Small cell lung cancer may respond to combination therapy

Researchers have now discovered that a combination of immune checkpoint blockade and targeted therapies that block normal DNA damage repair (DDR) achieved significant tumour regression in mouse models of small cell lung cancer (SCLC).

The University of Texas MD Anderson Cancer Center research suggests a promising new approach for treating patients with this aggressive cancer. The research, published in Cancer Discovery, suggest that the PARP inhibitor olaparib and other DDR inhibitors induce a rapid immune response and sensitise SCLC cells to immunotherapy, to which they were previously resistant.

According to corresponding author of the study lauren Averett Byers, small cell lung cancer, one of the most aggressive types of cancer, makes up about 15% of all lung cancers diagnosed in the US alone.

Standard treatment for advanced SCLC is chemotherapy, but recurrence is common and the average survival is only about 12 months, according to Byers. For about 30 years, there were no changes to this approach, but recently the use of immunotherapy in combination with chemotherapy has become a new standard. However, the benefits are minimal for patients.

Speaking about it, Byers said, “While the use of immunotherapy has revolutionised the way we treat lung cancer, we find that small cell lung cancers can escape the immune system very effectively, so we see a much lower response rate.”

He further added, “However, we want to do a lot better for our patients, and we think there’s a lot of room for further improvement.”

Previously, Byers discovered that DDR pathways were highly active in SCLC and blocking these pathways with drugs, such as PARP and CHK1 inhibitors, was effective in treating SCLC in the lab. Additionally, cancers with extensive amounts of DNA damage have been shown to respond better to immunotherapy.

The experts thus predicted that if they combined PARP inhibitors or other drugs that cause DNA damage with immune therapies, they might see a much greater response to the immune therapy.

Byers added, “We found that if we added either PARP or CHK1 inhibitors to immunotherapy, we saw a dramatic shrinkage of tumours. In fact, in some cases, the tumours disappeared completely.”

Combining the CHK1 inhibitor, prexasertib, or the PARP inhibitor, olaparib, together with an immune checkpoint inhibitor against PD-L1 resulted in significant tumour regression in SCLC mouse models, whereas immunotherapy alone had no effect.

The combination of PARP inhibitor and immunotherapy resulted in complete regression in all treated mice in as little as one week, leaving no tumours available for further analysis. The CHK1 combination treatment led to complete regression in 60 percent of treated mice.

The researchers discovered that DDR inhibitors activated an immune response in the mice, leading to an increase in cancer-killing immune cells in the tumours. This process was controlled by the STING pathway, which normally works to detect signals of a viral or bacterial infection. In this case, the STING pathway responded to DNA damage to activate the immune system, thus making SCLC cells susceptible to immunotherapy treatment.

“I think the results from this study are really compelling because of the dramatic activity that we saw with the combination of adding a targeted therapy to immune therapy,” said Byers, adding, “I think our findings can be rapidly translated into the clinic for our patients and also to other cancer types.”

Byers and colleagues hope to launch clinical trials to investigate the combination approach later this year, and expect this may also be effective in other cancer types defined by increased DNA damage, such as BRCA-mutant breast and ovarian cancers.

This study was supported by the Lung Cancer Moon Shot™, part of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

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First Published: Feb 19, 2019 16:20 IST

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