Combination immunotherapy with vaccine and oncolytic HSV virotherapy is time dependent.

PURPOSE: Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSVs) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell mediated immunity may lead to more durable tumor regression. EXPERIMENTAL DESIGN: To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine co-delivering peptide antigens and Toll-like receptor-7 and -8 agonists (TLR-7/8a) (referred to as SNAPvax™), that induces robust tumor specific T cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T cell responses, viral replication, and preclinical efficacy. RESULTS: The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax™ vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumour volume and increases in virus replication and tumor antigen specific CD8+ T cells. CONCLUSIONS: These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors.

Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates.

Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient-derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers.

Immunotherapy for Pediatric Brain and Spine Tumors: Current State and Future Directions.

BACKGROUND: Brain tumors are the most common solid tumors and the leading cause of cancer-related deaths in children. Incidence in the USA has been on the rise for the last 2 decades. While therapeutic advances in diagnosis and treatment have improved survival and quality of life in many children, prognosis remains poor and current treatments have significant long-term sequelae. SUMMARY: There is a substantial need for the development of new therapeutic approaches, and since the introduction of immunotherapy by immune checkpoint inhibitors, there has been an exponential increase in clinical trials to adopt these and other immunotherapy approaches in children with brain tumors. In this review, we summarize the current immunotherapy landscape for various pediatric brain tumor types including choroid plexus tumors, embryonal tumors (medulloblastoma, AT/RT, PNETs), ependymoma, germ cell tumors, gliomas, glioneuronal and neuronal tumors, and mesenchymal tumors. We discuss the latest clinical trials and noteworthy preclinical studies to treat these pediatric brain tumors using checkpoint inhibitors, cellular therapies (CAR-T, NK, T cell), oncolytic virotherapy, radioimmunotherapy, tumor vaccines, immunomodulators, and other targeted therapies. KEY MESSAGES: The current landscape for immunotherapy in pediatric brain tumors is still emerging, but results in certain tumors have been promising. In the age of targeted therapy, genetic tumor profiling, and many ongoing clinical trials, immunotherapy will likely become an increasingly effective tool in the neuro-oncologist armamentarium.

Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers.

PURPOSE: Oncolytic virotherapy with herpes simplex virus-1 (HSV) has shown promise for the treatment of pediatric and adult brain tumors; however, completed and ongoing clinical trials have utilized intratumoral/peritumoral oncolytic HSV (oHSV) inoculation due to intraventricular/intrathecal toxicity concerns. Intratumoral delivery requires an invasive neurosurgical procedure, limits repeat injections, and precludes direct targeting of metastatic and leptomeningeal disease. To address these limitations, we determined causes of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice. EXPERIMENTAL DESIGN: HSV-sensitive CBA/J mice received intraventricular vehicle, inactivated oHSV, or treatment doses (1×107 plaque-forming units) of oHSV, and toxicity was assessed by weight loss and IHC. Protective strategies to reduce oHSV toxicity, including intraventricular low-dose oHSV or interferon inducer polyinosinic-polycytidylic acid (poly I:C) prior to oHSV treatment dose, were evaluated and then utilized to assess intraventricular oHSV treatment of multiple models of disseminated CNS disease. RESULTS: A standard treatment dose of intraventricular oHSV damaged ependymal cells via virus replication and induction of CD8+ T cells, whereas vehicle or inactivated virus resulted in no toxicity. Subsequent doses of intraventricular oHSV caused little additional toxicity. Interferon induction with phosphorylation of eukaryotic initiation factor-2α (eIF2α) via intraventricular pretreatment with low-dose oHSV or poly I:C mitigated ependyma toxicity. This approach enabled the safe delivery of multiple treatment doses of clinically relevant oHSV G207 and prolonged survival in disseminated brain tumor models. CONCLUSIONS: Toxicity from intraventricular oHSV can be mitigated, resulting in therapeutic benefit. These data support the clinical translation of intraventricular G207.

Standard clinical approaches and emerging modalities for glioblastoma imaging.

Glioblastoma (GBM) is the most common primary adult intracranial malignancy and carries a dismal prognosis despite an aggressive multimodal treatment regimen that consists of surgical resection, radiation, and adjuvant chemotherapy. Radiographic evaluation, largely informed by magnetic resonance imaging (MRI), is a critical component of initial diagnosis, surgical planning, and post-treatment monitoring. However, conventional MRI does not provide information regarding tumor microvasculature, necrosis, or neoangiogenesis. In addition, traditional MRI imaging can be further confounded by treatment-related effects such as pseudoprogression, radiation necrosis, and/or pseudoresponse(s) that preclude clinicians from making fully informed decisions when structuring a therapeutic approach. A myriad of novel imaging modalities have been developed to address these deficits. Herein, we provide a clinically oriented review of standard techniques for imaging GBM and highlight emerging technologies utilized in disease characterization and therapeutic development.

