Radiation-induced enhancement of antitumor T cell immunity by VEGF-targeted 4-1BB costimulation
Menée à l'aide de modèles murins, cette étude met en évidence l'intérêt d'oligonucléotides synthétiques conjugués ciblant à la fois le facteur de croissance VEGF et le récepteur 4-1BB pour améliorer la réponse antitumorale des lymphocytes T induite par les radiations ionisantes et limiter parallèllement la toxicité des rayonnements
Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. While this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immune modulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy. Using an oligonucleotide aptamer platform, we show that radiation-induced VEGF-targeted 4-1BB costimulation potentiated both local tumor control and abscopal responses with equal or greater efficiency than 4-1BB, CTLA-4, or PD1 antibodies alone. Whereas 4-1BB and CTLA-4 antibodies elicited organ-wide inflammatory responses and tissue damage, VEGF-targeted 4-1BB costimulation produced no observable toxicity. These findings suggest that radiation-induced tumor-targeted immunotherapy can improve the therapeutic index and extend the reach of immunomodulatory agents.