In April 2011, Ms. Catherine, 59, in southern California, got a "death sentence": she was diagnosed with malignant melanoma. After surgery and chemotherapy, her condition is not improved, had to rely on a wheelchair life. The second half of 2012, she became one of the Merck PD-1 antibody drug clinical trial in KEYTRUDA patients. A turn for the better, a contrast examination showed that most of the tumors that had spread in the body of Catherine were stable, some of which were shrinking, and some even disappeared.
On September 4, 2014, Merck's new anticancer drug KEYTRUDA drugs pembrolizumab) through the FDA's accelerated approval channels become in the United States listed treatment of malignant melanoma first anti-PD-1 (suppression of programmed cell death factor 1) of the original research of new drugs.
For those is tenacious struggle with the disease of malignant melanoma and its related cancer patients, it is undoubtedly a ray of hope; for those who work in the first line of anticancer drug research experts and scholars. This is another breakthrough in cancer immunotherapy.
What is cancer immunotherapy? Why is this kind of anticancer drug resistant to PD-1 become a hot spot in the current academic circles? What is the mechanism? Why is the listing of KEYTRUDA attracted so much attention? Overwhelmed we invited the the author Dr. Liang Guibai the story of new drug research and development, with a wonderful big vernacular for you "818" medium details (exclusive science haoma).
■ 100 years ago, doctors Curry cancer cells, "the immune lore Law"
■ immune system powerful "magic mirror", resolutely eliminate intruders
■ cancer: cunning, "camouflage", evade the immune cells "hunt"
■ see how the cancer cells to the immune system irrigation "magic potion"
■ change the thinking: "is not cancer," the anti-cancer drug
■ Blocking feedback loop: the cancer cells exposed to the "broad daylight"
■ KEYTRUDA: expected against a variety of malignancies
■ interests are in the "double-edged sword"
■ Health is a new hope for a blessing, cancer patients
Immunotherapy is not a new concept. As early as 1891, American doctors William • Curry (William Coley) on the first attempt in tumor immunotherapy.
There were reports that, after individual cancer patients were infected with the bacteria, with infection subsided, cancer patients within the body also mysteriously disappears with. Curry doctors believe this is most likely due to a bacterial infection activates the patient's own immune system, and immune cells kill bacteria, but also kill the cancer cells. Thus, innovative Curry doctors began to try to give him cancer patients injected bacteria, artificially cause infection, in order to stimulate the patient's immune response, lore cancer cells.100 years later, Dr. Curry's first tumor immunotherapy in addition to the success of individual cases, the majority of cancer patients with little success, can not be large-scale promotion. However, cancer immunotherapy, but this new concept of basic research in the field of medicine has been widely recognized, and gradually made substantial progress, especially in the last 30 years.
The immune system's powerful "magic mirror"
Resolutely eliminate intruders
The immune system is essential for human health. Every day, we are inevitably exposed to a lot of bacteria, viruses and other pathogens and a variety of other sources, are immune cells all the time in search of every corner of the body, put them all "shut out." Occasionally there will be some "invaders" break through the first line of defense of the immune system, cause some damage to the human body. But subsequently triggered an immune response, in most cases still be able to timely and targeted implementation counterattack, clear invasion of the enemy, to restore the body to health.
The key to this powerful defense system is its identification system. In the human living environment, the intruder wide range of different features, so the body's immune system evolved out of a set of corresponding complex effective identification system, like a huge "magic mirror" so that all kinds of intruders nowhere hide.
However, the human immune system's "magic mirror" re strong, still have the cunning of "slip through the net." Mutating the original cancer is likely to be able to evade the immune system to produce mutations identified in the "magic mirror" of the dead in the long dark submerged AIDS, until in the human body to establish a "base" and become malignant, followed by diffusion into the body Other parts of the final to win the patient's life.
Cancer: cunning "camouflage"
Evade immune cells "hunt"
Now the popular medical theory holds that the human body almost all the time there will be sporadic original cancer cells, but most of them become climate, because the body's immune system to effectively identify these primitive cancer cells, and timely manner They removed.
