Jacob S. Young

Therapeutic cell carriers: A potential road to cure glioma

Many different experimental molecular therapeutic approaches have been evaluated in an attempt to treat brain cancer. However, despite the success of these experimental molecular therapies, research has shown that the specific and efficient delivery of therapeutic agents to tumor cells is a limitation. In this regard, cell carrier systems have garnered significant attraction due to their capacity to be loaded with therapeutic agents and carry them specifically to tumor sites. Furthermore, cell carriers can be genetically modified to express therapeutic agents that can directly eradicate cancerous cells or can modulate tumor microenvironments. This review describes the current state of cell carriers, their use as vehicles for the delivery of therapeutic agents to brain tumors, and future directions that will help overcome the present obstacles to cell carrier mediated therapy for brain cancer.

The Impact of Traumatic Brain Injury on the Aging Brain.

Traumatic brain injury (TBI) has come to the forefront of both the scientific and popular culture. Specifically, sports-related concussions or mild TBI (mTBI) has become the center of scientific scrutiny with a large amount of research focusing on the long-term sequela of this type of injury. As the populace continues to age, the impact of TBI on the aging brain will become clearer. Currently, reports have come to light that link TBI to neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, as well as certain psychiatric diseases. Whether these associations are causations, however, is yet to be determined. Other long-term sequelae, such as chronic traumatic encephalopathy (CTE), appear to be associated with repetitive injuries. Going forward, as we gain better understanding of the pathophysiological process involved in TBI and subclinical head traumas, and individual traits that influence susceptibility to neurocognitive diseases, a clearer, more comprehensive understanding of the connection between brain injury and resultant disease processes in the aging brain will become evident.

Sports-related concussions: diagnosis, complications, and current management strategies

Sports-related concussions (SRCs) are traumatic events that affect up to 3.8 million athletes per year. The initial diagnosis and management is often instituted on the field of play by coaches, athletic trainers, and team physicians. SRCs are usually transient episodes of neurological dysfunction following a traumatic impact, with most symptoms resolving in 7-10 days; however, a small percentage of patients will suffer protracted symptoms for years after the event and may develop chronic neurodegenerative disease. Rarely, SRCs are associated with complications, such as skull fractures, epidural or subdural hematomas, and edema requiring neurosurgical evaluation. Current standards of care are based on a paradigm of rest and gradual return to play, with decisions driven by subjective and objective information gleaned from a detailed history and physical examination. Advanced imaging techniques such as functional MRI, and detailed understanding of the complex pathophysiological process underlying SRCs and how they affect the athletes acutely and long-term, may change the way physicians treat athletes who suffer a concussion. It is hoped that these advances will allow a more accurate assessment of when an athlete is truly safe to return to play, decreasing the risk of secondary impact injuries, and provide avenues for therapeutic strategies targeting the complex biochemical cascade that results from a traumatic injury to the brain.

Advances in stem cells, induced pluripotent stem cells, and engineered cells: delivery vehicles for anti-glioma therapy

Introduction: A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is their incomplete distribution within the entirety of solid tumors such as malignant gliomas. Currently, cell-based carriers are making their way into the clinical setting as they offer the potential to selectively deliver many types of therapies to cancer cells. Areas covered: Here, we review the properties of stem cells, induced pluripotent stem cells and engineered cells that possess the tumor-tropic behavior necessary to serve as cell carriers. We also report on the different types of therapeutic agents that have been delivered to tumors by these cell carriers, including: i) therapeutic genes; ii) oncolytic viruses; iii) NPs; and iv) antibodies. The current challenges and future promises of cell-based drug delivery are also discussed. Expert opinion: While the emergence of stem cell-mediated therapy has resulted in promising preclinical results and a human clinical trial utilizing this approach is currently underway, there is still a need to optimize these delivery platforms. By improving the loading of therapeutic agents into stem cells and enhancing their migratory ability and persistence, significant improvements in targeted cancer therapy may be achieved.

