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The researchers have now discovered that a combination of immune-control point blockade and targeted therapies blocking normal repair of DNA damage (DDR) allowed for significant tumor regression in murine models of lung cancer small cells (CPPC).
Research at the MD Anderson Cancer Center at the University of Texas suggests a promising new approach to treating patients with this aggressive cancer. The research, published in Cancer Discovery, suggests that olaparib, a PARP inhibitor, and other DDR inhibitors induce a rapid immune response and sensitize SCLC cells to previously resistant immunotherapy.
According to the corresponding author of the study, Lauren Averett Byers, small cell lung cancer, one of the most aggressive types of cancer, accounts for about 15% of all diagnosed lung cancers in the United States only.
The standard treatment for advanced CPPC is chemotherapy, but recurrences are common and average survival is only about 12 months, according to Byers. For about 30 years, this approach has not changed, but the recent use of immunotherapy in combination with chemotherapy has become a new standard. However, the benefits are minimal for patients.
Speaking of this, Byers said, "While immunotherapy has revolutionized the way we treat lung cancer, we find that small cell lung cancers can very effectively escape the immune system, so we're seeing a rate of much weaker response. "
He added: "However, we want to do a lot better for our patients and we think there is still a lot to do."
Previously, Byers had discovered that DDR pathways were very active in CPPC and that blocking them with drugs, such as PARP and CHK1 inhibitors, was effective in the treatment of CPPC in the laboratory. In addition, it has been shown that cancers with significant damage to DNA respond better to immunotherapy.
The experts predicted that, if they combined PARP inhibitors or other drugs that cause DNA damage to immune therapies, they could get a much greater response to the therapy. immune.
Byers added, "We found that if we added PARP or CHK1 inhibitors to immunotherapy, we were witnessing a dramatic shrinkage of tumors. In fact, in some cases, the tumors have completely disappeared. "
The combination of the CHK1 inhibitor prexasertib or the PARP inhibitor, olaparib, with an immune-control point inhibitor directed against PD-L1 resulted in a regression significant tumor in SCLC mouse models, while immunotherapy alone had no effect.
The combination of the PARP inhibitor and immunotherapy resulted in complete regression in all treated mice in just one week, leaving no tumor available for further badysis. Combination treatment with CHK1 led to complete regression in 60% of treated mice.
The researchers found that DDR inhibitors activate an immune response in mice, resulting in an increase in the number of tumor-killing immune cells in tumors. This process was controlled by the STING pathway, which normally detects signals of viral or bacterial infection. In this case, the STING pathway reacted to DNA damage to activate the immune system, thus making the SCLC cells responsive to immunotherapy treatment.
"I think the results of this study are really compelling because of the dramatic activity that we observed by combining the addition of a targeted therapy to immune therapy," Byers said, adding : "I think our results can be quickly translated into a clinic. our patients and also to other types of cancer. "
Byers and his colleagues hope to launch clinical trials to study the combined approach later this year, and expect this to be equally effective in other types of cancer defined by increased DNA damage, such as that BRCA bad and ovarian mutations.
This study was funded by Moon Shot ™, a treatment for lung cancer, part of MD Anderson's Moon Shots ™ program, a collaborative effort to accelerate the development of scientific breakthroughs to achieve clinical breakthroughs to save the lives of patients.
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First published: February 19, 2019 16:20 IST
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