Immune Checkpoint Inhibitor More Effective When Combined with Immunocytokine

A study led by researchers at EPFL’s Swiss Institute for Experimental Cancer Research has found that combining an immunocytokine with an immune checkpoint inhibitor can enhance anti-tumor immunity against immunotherapy-resistant tumors.

Although immunotherapy has significantly impacted the treatment of cancer patients, and already boasts cases of long-term remission, many patients still either don’t respond to immunotherapy, or if they do, the effects are temporary.

In the study published today in Immunity, the team found a way to break down the resistance of mice with neuroendocrine pancreatic cancer. This cancer is very resistant to immune checkpoint inhibitor therapy.

Their solution involved a type of engineered protein-antibody fusion called an immunocytokine. They focused on the bispecific immunocytokine PD1-IL2v, which is newly developed by Roche and can home into tumors, wherein it activates killer T cells to attack the cancer cells driving tumor growth.

The researchers combined the immunocytokine PD1-IL2v with the immune checkpoint inhibitor anti-PD-L1, thereby enhancing anti-tumor immunity against immunotherapy-resistant tumors. “[PD1-IL2v] is even more effective when combined with an immune checkpoint inhibitor, anti-PD-L1,” write the authors.

“PD1-IL2v induces stronger and more specific expansion of anti-tumor T cells compared to conventional anti-PD-1 therapy by stimulating a specific subtype of T cells, whereas anti-PD-L1 targets and disrupts barriers erected in the tumor microenvironment, namely pro-tumoral macrophages and tumor vasculature, which collaborate to counteract the anti-tumor immunity.”

Combining the two molecules resulted in increased survival rates in tumor-bearing mice, producing a more sustained therapeutic effect than just the bispecific immunocytokine by itself. The combination improved therapeutic efficacy by reprogramming immunosuppressive tumor-associated macrophages and tumor vasculature to render the cancer easier to “detect” by immune cells.

“This innovative immunotherapeutic combination sensitizes immunotherapy-resistant tumors infiltrated with PD-1⁺ stem-like T cells, which have recently been found to be important for sustaining efficacious anti-tumor immune responses, leading to tumor destruction with consequent survival benefit,” says team leader Douglas Hanahan.