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.

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.

The efficacy of T cell–activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused nonantigen specific autologous lymphocytes could accumulate in intracranial tumors. We observed that nonspecific autologous CD8 ⁺ ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared with IL-2. Pretreatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and nontumor-specific T cell–dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8 ⁺ T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression ( CD9 ). We also observed that IL-7 increases S1PR1 transcription in human CD8 ⁺ T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors and that pretreatment with IL-7 ALT can boost the efficacy of subsequent T cell–activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pretreatment can be combined with T cell–activating therapies.

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.