Genoud et al. showed that BAL101553 prodrug, which provokes genomic instability, induced cytolysis of and low level HMGB1 release from immunologically cold, poorly mutated, ICB-resistant SB28 glioma cells in vitro. In an orthotopic mouse model, BAL101553, which has high BBB penetrance, slowed SB28 growth and synergized modestly with CD40 agonism even in mice lacking B and T cells. BAL101553 induced an IFNγ response gene signature in SB28 tumors and CD11b+CD49d+ myeloid cell infiltration. Highly mutated, immunogenic GL261 glioblastoma responded well to anti-PD-1 + anti-CTLA-4, but only modestly to BAL101553 + CD40 agonism in vivo.
Contributed by Paula Hochman
ABSTRACT: Glioblastoma is a highly malignant brain tumor with no curative treatment options, and immune checkpoint blockade has not yet shown major impact. We hypothesized that drugs targeting mitosis might impact the tumor microenvironment and sensitize cancer cells to immunotherapy. We used two glioblastoma mouse models with different immunogenicity profiles, GL261 and SB28, to test the efficacy of antineoplastic and immunotherapy combinations. The spindle assembly checkpoint activator BAL101553 (lisavanbulin), agonistic anti-CD40 antibody, and double immune checkpoint blockade (anti-PD-1 and anti-CTLA-4) were evaluated individually or in combination for treating orthotopic GL261 and SB28 tumors. Genomic and immunological analyses were used to predict and interpret therapy responsiveness. BAL101553 monotherapy increased survival in immune checkpoint blockade resistant SB28 glioblastoma tumors and synergized with anti-CD40 antibody, in a T-cell independent manner. In contrast, the more immunogenic and highly mutated GL261 model responded best to anti-PD-1 and anti-CTLA-4 therapy and more modestly to BAL101553 and anti-CD40 combination. Our results show that BAL101553 is a promising therapeutic agent for glioblastoma and could synergize with innate immune stimulation. Overall, these data strongly support immune profiling of glioblastoma patients and preclinical testing of combination therapies with appropriate models for particular patient groups.
Author Info: (1) Translational Research Center for Hemato-Oncology, University of Geneva, Faculty of Medicine, Geneva, Switzerland. (2) Translational Research Center for Hemato-Oncology, Univer
Author Info: (1) Translational Research Center for Hemato-Oncology, University of Geneva, Faculty of Medicine, Geneva, Switzerland. (2) Translational Research Center for Hemato-Oncology, University of Geneva, Faculty of Medicine, Geneva, Switzerland. (3) Translational Research Center for Hemato-Oncology, University of Geneva, Faculty of Medicine, Geneva, Switzerland. (4) Translational Research Center for Hemato-Oncology, University of Geneva, Faculty of Medicine, Geneva, Switzerland. (5) Department of Oncology, University Hospital of Geneva, Geneva, Switzerland. (6) Department of Oncology, Basilea Pharmaceutica International Ltd., Basel, Switzerland. (7) Department of Oncology, Basilea Pharmaceutica International Ltd., Basel, Switzerland. (8) Department of Oncology, Basilea Pharmaceutica International Ltd., Basel, Switzerland. (9) Translational Research Center for Hemato-Oncology, University of Geneva, Faculty of Medicine, Geneva, Switzerland.
