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文章裡可以看到 Johns Hopkins 正在深入研究現今對AntiPD1沒反應的病人
As long as cancer has been a recognized disease, doctors have believed the power to eliminate it existed within the immune system, but attempt after attempt to unlock this potential has largely failed. The potential always existed, but the key information needed to turn this promise into real treatments was locked away inside the DNA of tumor and immune cells.
Immune-based therapies reflect a different approach to treatment. Instead of targeting cancer cells, the new therapies target immune cells in and around cancers. Some treatments increase the number of immune cells summoned to the tumor, and others unleash the commands that send the immune cells to work against it. These types of immune therapies have had success alone, but perhaps their greatest power will come in combining them and, through precision medicine, using the biological clues within each patient’s cancer to guide treatment.
Unlike viruses and bacteria that are easily recognized by our immune system because they are so different, cancer originates from our own cells. As a result, it has all of the cellular mechanisms that are used by normal cells at its disposal. Cancer co-opts them selectively, using them like superpowers to grow, spread, and cloak themselves from the immune system.
There are two main actions at play in an immune reaction. The first is a “go” signal. “Our cells are constantly presenting our own proteins to our own immune system,” explains pathologist Bob Anders. One can think of DNA as the blueprint of a cell, and the proteins its genes encode are its building blocks. A protein from a mutated gene looks different than its normal counterpart. In the same way it recognizes bacteria and viruses, the patrolling immune system can recognize abnormal cells that don’t belong. “When immune cells come upon something that shouldn’t be there, they generate an immune reaction,” says Anders. This is the go signal. When the job is done and the invading cells are taken care of, the immune system issues a “stop” signal.
These stop signals are controlled by immune checkpoints like PD-1. In cancer, malignant cells hijack the “stop” signal to maintain their own survival. They send a deceptive message to cancer-killing immune cells that there is no problem. Immune cells arrive at the tumor, but they are duped with a false message that everything is OK. “Essentially, they’re told to go home. There is nothing to see here,” says pathologist Janis Taube.
This success revealed that the immune system could be employed against cancers beyond melanoma and kidney cancer. As important, it provided definitive proof that there was a common force at work to shut down an immune response to cancer.
The most recent clinical study provides clear evidence that for lung cancer patients whose immune cells express PD-1 or whose tumor cells express PD-L1, immune therapy works better than the best chemotherapy drugs and with far fewer side effects. In addition, patients with late-stage lung cancers frequently become resistant to chemotherapy, but Brahmer says that patients who respond to immune therapy tend to continue responding.
As for how long patients will continue to respond off treatment and whether there are any long-term effects of this type of immune therapy, it’s too soon to know. Pardoll, Topalian and collaborators are working to answer these questions. They also want to make sense of the varied responses. In some patients, tumors were held in check, neither growing nor shrinking. Other patients, like Ryan, experienced huge reductions in the size of their tumors, but they didn’t go away completely. Pardoll and Topalian have gone back to the laboratory to better understand the biology of these responses.
In virtually all patients, however, the responses appear to be long lasting. Some patients from the original clinical studies continue to do well. Such responses are virtually unheard of in advanced cancers. “We don’t know yet what the ultimate survival benefit will be, but for these early trials and these patients, the responses are lasting a long time,” says Pardoll. “We don’t have to intervene anymore with therapy. The patients’ own immune systems have taken over the battle.”
The list of responding cancers continues to grow. Bladder cancer, Hodgkin’s lymphoma and a few difficult-to-treat cancers, like triple-negative breast cancer and mesothelioma, are on it, with others, like certain ovarian, endometrial, colon, head and neck, stomach, liver, and esophageal cancers, expected to soon be added.
On the other hand, there are cancers, including prostate and pancreatic cancers, that remain largely resistant. “We need to address that on the research side,” says Topalian. Drake does not get a good response in all bladder cancer patients either. “In some patients, it works quite well, but in others, the cancer continues to grow,” he says. Understanding why some tumors do not respond is as important as learning why others do, he says. “If we can figure out when it works and how it works—what kinds of cells are involved and what is happening from an immunological standpoint—maybe we can take non-responders and make them responders,” Drake says.
There are currently about eight different types of antibodies that block PD-1 or PD-L1 on the market. The treatment is now FDA-approved for melanoma and lung cancers, and Pardoll says approvals for kidney cancer, bladder cancer, and Hodgkin’s lymphoma are anticipated by the end of 2015 or early 2016. They aren’t cheap, costing about $100,000 or more per year for each patient treated.
Johns Hopkins 醫師認為放療會激起免疫反應 anti-PD-1讓免疫反應
These new combinations will not be limited to immune agents. Animal research by radiation oncology fellow Andrew Sharabi and Drake found that focused radiation treatment, like that used in radiosurgery, stimulates an immune response against the cancer. Sharabi says cell damage caused by radiation deploys immune cells to the tumor site, and combining anti-PD-1 with radiosurgery unleashes an immune assault on the cancer. “Radiation opens the door, and anti-PD-1 therapy allows the immune cells to get to work,” says Sharabi.
Radiation oncologist Joseph Herman, Anders, and Taube find evidence that radiosurgery may be activating immune cells in pancreatic cancer as well, a cancer that currently does not respond well to anti-PD-1 treatment. Combining radiosurgery with the right immune-targeted drugs may increase responses in a variety of cancers. Anders is examining tumors that are traditionally treated with radiation, including head and neck cancers and esophageal cancers to look for expression of PD-L1 in tumor cells, an indicator that they might respond to an anti-PD-1 checkpoint blockade/radiation therapy combination.
Johns Hopkins 醫師相信病人先做放療化療或標靶 再做antiPD1 可以激起免疫反應治療原本無效的癌症(或病人)
Pardoll and Topalian are hopeful that combination therapies may be the key to converting currently nonresponding cancers like prostate cancer into responders. Similar to Sharabi and Drake’s work, Topalian believes that giving another kind of therapy up front, including radiation, chemotherapy or targeted therapies, and following with anti-PD-1 could provoke an immune response in currently resistant cancers.
發炎會吸引免疫細胞聚集? 我解釋一下 通常病毒細菌入侵 先天性免疫系統最先發現 白血球會吞噬病毒細菌 釋放出發炎物質 吸引其他免疫細胞加入戰鬥
發炎物質是免疫細胞傳遞訊息 這裡有敵人入侵的信號
She is working in her laboratory to see what therapies incite an inflammatory response in the tumor, because inflammation draws the attention of immune cells. These are the situations where adding anti-PD-1 has the potential to cause a synergistic immune response.
She and others are compiling this laboratory evidence. This component is critical, she says. “There are endless possibilities of potential treatment combinations. We can’t test them all, and we can’t simply do combinations of convenience,” says Topalian. “We have to let the research lead us, and then move to the clinic only with combinations supported by scientific evidence.”
Some cancers will respond to antiPD-1, but others will need more to get the immune system working. Pardoll is confident that working together over time Johns Hopkins experts will be able to figure out the right combinations to get the immune therapy moving against almost any cancer.
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