Innovative Drug Combination Breaks Down Cancer Resistance to Immunotherapy
Scientists have discovered a strategy to break down the resilience of mice with neuroendocrine pancreatic cancer in a new study. This malignancy is particularly resistant to checkpoint blockade immunotherapy, in which the patient receives a medicine (a checkpoint inhibitor) that stops proteins that normally limit immune responses from being overly strong but can also hinder immune cells (T cells) from killing cancer cells.
Douglas Hanahan’s group at EPFL’s Swiss Institute for Experimental Cancer Research conducted the study, which included the Ludwig Institute for Cancer Research, the Lausanne University Hospital (CHUV), the Swiss Institute for Bioinformatics, and Roche.
Immunocytokine PD1-IL2v Together With Immune Checkpoint Inhibitor Anti-PD-L1 Kills Cancer Cells
The researchers looked at an immunocytokine, which is a form of synthetic protein-antibody fusion that is increasingly employed in immunotherapy. They concentrated on the bispecific immunocytokine PD1-IL2v, which was recently produced by Roche and can home into tumors, where it activates killer T cells to assault the cancer cells that are driving tumor growth.
The immunocytokine PD1-IL2v was coupled with the immune checkpoint inhibitor anti-PD-L1, increasing anti-tumor immunity against immunotherapy-resistant malignancies. “[PD1-IL2v] becomes significantly more effective when paired with an immune checkpoint inhibitor, anti-PD-L1,” the authors write.
“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.”
The combination of the two molecules boosted survival rates in tumor-bearing animals, resulting in a more prolonged therapeutic impact than the bispecific immunocytokine alone. The combination boosted therapeutic efficacy by altering immunosuppressive tumor-associated macrophages and tumor vasculature, making it easier for immune cells to ‘detect’ the disease.
“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 Douglas Hanahan. He concludes: “These provocative results present a rationale for clinical trials aimed to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, perhaps initially in immunotherapy-resistant cancer patients with T cell infiltrated tumors.”
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