunity to the natural level of the human body. The research refers to the similar anti-PD therapy as "immune normalization therapy for tumors". So why does anti-PD therapy reduce both side effects and anti-tumor immunity?
Wang Jun, a doctor at Yale University School of Medicine, told the journal Chinese Journal of Science and Technology that this is due to the special mechanism of action against anti-PD therapy, including targeting the tumor microenvironment, rather than other healthy tissues; restoring anti-tumor to those already dysfunctional T cells. Function and prevention of newly arrived effector T cells dysfunctional in the tumor microenvironment (TME) and so on. When the PD pathway is blocked, these rejuvenated T cells and newly arrived immune cells will be protected from the PD pathway, which will help restore the immune response in TME and become anti-tumor cells. Effector cells.
In addition, studies suggest that an important but less well-known result of this normalization process is the production of memory T cells, which may be responsible for the long-lasting anti-tumor effect of anti-PD therapy.
Currently, the FDA has approved anti-PD therapy for metastatic melanoma, lung cancer, head and neck cancer, renal cell carcinoma, urothelial carcinoma, liver cancer, gastric cancer, Hodgkin's lymphoma, Merkel cell carcinoma, large B-cell lymphoma. , cervical cancer and any MSI+ tumor. Wang Jun said that unlike other immunotherapies, anti-PD therapy is suitable for a wider variety of tumors and is less restrictive in terms of dosage.
In the future, there may be multiple alternatives to anti-PD therapy
In addition to the B7-H1/PD-1 pathway, there are a number of molecular pathways that cause immunodeficiency in anti-tumor immune responses, which can serve as targets for restoring this response. Once identified and established, the molecular makeup and mechanisms of these immunodeficiencies will likely be potential targets for immunonormalization therapy and provide an alternative to those who do not respond to PD therapy.
But finding alternatives is no easy task, and there are still many obstacles to the development of new immune normalization therapies. First, the development of immunosuppression therapy relies on the identification of specific defects in the anti-tumor immune response and its molecular mechanisms, especially in different types of tumors, which is not an easy task. Second, as cancer progresses, it is also a challenge to determine which or which immunosuppressive pathways predominate in a particular patient to determine the optimal treatment. In addition, the combination of other therapies and anti-PD therapy may impair the efficacy of anti-PD therapy, and how to develop a combination of fundamental principles based on anti-PD therapy is particularly important. It is reported that the display team has discovered several other immune normalization therapy pathways, which are still in the early stage of research and development and clinical research.
Anti-PD therapy sets an example of minimizing irAEs while improving anti-tumor effects. Dong Zengjun said that the principles of immunology learned from the development of the B7-H1/PD-1 pathway and anti-PD therapy will lead us to design more effective tumor immuno-normalization therapies, find the best combination therapy, and promote cancer therapy. At the forefront, this may take a while, but time will eventually reveal the true face of mainstream therapy.
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