Combining DNA Damage Response Inhibitors with Immunotherapy Boosts SCLC Clearance, Mouse Study Shows

Combining DNA Damage Response Inhibitors with Immunotherapy Boosts SCLC Clearance, Mouse Study Shows

Combining anti-PD-L1 immunotherapies with agents that inhibit the DNA damage response (DDR) significantly enhances anti-tumor immunity and leads to rapid tumor disappearance in mouse models of small cell lung cancer (SCLC), a study reports.

These preclinical findings suggest that adding DDR inhibitors, such as Lynparza (olaparib) or prexasertib, to immune checkpoint inhibitors, such as Opdivo (nivolumab) or Tecentriq (atezolizumab)may work better for treating SCLC in patients.

Based on their promising results and the fact that many DDR inhibitors are already in clinical trials for SCLC, researchers hope to start the first clinical tests of the combo therapy in patients later this year.

The study, “Targeting DNA damage response promotes anti-tumor immunity through STING-mediated T-cell activation in small cell lung cancer,” was published in the journal Cancer Discovery.

SCLC is a difficult-to-treat type of cancer that accounts for about 15 percent of all lung tumors. Chemotherapy is the standard treatment for advanced SCLC, but the cancer frequently comes back, resulting in a poor prognosis.

Although immune checkpoint inhibitors are very promising, they are of little help for treating SCLC, as this tumor is often capable of escaping immunotherapies.

“However, we want to do a lot better for our patients, and we think there’s a lot of room for further improvement,” Lauren Averett Byers, MD, researcher at the University of Texas MD Anderson Cancer Center and senior leader of the new study, said in a press release.

In fact, Byers and her colleagues at MD Anderson may just have found SCLC’s Achilles heel.

Their research suggests that DDR inhibitors can rapidly boost an immune response and make SCLC cells more vulnerable to immunotherapy.

Earlier work from the Byers lab demonstrated that the pathways cells normally use to repair DNA damage, collectively called the DNA damage response, are overly active in SCLC tumors. 

Cancers usually rely on the DDR to repair their DNA as they grow, and the research group has shown that agents that target this pathway, such as poly (ADP) ribose polymerase (PARP) and checkpoint kinase 1 (CHK1) inhibitors, were effective in treating SCLC in the lab.

In addition, other studies have shown that cancers carrying extensive DNA damage 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,” Byers said.

Using a mouse model of SCLC, they found that adding Lynparza, a PARP inhibitor, or prexasertib, which is a CHK1 inhibitor, to an anti-PD-L1 antibody, led to a dramatic shrinkage of tumors. In contrast, immunotherapy alone had no significant effect.

“In fact, in some cases, the tumors disappeared completely,” Byers said.

The combo with Lynparza, given for as little as one week, led to complete tumor regression in all treated mice. The prexasertib combination led to complete regression in 60% of treated mice.

Looking deeper at the molecular mechanism behind this response, the researchers discovered that DDR inhibitors activate a type of immune cells able to kill cancer cells, called CD8+ T-cells, at the tumors.

This process was mediated by the activation of a pathway in cells called the STING pathway, which normally works to detect a viral or a bacterial infection.

DDR inhibitors promoted the increase in DNA damage, which activated the STING pathway, boosting an anti-cancer immune response and making SCLC cells susceptible to anti-PD-L1 immunotherapy.

“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,” Byers said.

“Because prexasertib, olaparib and other PARP inhibitors are already in clinical trials for SCLC, we expect that this hypothesis has the potential for rapid translation into the clinic,” the researchers wrote in their study.

Byers and her colleagues plan to start the first clinical trials to investigate their combo approach in SCLC patients later this year.

They also hope their strategy will prove effective for other types of cancer sensitive to DNA damage, such as BRCA-mutant breast and ovarian cancers.