To overcome the challenge of treating malignant brain tumors, oncolytic viruses (OVs) represent an innovative therapeutic approach, featuring unique mechanisms of action. The recent conditional ...approval of the oncolytic herpes simplex virus G47Δ as a therapeutic for malignant brain tumors marked a significant milestone in the long history of OV development in neuro-oncology.
This review summarizes the results of recently completed and active clinical studies that investigate the safety and efficacy of different OV types in patients with malignant gliomas. The changing landscape of the OV trial design includes expansion of subjects to newly diagnosed tumors and pediatric populations. A variety of delivery methods and new routes of administration are vigorously tested to optimize tumor infection and overall efficacy. New therapeutic strategies such as combination with immunotherapies are proposed that take advantage of the characteristics of OV therapy as an immunotherapy. Preclinical studies of OV have been active and aim to translate new OV strategies to the clinic.
For the next decade, clinical trials and preclinical and translational research will continue to drive the development of innovative OV treatments for malignant gliomas and benefit patients and define new OV biomarkers.
Emergence of mismatch repair (MMR) deficiency is a frequent mechanism of acquired resistance to the alkylating chemotherapeutic temozolomide (TMZ) in gliomas. Poly(ADP-ribose) polymerase inhibitors ...(PARPi) have been shown to potentiate TMZ cytotoxicity in several cancer types, including gliomas. We tested whether PARP inhibition could re-sensitize MSH6-null MMR-deficient gliomas to TMZ, and assessed the role of the base excision repair (BER) DNA damage repair pathway in PARPi-mediated effects.
Isogenic pairs of MSH6 wild-type and MSH6-inactivated human glioblastoma (GBM) cells (including both
wild-type and
mutant), as well as MSH6-null cells derived from a patient with recurrent GBM were treated with TMZ, the PARPi veliparib or olaparib, and combination thereof. Efficacy of PARPi combined with TMZ was assessed
. We used genetic and pharmacological approaches to dissect the contribution of BER.
While having no detectable effect in MSH6 wild-type GBMs, PARPi selectively restored TMZ sensitivity in MSH6-deficient GBM cells. This genotype-specific restoration of activity translated
, where combination treatment of veliparib and TMZ showed potent suppression of tumor growth of MSH6-inactivated orthotopic xenografts, compared with TMZ monotherapy. Unlike PARPi, genetic and pharmacological blockage of BER pathway did not re-sensitize MSH6-inactivated GBM cells to TMZ. Similarly, CRISPR PARP1 knockout did not re-sensitize MSH6-inactivated GBM cells to TMZ.
PARPi restoration of TMZ chemosensitivity in MSH6-inactivated glioma represents a promising strategy to overcome acquired chemoresistance caused by MMR deficiency. Mechanistically, this PARPi-mediated synthetic phenotype was independent of BER blockage and was not recapitulated by loss of PARP1.
Chimeric antigen receptor (CAR)-T-cell therapy for solid tumors is limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR-T cells directed ...against single antigens. Here, we developed a bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues. CART.BiTE cells secreted EGFR-specific BiTEs that redirect CAR-T cells and recruit untransduced bystander T cells against wild-type EGFR. EGFRvIII-specific CAR-T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive glioblastoma. However, CART.BiTE cells eliminated heterogenous tumors in mouse models of glioblastoma. BiTE-EGFR was locally effective but was not detected systemically after intracranial delivery of CART.BiTE cells. Unlike EGFR-specific CAR-T cells, CART.BiTE cells did not result in toxicity against human skin grafts in vivo.
Replication conditional oncolytic human adenovirus has long been considered a promising biological therapeutic to target high-grade gliomas (HGG), a group of essentially lethal primary brain cancer. ...The last decade has witnessed initiation and some completion of a number of Phase I and II clinical investigations of oncolytic adenovirus for HGG in the US and Europe. Results of these trials in patients are pivotal for not only federal approval but also filling an existing knowledge gap that primarily derives from the stark differences in permissivity to human adenovirus between humans and preclinical mouse models. DNX-2401 (Delta-24-RGD), the current mainstream oncolytic adenovirus with modifications in E1A and the fiber, has been shown to induce impressive objective response and long-term survival (>3 years) in a fraction of patients with recurrent HGG. Responders exhibited initial enlargement of the treated lesions for a few months post treatment, followed by shrinkage and near complete resolution. In accord with preclinical research, post-treatment specimens revealed virus-mediated alteration of the immune tumor microenvironment as evidenced by infiltration of CD8+ T cells and M1-polarized macrophages. These findings are encouraging and together with further information from ongoing studies have a potential to make oncolytic adenovirus a viable option for clinical management of HGG. This review deals with this timely topic; we will describe both preclinical and clinical development of oncolytic adenovirus therapy for HGG, summarize updated knowledge on clinical trials and discuss challenges that the field currently faces. Keywords: oncolytic adenovirus, high-grade, glioma, glioblastoma, immunotherapy, tumor microenvironment, pseudo-progression
PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived ...glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.
