Dupixent is a fully human monoclonal antibody that inhibits signaling in the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways. To date, Dupixent has been evaluated in more than 60 clinical trials involving more than 10,000 patients with a variety of chronic diseases driven in part by type 2 inflammation.
In 2017, Dupixent was approved for marketing by the U.S. FDA. To date, Dupixent's approved indications include conditions such as atopic dermatitis, asthma, chronic sinusitis with nasal polyposis, nodular itchy rash, and eosinophilic esophagitis. Just recently, Regenerative Elements and Sanofi also plan to submit a supplemental Biologics License Application (sBLA) to the FDA for Dupixent for the treatment of COPD before the end of the year. Dupixent is expected to be the first approved biologic for the treatment of this serious disease, the press release noted.
While Dupixent has undoubtedly achieved good results as an anti-inflammatory drug, a recent study by scientists at the Icahn School of Medicine at Mount Sinai, published in the journal Nature, suggests that Dupixent is also expected to be used in the field of cancer treatment.
The hypothesis that Dupixent may have a role in cancer treatment goes back several years. At that time, scientists at the Icahn School of Medicine at Mount Sinai were studying why most cancer patients do not benefit well from immune checkpoint inhibitors.
In preclinical studies, scientists found that conventional dendritic cell type 1 (DC1) cells play a key role in controlling patients' response to checkpoint blockade, and that the presence of these cells was associated with longer overall survival. However, the same DC1 cells have been found in the tumors of some immune checkpoint inhibitor-resistant patients, suggesting that there may be some alterations in the function of these cells, and that these alterations are likely to be responsible for the patient's resistance to immune checkpoint inhibitors.
In order to explore what exactly is altered in these DC1 cells, scientists at the Icahn School of Medicine at Mount Sinai performed single-cell RNA sequencing of mature DC cells (mregDC) enriched with immune regulatory molecules in patients with non-small cell lung cancer (NSCLC) and in mice. The results revealed that the upregulation of PD-L1 was associated with the IL-4 signaling pathway. They subsequently found that blocking IL-4 promoted IL-12 production by mregDC, expanded the tumor-infiltrating effector T-cell pool, and reduced tumor load. The findings were published in Nature in 2020.
Typically, the IL-4 signaling pathway is thought to be associated with asthma, allergies, and all atopic diseases, and its role in cancer has rarely been investigated and therefore not targeted for cancer therapy. And after this study, the researchers reasoned that blocking IL-4 would likely restore sensitivity to this class of drugs in patients who are resistant to immune checkpoint inhibitors.
So they tested this hypothesis in a mouse model of NSCLC. The results were surprising, as blocking IL-4 slowed tumor growth not only in mice that had responded only slightly to immunotherapy, but also in those that had not responded at all.
Following this positive result, the researchers quickly designed a small clinical study to validate it - combining Dupixent, which has been on the market for many years, has a proven safety profile for long-term use, and inhibits the IL-4 signaling pathway, with a PD-1/PD-L1 inhibitor to treat tumors treated with a PD-1/PD-L1 inhibitor alone. PD-L1 inhibitor monotherapy for the treatment of patients with refractory NSCLC whose disease has progressed after receiving PD-1/PD-L1 inhibitor monotherapy.