Abstract
Simple SummaryDesigner T and NK cells are a modality within immunotherapy that manipulates receptor-ligand interactions to enhance cells of the immune system to destroy cancer more effectively. Patient’s own immune cells are isolated, genetically modified to improve responses against cancers cells, expanded, and subsequently reintroduced into the individual. Several clinical trials to investigate immunotherapy strategies that may garner lasting benefit even for cancer patients with glioblastoma (GBM), a deadly brain cancer with limited treatment options, are underway. Therapeutic potential for gene editing technologies in limiting rejection and adverse reactions to improve treatment responses in preclinical models is now translating into enduring efficacy in GBM patients.Glioblastoma (GBM) is the most prevalent, aggressive primary brain tumour with a dismal prognosis. Treatment at diagnosis has limited efficacy and there is no standardised treatment at recurrence. New, personalised treatment options are under investigation, although challenges persist for heterogenous tumours such as GBM. Gene editing technologies are a game changer, enabling design of novel molecular-immunological treatments to be used in combination with chemoradiation, to achieve long lasting survival benefits for patients. Here, we review the literature on how cutting-edge molecular gene editing technologies can be applied to known and emerging tumour-associated antigens to enhance chimeric antigen receptor T and NK cell therapies for GBM. A tight balance of limiting neurotoxicity, avoiding tumour antigen loss and therapy resistance, while simultaneously promoting long-term persistence of the adoptively transferred cells must be maintained to significantly improve patient survival. We discuss the opportunities and challenges posed by the brain contexture to the administration of the treatments and achieving sustained clinical responses.
Highlights
Glioblastoma (GBM) is the most prevalent, aggressive primary brain tumour with a dismal prognosis
This review will focus on chimeric antigen receptors (CAR) T and natural killer (NK) cell immunotherapies for GBM, and the opportunities gene editing technologies offer in improving CAR therapy
Obstacles persist for effective, sustained CAR T cell therapy for solid cancers. These include non-ubiquitous expression of the target antigen, physical barriers such as the blood–brain barrier (BBB) and extracellular matrix, immunosuppressive cells and cytokines, which are all present within a hostile, often hypoxic tumour microenvironment [34]. These obstacles are compounded by antigen loss [69] and serious adverse events observed in CAR T clinical trials, such as immune effector cell-associated neurotoxicity syndrome (ICANS) [70] and cytokine release syndrome (CRS) [71] in a brain encapsulated in an unyielding, bony cranium
Summary
Patrolling leukocytes detect mutated, early transformed cells, deem them sufficiently “non-self” and co-ordinately eliminate them, as predicted by the cancer immunosurveillance concept [22]. Binding of the CD28 co-stimulatory receptor to the DCs’ CD80/86 receptor fully activates the cytotoxic T cells which migrate to infiltrate the tumour and kill the cells by locally releasing perforin and granzymes [23,24] These lymphocytes successfully eliminate the genetically unstable tumour cells with intrinsically high immunogenicity [25] through a series of successive stages [26]. The T cells effectively terminate their activation and proliferation as a means of avoiding autoimmunity, resulting in different phenotypes that either further activate Th1 immune responses or suppress via Th2-driven responses Surface receptors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and nuclear transcription factors attenuate T cell responses, where CTLA-4 competes with CD28 for binding to CD80/86, resulting in inhibitory downstream signalling [27].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