Hitting the nail on the head: combining oncolytic adenovirus-mediated virotherapy and immunomodulation for the treatment of glioma

Glioblastoma is a highly aggressive malignant brain tumor with a poor prognosis and the median survival 14.6 months. Immunomodulatory proteins and oncolytic viruses represent two treatment approaches that have recently been developed for patients with glioblastoma that could extend patient survival and result in better treatment outcomes for patients with this disease. Together, these approaches could potentially augment the treatment efficacy and strength of these anti-tumor therapies. In addition to oncolytic activities, this combinatory approach introduces immunomodulation locally only where cancerous cells are present. This thereby results in the change of the tumor microenvironment from immune-suppressive to immune-vulnerable via activation of cytotoxic T cells or through the removal of glioma cells immune-suppressive capability. This review discusses the strengths and weaknesses of adenoviral oncolytic therapy, and highlights the genetic modifications that result in more effective and targeted viral agents. Additionally, the mechanism of action of immune-activating agents is described and the results of previous clinical trials utilizing these treatments in other solid tumors are reviewed. The feasibility, synergy, and limitations for treatments that combine these two approaches are outlined and areas for which more work is needed are considered.

Synchrony between sensory and cognitive networks is associated with subclinical variation in autistic traits

Individuals with autistic spectrum disorders exhibit distinct personality traits linked to attentional, social, and affective functions, and those traits are expressed with varying levels of severity in the neurotypical and subclinical population. Variation in autistic traits has been linked to reduced functional and structural connectivity (i.e., underconnectivity, or reduced synchrony) with neural networks modulated by attentional, social, and affective functions. Yet, it remains unclear whether reduced synchrony between these neural networks contributes to autistic traits. To investigate this issue, we used functional magnetic resonance imaging to record brain activation while neurotypical participants who varied in their subclinical scores on the Autism-Spectrum Quotient (AQ) viewed alternating blocks of social and nonsocial stimuli (i.e., images of faces and of landscape scenes). We used independent component analysis (ICA) combined with a spatiotemporal regression to quantify synchrony between neural networks. Our results indicated that decreased synchrony between the executive control network (ECN) and a face-scene network (FSN) predicted higher scores on the AQ. This relationship was not explained by individual differences in head motion, preferences for faces, or personality variables related to social cognition. Our findings build on clinical reports by demonstrating that reduced synchrony between distinct neural networks contributes to a range of subclinical autistic traits.

Neural stem cell-mediated delivery of oncolytic adenovirus

The use of stem cells (SCs) as carriers for therapeutic agents has now progressed to early clinical trials. These clinical trials exploring SC‐mediated delivery of oncolytic adenoviruses will commence in the near future, hopefully yielding meritorious results that can provoke further scientific inquiry. Preclinical animal studies have demonstrated that SCs can be successfully loaded with conditionally‐replicative adenoviruses and delivered to the tumor, whereupon they may evoke pronounced therapeutic efficacy. In this protocol, we describe the maintenance of SCs, provide an analysis of optimal adenoviral titers for SC loading, and evaluate the optimized viral loading on SCs.

Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy

Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future.

Management of glioblastoma in elderly patients

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults over 55years of age. The median age of diagnosis for patients with GBM is 64years old, with the incidence of patients between 75 and 85 increasing. The optimal treatment paradigm for elderly GBM patients continues to evolve due to the higher frequency of age-related and/or medical co-morbidities. Geriatric GBM patients have historically been excluded from larger, controlled clinical trials due to their presumed decreased likelihood of a sustained treatment response and/or a prolonged good outcome. Here, we highlight current treatment considerations of elderly GBM patients with respect to surgical, radiotherapeutic and systemic modalities, with considerations for improving future clinical outcomes for this patient population.

A novel single-chain antibody redirects adenovirus to IL13Rα2-expressing brain tumors

The generation of a targeting agent that strictly binds to IL13Rα2 will significantly expand the therapeutic potential for the treatment of IL13Rα2-expressing cancers. In order to fulfill this goal, we generated a single-chain antibody (scFv47) from our parental IL13Rα2 monoclonal antibody and tested its binding properties. Furthermore, to demonstrate the potential therapeutic applicability of scFv47, we engineered an adenovirus by incorporating scFv47 as the targeting moiety in the viral fiber and characterized its properties in vitro and in vivo. The scFv47 binds to human recombinant IL13Rα2, but not to IL13Rα1 with a high affinity of 0.9 · 10−9 M, similar to that of the parental antibody. Moreover, the scFv47 successfully redirects adenovirus to IL13Rα2 expressing glioma cells both in vitro and in vivo. Our data validate scFv47 as a highly selective IL13Rα2 targeting agent and justify further development of scFv47-modified oncolytic adenovirus and other therapeutics for the treatment of IL13Rα2-expressing glioma and other malignancies.