UCLA scientists identify the tumor resistance mechanisms to immunotherapy in advanced melanoma -
UCLA researchers have identified the first mechanisms that determine how advanced melanoma can become resistant to the immune checkpoint inhibitors, a discovery that could lead to the development of new and improved treatments for the most deadly type of skin cancer.
immunotherapy using anti-PD-1 antibody pembrolizumab antibody (brand name Keytruda) has revolutionized the treatment of advanced melanoma. But a minority of patients who respond to treatment experience recurrence and yet the progression of their tumors, said Dr. Antoni Ribas, professor of hematology and oncology, and director of tumor immunology program at UCLA's Jonsson Comprehensive Cancer Center.
"The great promise of immunotherapy is to engage the immune system of our body fight against cancer, but the results should be long lasting," said Ribas. "We have now identified first time mechanisms that cancer cells can use to avoid recognition by T cells of the immune system and reduce the sensitivity to the attack. "
The study will be published online in the New England Journal of Medicine on July 13, 2016.
Directed by Jesse Zaretsky and Ribas, lead author of the study and a doctoral student in the laboratory Ribas, researchers analyzed melanoma tumor biopsies in patients who received pembrolizumab. The team compared tumor pairs, both before the patients began treatment and after relapse, which occurred several months to years later.
Of the four pairs of biopsies studied, the team found a tumor has lost a gene called B2M, resulting in a change in how cancer is recognized by the immune system. Two other tumors developed faults that disrupted the function of the JAK1 and JAK2 genes, which limited the effectiveness of the immune system to kill cancer cells.
"We found that although the T cells of the immune system remained, new active JAK1 and JAK2 changes have caused the tumor to become selectively deaf to the signals they sent normally indicate cells cancer to stop growing, while the genetic changes in B2M decreased ability of the immune system to recognize the cancer in the first place, "Zaretsky said. "These results can help to open up a whole new potential research and allow us to better understand acquired resistance to these promising treatments."
The team also found a fourth pair of biopsies n ' has been one of these genetic variations, indicating that other mechanisms to escape immune therapies can be discovered in the future, said Zaretsky, who is currently enrolled in UCLA-Caltech medical scientist training program.
team Ribas next pre-clinical models of development plans to further examine these genetic alterations. as scientists learn what these tumor resistance mechanisms are, they can combine inhibitor drugs that block roads multiple resistance and possibly make tumors much longer shrink, or disappear completely, Ribas said.
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