Zika virus (ZIKV) exhibits a tropism for brain tumor cells and has been used as an oncolytic virus to target brain tumors in mice with modest effects on extending median survival. Recent studies have highlighted the potential for combining virotherapy and immunotherapy to target cancer. We postulated that ZIKV could be used as an adjuvant to enhance the long-term survival of mice with malignant glioblastoma and generate memory T-cells capable of providing long-term immunity against cancer remission. To test this hypothesis mice bearing malignant intracranial GL261 tumors were subcutaneously vaccinated with irradiated GL261 cells previously infected with the ZIKV. Mice also received intracranial injections of live ZIKV, irradiation attenuated ZIKV, or irradiated GL261 cells previously infected with ZIKV. Long-term survivors were rechallenged with a second intracranial tumor to examine their immune response and look for the establishment of protective memory T-cells. Mice with subcutaneous vaccination plus intracranial irradiation attenuated ZIKV or intracranial irradiated GL261 cells previously infected with ZIKV exhibited the greatest extensions to overall survival. Flow cytometry analysis of immune cells within the brains of long-term surviving mice after tumor rechallenge revealed an increase in the number of T-cells, including CD4+ and tissue-resident effector/ effector memory CD4+ T-cells, in comparison to long-term survivors that were mock-rechallenged, and in comparison to naïve untreated mice challenged with intracranial gliomas. These results suggest that ZIKV can serve as an adjuvant to subcutaneous tumor vaccines that enhance long-term survival and generate protective tissue-resident memory CD4+ T-cells.

Deep brain stimulation (DBS) has become an important tool in the management of a wide spectrum of diseases in neurology and psychiatry. Target selection is a vital aspect of DBS so that only the desired areas are stimulated. Segmented leads and current steering have been shown to be promising additions to DBS technology enabling better control of the stimulating electric field. Recently introduced orientation selective DBS (OS-DBS) is a related development permitting sensitization of the stimulus to axonal pathways with different orientations by freely controlling the primary direction of the electric field using multiple contacts. Here, we used OS-DBS to stimulate the subthalamic nucleus (STN) in healthy rats while simultaneously monitoring the induced brain activity with fMRI. Maximal activation of the sensorimotor and basal ganglia-thalamocortical networks was observed when the electric field was aligned mediolaterally in the STN pointing in the lateral direction, while no cortical activation was observed with the electric field pointing medially to the opposite direction. Such findings are consistent with mediolateral main direction of the STN fibers, as seen with high resolution diffusion imaging and histology. The asymmetry of the OS-DBS dipolar field distribution using three contacts along with the potential stimulation of the internal capsule, are also discussed. We conclude that OS-DBS offers an additional degree of flexibility for optimization of DBS of the STN which may enable a better treatment response.

Blastocyst complementation combined with gene editing is an emerging approach in the field of regenerative medicine that could potentially solve the worldwide problem of organ shortages for transplantation. In theory, blastocyst complementation can generate fully functional human organs or tissues, grown within genetically engineered livestock animals. Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ development can open a niche for human stem cells to occupy, thus generating human tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung, and skeletal muscle, as well as cells of the immune and nervous systems. Within each of these organ systems, we identify and discuss (i) the common causes of organ failure; (ii) the current state of regenerative therapies; and (iii) the candidate genes to knockout and enable specific exogenous organ development via the use of blastocyst complementation. We also highlight some of the current barriers limiting the success of blastocyst complementation.

The potential for developing gene therapy technologies is evident from the recent surge in research activity. The use of these emerging technologies, along with blastocyst complementation, could greatly enhance our ability to produce exogenic organs and cells in a relatively short period of time. Furthermore, the generation of human–animal organ chimeras, together with their associated vasculature, could be developed to overcome the global problem of organ shortage for transplantation, as well as complications associated with immune rejection. It will be imperative that we understand the underlying conditions for stem cell growth in a developmental environment, to determine if cross-species chimeras can be therapeutically developed. Importantly, the combination of gene editing and blastocyst complementation has created an entirely new and exciting field of medicine, one that we envision will have a critical role for precision medicine.

Glioma treatments are faced with challenges, including the inability to fully eliminate cancer stem cells, the immunosuppressive tumor microenvironment, and the blood brain barrier. Although progress has been made with surgical, radiation, and chemotherapies, prognosis for patients remains poor. Rapidly emerging immunotherapies may be able to address the challenges that conventional techniques cannot. Immunotherapies manipulate the patient’s immune system to selectively combat malignancies. Therapies often work to enhance T-cell and natural killer (NK) cell function, which can both eliminate tumor cells and enhance remission. Vaccines encourage in vivo development of anti-tumor T-cells and NK cells, while adoptive transfer techniques focus on engineering immune cells ex vivo before reintroducing them to patients. Vaccine and adoptive transfer therapies have been shown to induce enhanced immune responses in patients but have not always correlated with improved outcomes, likely because of the tumor immunosuppressive microenvironment. Checkpoint inhibitors can impair these tumor immunosuppressive capabilities. Although no one treatment has been able to consistently eliminate gliomas and maintain remission, combinations of vaccines or adoptive transfer techniques in conjunction with immune checkpoint inhibitors offers promise.

Previous studies have demonstrated that the tropism of Zika virus (ZIKV) for human neural stem cells (NSCs) leads to severe brain malformations. The proposed mechanisms underlying these brain malformations are thought to include the induction of apoptosis in neural progenitor/stem cells (Zhang et al., Nucleic Acid Res. 44:8610–8620, 2016). Previously, we observed many similarities between NSCs and brain tumor stem cells (BTSCs) (Wu et al., Stem Cells Dev., 17:173–184, 2008) and sought to determine if BTSC could support ZIKV replication. ZIKV infection of skin cells in vitro is mediated by the receptors AXL, DC-SIGN, TIM1, and TYRO3 (Hamel et al., J Virol. 89:8880–8896, 2015). We examined human embryonic brain tissue and have observed that the putative ZIKV receptor TIM1 is expressed by neuronal and astrocytic progenitor cells. Given the similarities between NSCs and BTSCs we examined human and rodent brain tumor cells for putative ZIKV receptor expression. We found TIM1 expression by human GBM6 glioma cells and murine GL261 gliomas. In tissue culture studies, incubation of ZIKV with human GBM6 cells led to high levels of infection. To determine the effects of ZIKV on tumor growth in vivo, we transplanted GL261 cells into the striatal area of the brain in syngeneic C57B/6 mice. Intra-tumoral injections of ZIKV were administered immediately after intra-cranial tumor implantation. Tumor-bearing mice receiving intra-tumoral injections of ZIKV exhibited prolonged survival in comparison to untreated mice. Together these results suggest that ZIKV may have potential as an oncolytic virus for targeting malignant brain tumors. (This work was supported in part by a grant from the Randy Shaver Cancer Research Foundation).