Tumors grow and persist in part because they squelch the immune system, but researchers have recently turned the tables with treatments that fast track immune cells to malignant cells. The strategy is effective in some patients, however, and to date has been shown to work in only a few types of cancer. But online education today Nature reveal how an immunotherapy type is called the immune checkpoint inhibitors, can be targeted to new cancers -and how physicians can distinguish patients who are most likely to benefit from these drugs.
"as a unit, the papers fulfill many of the gaps in our understanding" about these cancer immunotherapies, said Jedd Wolchok, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, who was not connected to the study.
tumors can remove cytotoxic T cells that normally attack by the activation of two surface receptors of immune cells, CTLA4 and PD-1. But the CTLA4 and blocking PD-1 with antibodies can free T cells Several clinical trials with incurable cancer patients showed dramatic effects of these antibodies. "What we see is the control of long-term illness," said Wolchok. "In some cases, people are living long enough to die of other causes."
Timid researchers away from the c-word cure, but they say that these immune checkpoint inhibitors could eventually transform cancer into a manageable disease more like diabetes or HIV. "The immune system may be able to keep the tumor under control, even if it does not remove all the last cell," says immunologist cancer Drew Pardoll from Johns Hopkins University School of Medicine in Baltimore, Maryland. The prospects of such led Science to anoint cancer immunotherapy as discovery of the year for 2013.
Yet so far, published studies have confirmed that the checkpoint inhibitors only work in kidney cancer, melanoma, and lung cancer. even in these cancers, usually less than half of the patients benefit.
in one of the new studies, led a team by Thomas Powles oncologist at Queen Mary University of London tested a new antibody created by Genentech of South San Francisco, California, in a different cancer. a form of bladder cancer difficult to treat instead of blocking PD 1 of immune cells, the antibody disables PD-L1, a protein that cancer cells and other cells have to stimulate PD-1 and inhibit T cell study funded by Genentech showed that the antibody decreased the bladder tumors in 26% of patients. The therapy for this cancer has not progressed in 25 years, notes Hopkins medical oncologist Julie Brahmer, who was not connected to the research. "This is truly revolutionary," she said.
In a second study, also funded by Genentech, translational oncologist Roy Herbst of the Yale School of Medicine and his colleagues tested the antibody against several other types of incurable cancers. patients in this trial "had exhausted one, two, three lines of therapy," Herbst said, but he and his colleagues found that the antibody caused tumors to shrink in lung cancer, head cancer and neck, melanoma and other tumor types. "It is unexpected and exciting to see one drug affecting so many types of cancer," says Suzanne Topalian, a cancer immunologist at Hopkins who has not participate in any of the studies.
Still, less than 20% of patients in the Yale experiment saw their tumors reduced. "It is a great puzzle to predict who will benefit from these treatments," said Herbst When he and his colleagues analyzed the test patient tumors, they found a possible explanation. Variation in the amount of PD -L1 not manufactured by cancer cells but rather by immune cells that had invaded the tumor. (cancer cells can somehow force immune cells to make them self-inhibitory molecules.) If these cells produce a lot of invasion protein, patients are more likely to respond to antibody therapy. level test PD-L1 in tumors of patients may allow doctors to identify people who are most likely to benefit from the new antibody, said Herbst.
in a third Nature study, immunologist of the tumor and the doctor Antoni Ribas of the University of California, Los Angeles, and colleagues identified another biomarker that could help to improve the rate of successful antibody immuno-awakening. After examined biopsy samples of melanoma tumors from 46 participants to clinical trials treated with PD-1 blocking antibody, the researchers found that the best omen of successful treatment was plenty of cytotoxic T cells at the edge of you die. More cells crowded into the edge of the tumor, the better.
To confirm their findings and evaluate its usefulness, Ribas and his colleagues then analyzed biopsy samples from melanoma patients in a clinical trial at another hospital. Using this single function, they correctly predicted how 13 of the 15 patients would respond to antibody therapy. "A test that detects the presence of [cytotoxic T] cells in tumors could be the first decision point in the treatment of patients," said Ribas.
The researchers are already studying how to use the results of these studies improve cancer immunotherapy, possibly in combination with other types of treatments. "the next use is in combination with other drugs against cancer for more impact," says Topalian.
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