Clinical advances in oncolytic virotherapy for pediatric brain tumors.

Malignant brain tumors constitute nearly one-third of cancer diagnoses in children and have recently surpassed hematologic malignancies as the most lethal neoplasm in the pediatric population. Outcomes for children with brain tumors are unacceptably poor and current standards of care-surgical resection, chemotherapy, and radiation-are associated with significant long-term morbidity. Oncolytic virotherapy has emerged as a promising immunotherapy for the treatment of brain tumors. While the majority of brain tumor clinical trials utilizing oncolytic virotherapy have been in adults, five viruses are being tested in pediatric brain tumor clinical trials: herpes simplex virus (G207), reovirus (pelareorep/Reolysin), measles virus (MV-NIS), poliovirus (PVSRIPO), and adenovirus (DNX-2401, AloCELYVIR). Herein, we review past and current pediatric immunovirotherapy brain tumor trials including the relevant preclinical and clinical research that contributed to their development. We describe mechanisms by which the viruses may overcome barriers in treating pediatric brain tumors, examine challenges associated with achieving effective, durable responses, highlight unique aspects and successes of the trials, and discuss future directions of immunovirotherapy research for the treatment of pediatric brain tumors.

Targeting oncometabolism to maximize immunotherapy in malignant brain tumors.

Brain tumors result in significant morbidity and mortality in both children and adults. Recent data indicate that immunotherapies may offer a survival benefit after standard of care has failed for malignant brain tumors. Modest results from several late phase clinical trials, however, underscore the need for more refined, comprehensive strategies that incorporate new mechanistic and pharmacologic knowledge. Recently, oncometabolism has emerged as an adjunct modality for combinatorial treatment approaches necessitated by the aggressive, refractory nature of high-grade glioma and other progressive malignant brain tumors. Manipulation of metabolic processes in cancer and immune cells that comprise the tumor microenvironment through controlled targeting of oncogenic pathways may be utilized to maximize the efficacy of immunotherapy and improve patient outcomes. Herein, we summarize preclinical and early phase clinical trial research of oncometabolism-based therapeutics that may augment immunotherapy by exploiting the biochemical and genetic underpinnings of brain tumors. We also examine metabolic pathways related to immune cells that target tumor cells, termed "tumor immunometabolism". Specifically, we focus on glycolysis and altered glucose metabolism, including glucose transporters, hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase, glutamine, and we discuss targeting arginase, adenosine, and indoleamine 2,3-dioxygenase, and toll-like receptors. Lastly, we summarize future directions targeting metabolism in combination with emerging therapies such as oncolytic virotherapy, vaccines, and chimeric antigen receptor T cells.

The impact of edema and fiber crossing on diffusion MRI metrics assessed in an ex vivo nerve phantom: Multi-tensor model vs. diffusion orientation distribution function.

Diffusion tensor imaging (DTI) has been employed for over 2 decades to noninvasively quantify central nervous system diseases/injuries. However, DTI is an inadequate simplification of diffusion modeling in the presence of coexisting inflammation, edema and crossing nerve fibers. We employed a tissue phantom using fixed mouse trigeminal nerves coated with various amounts of agarose gel to mimic crossing fibers in the presence of vasogenic edema. Diffusivity measures derived by DTI and diffusion basis spectrum imaging (DBSI) were compared at increasing levels of simulated edema and degrees of fiber crossing. Furthermore, we assessed the ability of DBSI, diffusion kurtosis imaging (DKI), generalized q-sampling imaging (GQI), q-ball imaging (QBI) and neurite orientation dispersion and density imaging to resolve fiber crossing, in reference to the gold standard angles measured from structural images. DTI-computed diffusivities and fractional anisotropy were significantly confounded by gel-mimicked edema and crossing fibers. Conversely, DBSI calculated accurate diffusivities of individual fibers regardless of the extent of simulated edema and degrees of fiber crossing angles. Additionally, DBSI accurately and consistently estimated crossing angles in various conditions of gel-mimicked edema when compared with the gold standard (r2 = 0.92, P = 1.9 × 10-9 , bias = 3.9°). Small crossing angles and edema significantly impact the diffusion orientation distribution function, making DKI, GQI and QBI less accurate in detecting and estimating fiber crossing angles. Lastly, we used diffusion tensor ellipsoids to demonstrate that DBSI resolves the confounds of edema and crossing fibers in the peritumoral edema region from a patient with lung cancer metastasis, while DTI failed. In summary, DBSI is able to separate two crossing fibers and accurately recover their diffusivities in a complex environment characterized by increasing crossing angles and amounts of gel-mimicked edema. DBSI also indicated better angular resolution compared with DKI, QBI and GQI.

