Researchers at the Icahn School of Medicine at Mount Sinai have identified an allergy pathway that, when blocked, unleashes antitumor immunity in mouse models of non-small cell lung cancer (NSCLC).  The team reported data from an early clinical trial evaluating treatment using an anti-allergy drug that blocks the interleukin-4 receptor (IL-4Rα), in combination with PD-1/PD-L1 immune checkpoint blockade, in six patients with non-small cell lung cancer (NSCLC) that had progressed when treated using immunotherapy alone. Checkpoint blockade is a type of cancer immunotherapy that can unleash the cancer-killing activity of T cells.

Results from the trial confirmed that combining immunotherapy with the IL-4Rα blocking antibody dupilumab boosted patients’ immune systems, and one of the six individuals demonstrated significant tumor reduction and a near-complete clinical response two months after treatment. The reported studies were headed by Miriam Merad, MD, PhD, director of the Marc and Jennifer Lipschultz Precision Immunology Institute and chair of the Department of Immunology and Immunotherapy at the Icahn School of Medicine at Mount Sinai.

Merad and colleagues described their research and trial findings in Nature, in a paper titled “An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis.

“Immunotherapy using checkpoint blockade has revolutionized treatment for non-small cell lung cancer, the most common form of lung cancer, but currently only about a third of patients respond to it alone, and in most patients, the benefit is temporary,” said Merad.

NSCLC accounts for more than 1.6 million annual deaths worldwide, the authors wrote. “A key driver of cancer progression is thought to be the tumor microenvironment (TME), which in NSCLC is dominated by macrophages that support tumour growth through diverse mechanisms.” And while myeloid cells are known to suppress antitumour immunity, the molecular drivers of immunosuppressive myeloid cell states are not well understood, the team continued.

“A big focus of our program TARGET is to use single cell technology and artificial intelligence to identify molecular immune programs that can dampen tumor immune response to checkpoint blockade,” Merad added. The team had previously mapped the immune landscape of human and mouse NSCLC tumors using single-cell RNA sequencing, (scRNA-seq), and found a high degree of similarity between the two species. Interestingly, they found that blocking IL-4 strongly reduced lung tumor burden in mouse models of lung cancer. Further tests using a panel of conditional knockout mice found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumor burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect.

IL-4 was subsequently found to transcriptionally program the development of immunosuppressive tumor-promoting myeloid cells. The collective data, the team summarized “define a model in which bone marrow type 2 granulocytes sense distal cues produced by NSCLC tumors and subsequently direct the development of immunosuppressive myeloid cells through the production of IL-4.”

First study author Nelson LaMarche, PhD, further explained, “Using single cell technologies, we discovered that the immune cells infiltrating lung cancers, as well as other cancers we studied, exhibited characteristics of a ‘type 2’ immune response, which is commonly associated with allergic conditions like eczema and asthma.” LaMarche is a postdoctoral research fellow in the Merad lab.

The team had demonstrated that in mouse models, anti-IL4 treatment boosted the response to anti-PD-L1 immunotherapy, indicating that the two treatments have synergistic effects “These results led us to explore whether we could repurpose a medication typically used for allergic conditions to ‘rescue’ or enhance tumor response to checkpoint blockade,” further commented Thomas Marron, MD, PhD, director of the Early Phase Trial Unit at Mount Sinai’s Tisch Cancer Center, and co-senior author of the study.

“On the basis of these preclinical data, we designed and opened a Phase Ib trial in which patients with relapsed/refractory NSCLC who had progressed on PD-1/PD-L1 blockade continue PD-1/PD-L1 blocking antibody treatment while adding IL-4Rα blockade with dupilumab … in an attempt to induce or rescue an antitumor immune response,” the authors reported. Dupilumab is a fully humanized monoclonal antibody to IL-4Rα, which is FDA approved for use in multiple allergy indications. However, as the team continued, “The use of dupilumab has yet to be explored specifically in cancer.”

Describing the results of the subsequent trail, Marron said, “Strikingly, we found that IL-4 blockade enhanced lung cancer response to checkpoint blockade in mice and in six lung cancer patients with treatment-resistant disease. In fact, one patient whose lung cancer was growing despite checkpoint blockade had nearly all their cancer disappear after receiving just three doses of the allergy medication, and his cancer remains controlled today, over 17 months later.”

Chest scans showing lung tumors in a patient with metastatic non-small cell lung cancer prior to and after receiving dupilumab with conventional immunotherapy.
Chest scans showing lung tumors in a patient with metastatic non-small cell lung cancer prior to and after receiving dupilumab with conventional immunotherapy. [LaMarche et al., Nature.]
And as the authors wrote in their paper, “… we found that dupilumab co-administration drove a rapid (day 4) upregulation of proinflammatory cytokines that are known to promote antitumor immune responses … Additionally, dupilumab induced an expansion of circulating effector CD8 T cells and antibody-producing plasma cells, both of which are essential for the response to PD-1/PD-L1 blockade.”

The researchers are encouraged by the initial study results but emphasize the need for larger clinical trials to validate the drug’s efficacy in treating NSCLC. Beyond the early trial findings reported in the current Nature paper, the investigators have now expanded the clinical trial, adding dupilumab to checkpoint blockade for a larger group of lung cancer patients. Dr Marron in addition recently received a grant from the Cancer Research Institute to study the effects in early-stage lung cancer. Through these trials the researchers are searching for biomarkers that can predict which cancer patients might benefit from dupilumab treatment and which may not.

While acknowledging the need for further trials and investigation, the authors nevertheless concluded, “Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.”

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