Opinion statement At this time, there are no FDA-approved immune therapies for glioblastoma (GBM) despite many unique therapies currently in clinical trials. GBM is a highly immunosuppressive tumor and there are limitations to a safe immune response in the central nervous system. To date, there have been several failures of phase 3 immune therapy clinical trials in GBM. These trials have targeted single components of an antitumor immune response. Learning from these failures, the future of immunotherapy for GBM appears most hopeful for combination of immune therapies to overcome the profound immunosuppression of this disease. Understanding biomarkers for appropriate patient selection as well as tumor progression are necessary for implementation of immunotherapy for GBM

Nicotine is the primary psychoactive substance in tobacco, and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the α4β2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal as well as nicotine-induced behaviors. Although α4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addiction, mental illness, and movement control in humans. We developed a unique model system to examine the role of α4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the α4 subunit from dopaminergic neurons in mice. The loss α4 mRNA and α4β2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of α4β2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. α4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. α4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze, and elimination of α4β2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of α4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression; however, nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine-related behaviors.

Malignant brain tumors such as glioblastoma (GBM) and brain metastasis have poor prognosis despite conventional therapies. Successful use of vaccines and checkpoint inhibitors in systemic malignancy has increased the hope that immune therapies could improve survival in patients with brain tumors. Manipulating the immune system to fight malignancy has a long history of both modest breakthroughs and pitfalls that should be considered when applying the current immunotherapy approaches to patients with brain tumors. Therapeutic vaccine trials for GBM date back to the mid 1900s and have taken many forms; from irradiated tumor lysate to cell transfer therapies and peptide vaccines. These therapies were generally well tolerated without significant autoimmune toxicity, however also did not demonstrate significant clinical benefit. In contrast, the newer checkpoint inhibitors have demonstrated durable benefit in some metastatic malignancies, accompanied by significant autoimmune toxicity. While this toxicity was not unexpected, it exceeded what was predicted from pre-clinical studies and in many ways was similar to the prior trials of immunostimulants. This review will discuss the history of these studies and demonstrate that the future use of immune therapy for brain tumors will likely need a personalized approach that balances autoimmune toxicity with the opportunity for significant survival benefit.

Management of non-small cell lung cancer (NSCLC) with brain metastasis (BrM) has been revolutionized by identification of molecular subsets that have targetable oncogenes. Historically, survival for NSCLC with symptomatic BrM was weeks to months. Now, many patients are surviving years with limited data to guide treatment decisions. Tumors with activating mutations in epidermal growth factor receptor (EGFRact+) have a higher incidence of BrM, but a longer overall survival. The high response rate of both systemic and BrM EGFRact+ NSCLC to tyrosine kinase inhibitors (TKIs) has led to the rapid incorporation of new therapies but is outpacing evidence-based decisions for BrM in NSCLC. While whole brain radiation therapy (WBRT) was the foundation of management of BrM, extended survival raises concerns for the subacute and late effects radiotherapy. We favor the use of TKIs and delaying the use of WBRT when able. At inevitable disease progression, we consider alternative dosing schedules to increase CNS penetration (such as pulse dosing of erlotinib) or advance to next generation TKI if available. We utilize local control options of surgery or stereotactic radiosurgery (SRS) for symptomatic accessible lesions based on size and edema. At progression despite available TKIs, we use pemetrexed-based platinum doublet chemotherapy or immunotherapy if the tumor has high expression of PDL-1. We reserve the use of WBRT for patients with more than 10 BrM and progression despite TKI and conventional chemotherapy, if performance status is appropriate.

As a result of treatment and diagnosis, adults with primary or metastatic brain tumors experience comorbidities that impacts their health and well-being. The Children’s Oncology Group has guideline recommendations for childhood survivors of brain tumors; however, guidelines for monitoring long-term sequela among adult brain tumor survivors are lacking. The purpose of this review is to present the screening recommendations for the long-term complications after brain tumor treatment from a multidisciplinary panel of healthcare professionals. Chronic complications identified include cognitive dysfunction, vasculopathy, endocrinopathy, ophthalmic, ototoxicity, physical disability, sleep disturbance, mood disorder, unemployment, financial toxicity, and secondary malignancy. We invited specialists across disciplines to perform a literature search and provide expert recommendations for surveillance for long-term complications for adult brain tumor survivors. The Brain Tumor Center Survivorship Committee recommends routine screening using laboratory testing, subjective assessment of symptoms, and objective evaluations to appropriately monitor the complications of brain tumor treatments. Effective monitoring and treatment should involve collaboration with primary care providers and may require referral to other specialties and support services to provide patient-centered care during neuro-oncology survivorship. Further research is necessary to document the incidence and prevalence of medical complications as well as evaluate the efficacy of screening and neuro-oncology survivorship programs.