Abstract
Allogeneic natural killer (aNK) cell adoptive therapy has the potential to dramatically impact clinical outcomes of glioblastoma multiforme (GBM). However, in order to exert therapeutic activity, NK cells require tumor expression of ligands for activating receptors, such as MHC Class I peptide A/B (MICA/B) and ULBPs. Here, we describe the use of a blood–brain barrier (BBB) permissive supramolecular cationic drug vehicle comprising an inhibitor of the chaperone heat shock protein 90 (Hsp90), which sustains a cytotoxic effect on GBM cells, boosts the expression of MICA/B and ULBPs on the residual population, and augments the activity of clinical-grade aNK cells (GTA002). First, we identify Hsp90 mRNA transcription and gain of function as significantly upregulated in GBM compared to other central nervous system tumors. Through a rational chemical design, we optimize a radicicol supramolecular prodrug containing cationic excipients, SCI-101, which displays >2-fold increase in relative BBB penetration compared to less cationic formulations in organoids, in vitro. Using 2D and 3D biological models, we confirm SCI-101 sustains GBM cytotoxicity 72 h after drug removal and induces cell surface MICA/B protein and ULBP mRNA up to 200% in residual tumor cells compared to the naked drug alone without augmenting the shedding of MICA/B, in vitro. Finally, we generate and test the sequential administration of SCI-101 with a clinical aNK cell therapy, GTA002, differentiated and expanded from healthy umbilical cord blood CD34+ hematopoietic stem cells. Using a longitudinal in vitro model, we demonstrate >350% relative cell killing is achieved in SCI-101–treated cell lines compared to vehicle controls. In summary, these data provide a first-of-its-kind BBB-penetrating, long-acting inhibitor of Hsp90 with monotherapy efficacy, which improves response to aNK cells and thus may rapidly alter the treatment paradigm for patients with GBM.
Highlights
glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the brain and one of the deadliest malignancies (Ostrom et al, 2016)
We queried the open repository of The Cancer Genome Atlas (TCGA) and molecular gene expression data in cBioPortal (CBIOportal.org) and compared central nervous system (CNS) tumor subtypes including astrocytoma, GBM, and oligodendrocyte malignancies for the expression of heat shock protein 90 (Hsp90) mRNA (HSP90AA1)
We interrogated the mRNA expression of Hsp90 co-chaperones from two GBM clinical datasets, including cell division cycle 37 (CDC37), stressinduced phosphoprotein 1 (STIP1), and Hsp90 class B, demonstrating a clear upregulation of HSP90AA1 in each (Figure 1C)
Summary
GBM is the most common and aggressive primary malignant tumor of the brain and one of the deadliest malignancies (Ostrom et al, 2016). Once T-cells penetrate into GBM, they have been observed, in vivo, to become dysfunctional via various mechanisms (Woroniecka et al, 2018). For this reason, among others, immune checkpoint blockade and various other immunotherapeutic approaches have proven lackluster in the clinical management of GBM (Weenink et al, 2020). While there are ongoing pre-clinical studies to identify effective Hsp inhibitors for GBM (Chen et al, 2020), achieving effective and non-toxic strategies that augment immunogenicity remains an unaddressed challenge
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