The immune system is able to recognize cancer cells, since cancer cells different from normal human cell surface markers characteristic of molecule. Early cancer immunotherapy, non-selective methods used, such as doctors Curry human bacterial infections, to enhance the body's immune response, so the effect is not ideal. Later, scientists are using cell surface markers characteristic of molecules as artificial antigen, culture targeted antibody, and then injected into a patient, the efficacy of some improvement, but still far from expectations. why? The latest findings show that cancer cells have a cunning "cover-up", can evade the immune cells "raid."
One of the biggest features of cancer cells, is it fast and more heterosexual mutations, it is also possible to produce a functional molecular markers allows the body's immune system passivation. Once the immune system is exposed to these passivation labeled molecules, it seems to be filling a "magic potion", even if we can confirm the cancer cell surface markers characteristic of molecules seems to "ignore", no longer recognize it as invasion of the enemy. As a result, these cancer cells into immune "magic mirror" of the dead, have the opportunity to gain a firm foothold in the human body, and await development.
Look how the cancer cells to the immune system irrigation "magic potion"
In the currently known cancer "camouflage" among the surface of cancer cells programmed cell death ligand-1 (PD-L1) is the most common kind, the first to discover the key ligands are well-known Yale University Chinese scientist Professor Chen Lieping. 2002, Professor Chen's research team first clarified PD-L1 is one of the main mechanisms of cancer cells to evade immune attack, for which in 1992 he found immune T- cell surface programmed cell death factor (PD-1) Japanese scientists Tasuku Honjo (Tasuku Honjo) and together with two other American scientists won the 2014 American Institute for Cancer Research annual William Curry • Outstanding Research Award.
Programmed cell death PD-1, is one of the regulation of the receptor in the immune system, "patrol" --T- cell surface, and its main task is to prevent autoimmune disease (autoimmune diseases). The so-called "autoimmune disease" refers to the body's immune system, "regardless of friend and foe, recognize Friends become enemies," for their own attack normal cells or organs, the consequences are very serious. In this case, by the "unprovoked attack" by releasing its own cells targeted ligands, feedback to the program cell death, so that the immune cells to stop their attack. Cancer is the use of the immune system in this important signal feedback loop cunningly escaped recognition T- cells.
Another thought: "not cancer," the anti-cancer drug
Before the emergence of cancer immunotherapy, all anticancer drugs are against the cancer cells themselves: the anti-cancer drug Well, how can do is not cancer? These drugs kill cancer cells by directly achieve the therapeutic effect. But another significant feature of cancer cells in addition to the rapid variation is that it is more than normal cells strong vitality, so a direct anti-cancer drugs to kill cancer cells, but will inevitably kill the body's normal cells. Therefore, the completion of a course of chemotherapy will be a great damage to the body of the patient, it will take a long time to recover. More importantly, chemotherapy for cancer cells often not thorough enough, it can not be eradicated, in time, will come back.
Now, we find out the cancer "camouflage", you can change the thinking of the right medicine: you programmed cell death instead of using a feedback loop it? I wanted a way to cut off the medication to the circuit, put your immune cells exposed to the light of day, so you have nowhere to hide.
Blocking feedback loop: the cancer
Exposed to the "broad daylight"
Cancer immunotherapy from a new perspective, by helping the immune system to effectively identify cancer cells, thus in one fell swoop destroy the cancer cells. In this sense, Merck's cancer drug KEYTRUDA fact is not cancer, because it is not against the cancer itself. Leaving the body's immune system, KEYTRUDA in vitro in a test tube is not to kill the cancer cells. It played a role in the body by blocking the immune system in a signal feedback loop, so that cancer cells no loopholes.
