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Immunotherapy and DNA damage repair combo could target lung cancer

Combination therapy with a CHK1 or PARP inhibitor, with an immune checkpoint inhibitor caused the regression of small cell lung cancer in all mice treated…

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

Scientists have used the study results to suggest that the PARP inhibitor olaparib and other DDR inhibitors induce a rapid immune response and sensitise small lung cancer cells to immunotherapy, the therapy they were initially resistant to.

Associate Professor of Thoracic/Head & Neck Medical Oncology, Dr Lauren Averett Byers, at the University of Texas MD Anderson Cancer Center mentioned how small cell lung cancer affects around 30,000 patients in the US each year, and corresponds to around 15 percent of all lung cancers in the US. The average survival is currently around 12 months, as recurrence after treatment is common.

Initial treatment consists of chemotherapy, with the use of immunotherapy in combination with chemotherapy becoming a new standard. However, the benefits are known to be minimal for the patients involved. 

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

The research team previously discovered that DDR pathways were highly active in small cell lung cancer, and as such, preventing this using PARP and CHK1 inhibitors resulted in the treatment of the cancer in the lab. 

Cancer with extensive amounts of DNA damage have been shown to respond better to immunotherapy.

“Therefore, we predicted that if we combined PARP inhibitors or other drugs that cause DNA damage with immune therapies, we might see a much greater response to the immune therapy,” said Prof Byers. “We found that if we added either PARP or CHK1 inhibitors to immunotherapy, we saw a dramatic shrinkage of tumors. In fact, in some cases, the tumors disappeared completely.” 

Combining the CHK1 inhibitor, prexasertib, or the PARP inhibitor, olaparib, together with an immune checkpoint inhibitor against PD-L1 resulted in tumour regression in mouse models, with immunotherapy alone having no effect. The combination treatment resulted in complete regression of the cancer in one week in all mice treated.

“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 Prof Byers. “I think our findings can be rapidly translated into the clinic for our patients and also to other cancer types.”

The researchers suggested how the results of the study could suggest a promising method of attacking this type of cancer in patients.

The study was published in the journal Cancer Discovery.

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