Evaluate immuno-sensitization and radio-sensitization potential by long-acting interleukin-15 with albumin binding domain

Background and Purpose: Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis. Due to it high heterogeneity and immunosuppressive characteristics, the efficacy of standard treatments included chemotherapy (temozolomide) and radiotherapy (RT) is limited. Though recent studies indicated the promising outcome of immune checkpoint inhibitors (ICIs) in various solid tumors, the moderate response and no obvious survival benefit were reported in GBM. Further research is needed to identify biomarkers of response and therapies to rationally combine with ICIs. Studies also reported that the activation of the FGF/FGFR signaling pathway is associated with poor prognosis of GBM. Furthermore, interleukin-2 (IL-2) combined with programmed death-ligand 1 (PD-L1) antibody has been testing on clinical trial with potential outcome. However, the activation of immunosuppressive cells of IL-2 that cause activation-induced cell death (AICD) is the major drawback of it. To identify other combination cytokine with immunoactivation property as IL-2 but may not accompany with its drawback is important. IL-15 is another promising biological drug, which plays a central role in activation and survival of natural killer T and B cells, but with short half-life and unknown penetration ability toward blood brain barrier (BBB). Goal and specific aims: This proposed study aims to investigate the therapeutic efficacy and the underlying mechanism of hIL-15-ABD combined with RT or ICIs in GBM. Research design: We developed a new conjugation for of IL-15, which fusion albumin binding domain protein to increase its half-life, owns superior pharmacokinetic profile, and carry with BBB penetration capacity compared to original form of hIL-15 and named as hIL-15-ABD. The specific aims has included: ① Investigate whether hIL-15-ABD has superior anti-GBM effect compared with hIL-15 or ALT-803 (an IL-15 superagonist in clinical trial) and validate its potential mechanism. We will also investigate the regulation of hIL-15-ABD on tumor microenvironment by evaluating the change of CD8+ T cells, NK cells, myeloid-derived suppressor cells (MDSCs), M1 macrophage (M2) and M2 macrophage (M2). ②Second, we will address whether hIL-15-ABD may sensitize GBM to RT or ICIs treatment. We will evaluate the efficacy and mechanism of hIL-15-ABD combined with RT, PD-1 or PD-L1 inhibitors, respectively in an orthotopic glioblastoma mouse model. We will also develop a xenograft mice model to validate abscopal effect of RT combined with hIL-15-ABD. In addition, we will use ③humanized PD-1+/+ mouse model to further validate the treatment efficacy of a clinically approved PD-1 inhibitor combined with hIL-15-ABD. Significance: The major novelty of this project is that the treatment efficacy and mechanism of IL-15 combined with RT or ICIs in GBM have not been well-studied. The modified hIL-15-ABD from our group showed prolonged half-life and better pharmacokinetic profile as compared with the original form of hIL-15 which may be able to apply on clinic.