As a "patrol" of T- cells under normal conditions in the "alert" status, only to find that when the enemy into the "battle" state, this process is called activation of T- cells. As mentioned above, when the surface of cancer cells and immune T- PD-L1 cell surface PD-1 binding, immune T- cell activation was inhibited, can not enter the "battle" state, so we stopped for cancer attack. In order to prevent and PD-1 binding of PD-L1, Merck's scientists PD-1 as artificial antigen, train specifically for the PD-1 monoclonal antibody. This antibody was injected into the blood of patients with cancer, they can form a stable complex with the T- cell surface PD-1. When Thus, these T- cells were met and to identify cancer cells, cancer cell surface of T- cell activation inhibitor of PD-L1 will not start up.
Exposed to the cancer cells before the immune system is facing a targeted annihilation. Because the immune cells to recognize cancer cells and normal human cells, it is possible in the case of loss of normal cells from the cancer completely cleared out. At the same time we have reason to believe that long-term memory ability of the immune system, but also will effectively prevent slipping through the net of cancer comeback.
Expected against a variety of malignancies
Since PD-1 antibody is not directed against the cancer cells themselves, so in theory, as long as it can effectively identify immune T- cell cancer, if the cancer cells to escape immune response "camouflage" mainly through PD- L1 and PD-1 binding, then the PD-1 antibody should be effective.
From the currently known clinical results, in addition to outside of malignant melanoma, PD-1 antibody indeed non-small cell lung cancer, renal cell carcinoma and other cancers have a significant effect, and PD-1 antibody and other anti-cancer drugs The combination therapy is generally more optimistic about the industry. We have reason to look forward to in the near future PD-1 antibody can be more widely used to treat a variety of cancers.
Interests are in the "double-edged sword"
However, by regulating the body's immune system to kill cancer cells, not only not a surefire plan, but also with considerable risk, it is of interest are in the "double-edged sword."
As mentioned above, the immune system in the presence of the signal feedback loop must have its reasons, PD-1 expression in the immune T- cells can never be just to give cancer cells may appear to stay a way out. When the immune system is activated PD-1 antibody artificially, it is likely to bring a series of immune and endocrine system disorders, which is a common problem faced by tumor immunotherapy. Animal experiments showed that mice PD-1 gene knockout is prone to autoimmune disease, pituitary gland disorders and other adverse reactions. In human clinical trials, these immune system-related side effects in a few patients who have appeared, if not treated, the consequences are very serious.
Fortunately, modern medicine for immune system disorders have a considerable degree of understanding. Through rigorous tracking and monitoring, medical staff can be found a few patients as early as possible side effects due to immune therapy and produce timely adjust the intensity of the cycle immunotherapy, and medication to alleviate adverse reactions by patients with immune disorders caused.
Although immunotherapy will play an increasingly important role in cancer treatment, but it is by no means to play a few needles to solve the problem of a panacea. PD-1 antibody for use must be under the strict control of professional doctors, otherwise unpredictable consequences.
Health is a new hope blessing, cancer patients
Merck in clinical trials, there are a lot like the beginning of this story referred to herein Ms. Catherine. According to data provided by the American Cancer Society, about 7.6 million people in the United States each year are diagnosed with malignant melanoma patients, and therefore the number of deaths each year is about 10,000. Prior to this, the majority of patients after diagnosis of advanced life lasts no more than 1 year. Merck's clinical trial data show that patients with advanced malignant melanoma after receiving a one-year survival rate was 69% KEYTRUDA therapy, 18-month survival rate was 62%, of which 34% of patients the tumor is reduced by more than 30% , the effect is very significant.
In early 2013, in order to allow a wider range of malignant melanoma patients receive timely treatment, KEYTRUDA FDA was identified as "breakthrough therapy" to enter fast-track channels to be highly valued. Merck also mobilize substantial resources to carry out an up to 1,000 cases (the largest in the history) of "unconventional" a clinical trial, and strive to obtain proof of concept efficacy and safety data in a short time, while greatly accelerate clinical trials progress, results in a short period of three years based primarily on an early clinical data on the launch of the first PD-1 inhibition antibody, and in the overall US market within a week, the majority of malignant melanoma patients receive timely treatment.
Currently, Merck's clinical trials have been extended to other KEYTRUDA multiple non-small cell lung cancer and other cancers, this is the gospel cause cancer patients waiting.
Text / Dr. Liang Guibai
