In an international project with pharma company Sprint Bioscience, scientists at the Luxembourg Institute of Health (LIH), led by Dr Bassam Janji, have developed an approach that turns “cold” tumours “hot”, making them responsive to immunotherapy.
“Cold”, immune-desert tumours are classically immunotherapy-resistant. “Hot” or inflamed tumours, by contrast, are infiltrated by the immune system and responsive to immunotherapy.
Vps34 is a protein key to initiating the process of autophagy, a process of “self-digestion” that allows cancer cells to acquire nutrients to sustain their growth. The scientists teamed up with Swedish pharma company Sprint Bioscience, which has developed the molecule SB02024, shown to successfully inhibit autophagy. Using the lead compound SB02024, the scientists leveraged on several molecules and techniques, using preclinical mouse models to evaluate the effects of genetically and pharmacologically targeting Vps34 on tumour growth and mice survival.
Their findings highlighted Vps34 inhibitors as valuable drugs making tumours eligible or responsive to immunotherapy based on Immune checkpoint inhibitors (ICI). Furthermore, Dr Janji’s team showed that combining the Vps34 inhibitor SB02024 with anti-PD-1 significantly improves the efficacy of this ICI in resistant melanoma and colorectal cancer.
Immune checkpoint inhibitors (ICI), exemplified by anti-PD-1, are immunotherapeutic drugs that act by removing the “brakes” on the immune system and unleashing an immune attack on cancer cells. While these drugs are very promising for the treatment of many cancers, few cancer patients show significant therapeutic benefits when treated with ICI alone. One of the major causes of tumour unresponsiveness to ICI is the poor infiltration of cytotoxic immune cells into the tumour bed. Therefore, approaches that drive immune cells into cold poorly infiltrated tumours would significantly enhance the therapeutic benefit of immunotherapy based on ICI.
The study was carried out in collaboration with Sprint Bioscience (Sweden), the Centre Hospitalier de Luxembourg (CHL), the Karolinska Institute (Sweden) and the University of Pennsylvania (USA).
The study, co-authored by Dr Bassam Janji and Dr Guy Berchem, was published on 29 April 2020 in the prestigious journal Science Advances, with the full title “Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti–PD-1/PD-L1 immunotherapy”.