The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect ...glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.
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•Macrophages induce the MES-like state of glioblastoma cells•Induction is mediated by macrophage-derived OSM interacting with OSMR/LIFR-GP130•Subsets of glioblastoma-associated macrophages express a related MES-like program•The MES-like state in glioblastoma is associated with cytotoxic T cells programs
Hara et al. combine single-cell RNA sequencing and functional experiments to explore the crosstalk between glioblastoma and the microenvironment, revealing that macrophage-derived OSM induces the mesenchymal-like state of glioblastoma, a state associated with upregulation of major histocompatibility complex genes, and with potential implications for immunotherapy.
Glioblastoma (GBM), a fatal brain cancer, contains a subpopulation of GBM stem-like cells (GSCs) that contribute to resistance to current therapy. Angiogenesis also plays a key role in GBM ...progression. Therefore, we developed a strategy to target the complex GBM microenvironment, including GSCs and tumor vasculature.
We evaluated the cytotoxic effects of VEFGR tyrosine kinase inhibitor (TKI) axitinib
and then tested antitumor efficacy of axitinib in combination with oncolytic herpes simplex virus (oHSV) expressing antiangiogenic cytokine murine IL12 (G47Δ-mIL12) in two orthotopic GSC-derived GBM models: patient-derived recurrent MGG123 GSCs, forming vascular xenografts in immunodeficient mice; and mouse 005 GSCs, forming syngeneic tumors in immunocompetent mice.
GSCs form endothelial-like tubes and were sensitive to axitinib. G47Δ-mIL12 significantly improved survival, as did axitinib, while dual combinations further extended survival significantly compared with single therapies alone in both models. In MGG123 tumors, axitinib was effective only at high doses (50 mg/kg), alone and in combination with G47Δ-mIL12, and this was associated with greatly decreased vascularity, increased macrophage infiltration, extensive tumor necrosis, and PDGFR/ERK pathway inhibition. In the mouse 005 model, antiglioma activity, after single and combination therapy, was only observed in immunocompetent mice and not the T-cell-deficient athymic mice. Interestingly, immune checkpoint inhibition did not improve efficacy.
Systemic TKI (axitinib) beneficially combines with G47Δ-mIL12 to enhance antitumor efficacy in both immunodeficient and immunocompetent orthotopic GBM models. Our results support further investigation of TKIs in combination with oHSV for GBM treatment.
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Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate ...dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.
Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used ...single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy.
-mutant gliomas are dependent upon the canonical coenzyme NAD
for survival. It is known that PARP activation consumes NAD
during base excision repair (BER) of chemotherapy-induced DNA damage. We ...therefore hypothesized that a strategy combining NAD
biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD
depletion-mediated cytotoxicity in mutant
cancer cells. To investigate the impact of temozolomide on NAD
metabolism, patient-derived xenografts and engineered mutant
-expressing cell lines were exposed to temozolomide,
and
, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD
biosynthesis. The acute time period (<3 hours) after temozolomide treatment displayed a burst of NAD
consumption driven by PARP activation. In
-mutant-expressing cells, this consumption reduced further the abnormally lowered basal steady-state levels of NAD
, introducing a window of hypervulnerability to NAD
biosynthesis inhibitors. This effect was selective for
-mutant cells and independent of methylguanine methyltransferase or mismatch repair status, which are known rate-limiting mediators of adjuvant temozolomide genotoxic sensitivity. Combined temozolomide and NAMPT inhibition in an
-mutant cancer model exhibited enhanced efficacy compared with each agent alone. Thus, we find
-mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting nonredundant NAD
pathways yield potent anticancer efficacy
Such targeting of convergent metabolic pathways in genetically selected cancers could minimize treatment toxicity and improve durability of response to therapy.
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