Immunotherapy is a way of treating cancer reprogramming the patient’s immune system to attack his tumor. This cutting-edge approach has had a significant impact on the treatment of cancer patients, and already has cases of long-term remission.
However, many patients remain unresponsive to immunotherapy or, if they do, the effects are temporary, highlighting the importance of better understanding the mechanisms that make cancers resistant to this type of treatment.
Pancreatic neuroendocrine cancer is highly resistant to a type of immunotherapy called checkpoint blockade, in which the patient is given a drug (a checkpoint inhibitor) that blocks proteins that normally prevent immune responses from being too strong, but they can also stop immune cells (T cells) from killing cancer cells.
The study was led by the group of Douglas Hanahan, from EPFL’s Swiss Institute for Experimental Cancer Research, with the Ludwig Institute for Cancer Research, the University Hospital Lausanne (CHUV), the Swiss Institute for Bioinformatics and Roche.
The scientists evaluated a type of protein-antibody fusion called an immunocytokine, which is increasingly used in immunotherapy. They focused on the bispecific immunocytokine PD1-IL2v, recently developed by Roche and capable of entering tumors, where it activates killer T cells to attack cancer cells driving tumor growth.
The researchers combined the immunocytokine PD1-IL2v with the immune checkpoint inhibitor anti-PD-L1, thereby enhancing antitumor immunity against tumors resistant to immunotherapy. “The [PD1-IL2v] it is even more effective when combined with an immune checkpoint inhibitor, anti-PD-L1,” the authors write.
“PD1-IL2v induces a stronger and more specific expansion of antitumor T cells compared to conventional anti-PD-1 therapy by stimulating a specific T cell subtype, while anti-PD-L1 targets and disrupts the barriers erected in the tumor microenvironment, namely pro-tumor macrophages and tumor vasculature, which collaborate to counteract anti-tumor immunity.
The combination of the two molecules resulted in an increased survival rate in tumor-bearing mice, producing a more sustained therapeutic effect than the bispecific immunocytokine alone. The combination improved therapeutic efficacy by reprogramming macrophages immunosuppressants associated with the tumor and tumor vasculature to make the cancer easier to “detect” by immune cells.
“This innovative immunotherapeutic combination sensitizes immunotherapy-resistant tumors infiltrated with PD-1+ T-lymphocytes, which have recently been shown to be important in maintaining effective antitumor immune responses, leading to tumor destruction with consequent benefit for survival and concludes: “These provocative results present a rationale for clinical trials aimed at evaluating combination therapy of PD1-IL2v and anti-PD-L1, perhaps initially in immunotherapy-resistant cancer patients with T cell-infiltrated tumors.” .