Immune checkpoint inhibitors, which unleash the body’s anti-tumor immune response, have been available for triple-negative breast cancer (TNBC). But many people do not respond to the therapy or acquire resistance to it. Now, a team of scientists in Spain has discovered a promising approach to improve immunotherapy’s effectiveness in this aggressive type of breast cancer.
In TNBC, cancer stem cells can hide from the immune system, thwarting immuno-oncology strategies, a team led by Hospital del Mar Medical Research Institute (IMIM) found. Dialing up expression of a protein called LCOR could make the stem cells visible to the immune system, opening up the tumors for killing by immune cells, the team reported in a study published in the journal Nature Cancer.
Inspired by the mRNA technology used in COVID-19 vaccines, the researchers designed an mRNA therapy to produce LCOR. In mice, the therapy showed markedly improved anti-tumor results when combined with an anti-PD-L1 checkpoint inhibitor.
IMIM has filed a patent on the findings and is creating a biotech spinoff to further develop the mRNA therapy.
Cancer stem cells may constitute up to 50% of the tumor population in TNBC and can give rise to new tumors. LCOR mediates the differentiation of breast cancer stem cells, so the IMIM team was curious about whether the protein plays a role in resistance to checkpoint inhibition in TNBC.
Studying PD-L1 immunotherapy-resistant tumors harvested from mice, the researchers found that cancer stem cells with low LCOR expression showed reduced antigen processing and presentation machinery. The process of presenting antigens on cell surface is a critical step for the immune system to differentiate normal cells from tumor cells and attack the latter.
In lab dishes, TNBC tumor cells with LCOR over-expression increased T-cell activation as more T cells entered and killed off the tumors. What’s more, LCOR appeared to increase PD-L1 expression on the tumor cells, creating an ideal situation for anti-PD-1/L1 therapy, the team found.
The researchers also examined tumor samples from TNBC patients in several clinical trials of PD-1/L1 inhibitors including Roche’s Tecentriq, Bristol Myers Squibb’s Opdivo and AstraZeneca’s Imfinzi. They linked higher LCOR expression to better responses to checkpoint inhibitors.
To test the theory, the scientists applied anti-PD-L1 therapy in mouse models of TNBC. Control tumors continued growing, the team reported, whereas LCOR-over-expressing tumors regressed, with no signs of cancer by 20 days in all mice.
In five independent experiments, the team observed complete response in 49 out of 50 LCOR-over-expressing tumors, and the only case that failed somehow had lost the expression of LCOR.
After one year of follow-up, none of the 15 animals had tumors recur, and all their glands were tumor-free, “suggesting that we had irreversibly eradicated the tumors and cured these mice,” the researchers wrote in the study.
The huge success of mRNA vaccines against COVID-19 proved that delivering mRNA to express therapeutic proteins is a viable strategy. So, the IMIM team designed an mRNA therapy to restore LCOR expression in tumor cells.
In mice, treatment with the LCOR mRNA therapy and a PD-L1 inhibitor led to significantly longer survival and complete elimination of lung metastasis compared with a PD-L1 inhibitor and a control therapy.
Although the FDA has approved checkpoint inhibitors for TNBC, there’s still a need for improvement. Merck & Co.’s PD-1 inhibitor Keytruda was approved alongside chemotherapy to treat patients with advanced TNBC whose tumors express PD-L1 at a combined positive score of 10 or above. But in the KEYNOTE-355 trial that earned Keytruda the approval, only half of patients responded.
Last year, Roche decided to withdraw Tecentriq’s TNBC indication in the U.S. after a confirmatory clinical trial pairing the PD-L1 inhibitor with the chemotherapy paclitaxel failed to confer a survival benefit over chemo alone in PD-L1-positive patients.
The IMIM researchers believe their data support LCOR as a promising target for enhancing the efficacy of checkpoint inhibitors in TNBC. The LCOR mRNA therapy, by increasing antigen presentation in tumor cells, could work in concert with a PD-1/L1 inhibitor, they said.
“What is important is that the experimental results demonstrate an unprecedented sensitization of triple-negative breast cancer to immunotherapy, making resistant tumors virtually curable,” Joan Albanell, M.D., the study’s co-senior author, said in a statement. “This unequivocally motivates us to investigate therapeutic strategies that may culminate in clinical trials, and to explore whether it could be applicable to other tumors.”