We have only recently begun to understand how cancer metabolism affects antitumor responses and immunotherapy outcomes. Certain immunometabolic targets have been actively pursued in other tumor types, however, glioblastoma research has been slow to exploit the therapeutic vulnerabilities of immunometabolism. In this review, we highlight the pathways that are most relevant to glioblastoma and focus on how these immunometabolic pathways influence tumor growth and immune suppression. We discuss hypoxia, glycolysis, tryptophan metabolism, arginine metabolism, 2-Hydroxyglutarate (2HG) metabolism, adenosine metabolism, and altered phospholipid metabolism, in order to provide an analysis and overview of the field of glioblastoma immunometabolism.
Glioblastoma is the the most common primary brain tumor in adults. Onset of disease is followed by a uniformly lethal prognosis and dismal overall survival. While immunotherapies have revolutionized treatment in other difficult-to-treat cancers, these have failed to demonstrate significant clinical benefit in patients with glioblastoma. Obstacles to success include the heterogeneous tumor microenvironment (TME), the immune-privileged intracranial space, the blood–brain barrier (BBB) and local and systemic immunosuppressions. Monoclonal antibody-based therapies have failed at least in part due to their inability to access the intracranial compartment. Bispecific T-cell engagers are promising antibody fragment-based therapies which can bring T cells close to their target and capture them with a high binding affinity. They can redirect the entire repertoire of T cells against tumor, independent of T-cell receptor specificity. However, the multiple challenges posed by the TME, immune privilege and the BBB suggest that a single agent approach may be insufficient to yield durable, long-lasting antitumor efficacy. In this review, we discuss the mechanism of action of T-cell engagers, their preclinical and clinical developments to date. We also draw comparisons with other classes of multispecific antibodies and potential combinations using these antibody fragment therapies.
Combining Immunotherapy for Glioblastoma patents related to PEP-CMV DC vaccine with tetanus, as well as poliovirus vaccine and D2C7 in the treatment of glioblastoma. JHS has an equity interest in Annias Immunotherapeutics, which has licensed intellectual property from Duke related to the use of the pepCMV vaccine in the treatment of glioblastoma. 18. JS reports research funding to his institution from Bayer, Roche, Bristol Myers Squiib, Abbvie, Astra Zeneca, MSD, AbbVie and Astellas. 19. DB is co-owner of Berry Consultants, LLC, a company that designs adaptive Bayesian clinical trials for pharmaceutical and medical device companies, NIH cooperative groups, patient advocacy groups, and international consortia. 20. GZ reports no conflicts of interest. 21. TFC is a co-inventor on patent 62/819,322 licensed to Katmai Pharmaceuticals and a Member of the board for the 501c3 Global Coalition for Adaptive Research. 22. MPM reports consultant or advisory roles for Zap, Mevion, Karyopharm, Tocagen and Astra-Zeneca; and Board of Directors options from Oncoceutics. 23. SPreports consultant or advisory roles for Syntalogic, the MITRE Corporation, and Omnitura. 24. MW has received research grants from AbbVie, Adastra, BMS, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Quercis, and Roche; and honoraria for lectures or advisory board participation or consulting from AbbVie, BMS, Celgene, MSD, Merck (EMD), Novocure, Orbus, Roche, and Tocagen. 25. ABH reports consultant or advisory roles for Caris Life Sciences and WCG Oncology; royalties on licensed intellectual property from Celldex Therapeutics and DNAtrix; research funding from Celularity, Carthera, Codiak, and Moleculin. 26. MK reports consultant or advisory roles for Janssen,
Background:Epidermoid and dermoid cyst comprise <1% of spinal tumors and may be congenital (hamartoma) or acquired (iatrogenic) in origin. Epidermoid cysts within the neuraxis are rare benign neoplasms that are most commonly located in the intracranial region.Case Description:Here, we report the a case of an acquired intradural extramedullary epidermoid cyst involving the thoracic region in an adult female who had no associated history of an accompanying congenital spinal deformity.Conclusion:Early diagnosis and immediate surgical intervention reduce patient morbidity. Near complete or subtotal excision of the cyst wall is warranted to prevent inadvertent injury to the spinal cord thus minimizing neurological morbidity.
Glioblastoma is an immunologically ‘cold’ tumor, which are characterized by absent or minimal numbers of tumor-infiltrating lymphocytes (TILs). For those tumors that have been invaded by lymphocytes, they are profoundly exhausted and ineffective. While many immunotherapy approaches seek to reinvigorate immune cells at the tumor, this requires TILs to be present. Therefore, to unleash the full potential of immunotherapy in glioblastoma, the trafficking of lymphocytes to the tumor is highly desirable. However, the process of T cell recruitment into the central nervous system (CNS) is tightly regulated. Naïve T cells may undergo an initial licensing process to enter the migratory phenotype necessary to enter the CNS. T cells then must express appropriate integrins and selectin ligands to interact with transmembrane proteins at the blood–brain barrier (BBB). Finally, they must interact with antigen-presenting cells and undergo further licensing to enter the parenchyma. These T cells must then navigate the tumor microenvironment, which is rich in immunosuppressive factors. Altered tumoral metabolism also interferes with T cell motility. In this review, we will describe these processes and their mediators, along with potential therapeutic approaches to enhance trafficking. We also discuss safety considerations for such approaches as well as potential counteragents.
Early Intervention in Psychosis (EIP) services aim to rapidly initiate specialist packages of care for those people newly experiencing symptoms. The intention of such rapid engagement is to mitigate the negative effects of a prolonged duration of untreated psychosis. Aiming to achieve a ‘parity of esteem’ between mental and physical health, a new target was introduced by the National Health Service (NHS) England, where 50% of new referrals were expected to receive a concordant package of care within 2 weeks from the National Institute for Health and Care Excellence. A baseline assessment in late 2014 found that just 21% of all referrals received and accepted met this target within the EIP Team for the North-East London NHS Foundation Trust. This project sought to improve the team’s performance, seeking input from all team members and using an iterative process with the primary aim of meeting the target ahead of its roll-out. It was determined that the relatively high number of inappropriate referrals (34% at baseline) is a key causative agent in delaying staff from processing eligible cases in a timely fashion. These are defined as referrals which do not meet basic eligibility criteria such as no previous treatment for psychosis. Interventions were therefore designed targeting three domains of improving staff awareness of the new target, improving efficiency by changing the case allocation process and improving the referral pathway for external sources. The impact of these changes was re-evaluated over two cycles beyond baseline. By the final cycle, 62% of new referrals were seen within 2 weeks, while inappropriate referrals declined to just 3%. The multi-interventional nature of this project limits its generalisability and further work should be carried out to identify those changes that were most impactful. Nevertheless, focused targeting of the referral pathway may prove to be of benefit to other EIP services struggling with lengthy wait times.
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