Diffusion Histology Imaging Combining Diffusion Basis Spectrum Imaging (DBSI) and Machine Learning Improves Detection and Classification of Glioblastoma Pathology.

PURPOSE: Glioblastoma (GBM) is one of the deadliest cancers with no cure. While conventional MRI has been widely adopted to examine GBM clinically, accurate neuroimaging assessment of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation remains an unmet need in the clinical management of GBMs. EXPERIMENTAL DESIGN: We employ a novel diffusion histology imaging (DHI) approach, combining diffusion basis spectrum imaging (DBSI) and machine learning, to detect, differentiate, and quantify areas of high cellularity, tumor necrosis, and tumor infiltration in GBM. RESULTS: Gadolinium-enhanced T1-weighted or hyperintense fluid-attenuated inversion recovery failed to reflect the morphologic complexity underlying tumor in patients with GBM. Contrary to the conventional wisdom that apparent diffusion coefficient (ADC) negatively correlates with increased tumor cellularity, we demonstrate disagreement between ADC and histologically confirmed tumor cellularity in GBM specimens, whereas DBSI-derived restricted isotropic diffusion fraction positively correlated with tumor cellularity in the same specimens. By incorporating DBSI metrics as classifiers for a supervised machine learning algorithm, we accurately predicted high tumor cellularity, tumor necrosis, and tumor infiltration with 87.5%, 89.0%, and 93.4% accuracy, respectively. CONCLUSIONS: Our results suggest that DHI could serve as a favorable alternative to current neuroimaging techniques in guiding biopsy or surgery as well as monitoring therapeutic response in the treatment of GBM.

MRI-based assessment of function and dysfunction in myelinated axons.

Repetitive electrical activity produces microstructural alteration in myelinated axons, which may afford the opportunity to noninvasively monitor function of myelinated fibers in peripheral nervous system (PNS)/CNS pathways. Microstructural changes were assessed via two different magnetic-resonance-based approaches: diffusion fMRI and dynamic T2 spectroscopy in the ex vivo perfused bullfrog sciatic nerves. Using this robust, classical model as a platform for testing, we demonstrate that noninvasive diffusion fMRI, based on standard diffusion tensor imaging (DTI), can clearly localize the sites of axonal conduction blockage as might be encountered in neurotrauma or other lesion types. It is also shown that the diffusion fMRI response is graded in proportion to the total number of electrical impulses carried through a given locus. Dynamic T2 spectroscopy of the perfused frog nerves point to an electrical-activity-induced redistribution of tissue water and myelin structural changes. Diffusion basis spectrum imaging (DBSI) reveals a reversible shift of tissue water into a restricted isotropic diffusion signal component. Submyelinic vacuoles are observed in electron-microscopy images of tissue fixed during electrical stimulation. A slowing of the compound action potential conduction velocity accompanies repetitive electrical activity. Correlations between electrophysiology and MRI parameters during and immediately after stimulation are presented. Potential mechanisms and interpretations of these results are discussed.

Recent advances in the diagnosis and management of Gaucher disease.

INTRODUCTION: Gaucher disease, the autosomal recessive deficiency of the lysosomal enzyme glucocerebrosidase, is associated with wide phenotypic diversity including non-neuronopathic, acute neuronopathic, and chronic neuronopathic forms. Overlap between types can render definitive diagnoses difficult. However, differentiating between the different phenotypes is essential due to the vast differences in clinical outcomes and response to therapy. Genotypic information is helpful, but cannot always be used to make clinical predictions. Current treatments for Gaucher disease, including enzyme replacement therapy and substrate reduction therapy, can reverse many of the non-neurological manifestations, but these therapies must be administered continually and are extremely costly. AREAS COVERED: We reviewed the literature concerning the varied clinical presentations of Gaucher disease throughout the lifetime, along with treatment options, management goals, and current and future research challenges. A PubMed literature search was performed for relevant publications between 1991 to January 2018. EXPERT COMMENTARY: Interest and research in the field of Gaucher disease is rapidly expanding. However, significant barriers remain in our ability to predict phenotype, assess disease progression using objective biomarkers, and determine optimal treatment strategy on an individual basis. As the field grows, we anticipate identification of genetic modifiers, new biomarkers, and small-molecule chaperone therapies, which may improve patient quality of life.