All in the head: obstacles for immune rejection of brain tumours.

Tumour immunology and immunotherapy is a highly active field, a clinical testing ground for cutting edge immunological techniques and concepts. But this is after many years of fundamental advances in basic immunology. In this article we suggest that immunotherapy for brain tumours cannot be rationally advanced as rapidly as that for tumours in other sites. Our understanding of anti-tumour immune responses in the brain is sketchy and frequently extrapolated from other tissues having little in common with the central nervous system (CNS). The result is that current clinical trials are built upon shakier foundations, with the somewhat naive optimism that what is looking hopeful for other tumours will also be applicable to cerebral malignancies. But of course it is easy to criticise such well-meaning attempts to treat currently incurable cancers. In the basic and preclinical domain, brain tumour models that are readily applicable to the design of future immunotherapies are only in their infancy. The ideal transplantable tumour that reiterates the key features of a malignant primary astrocytoma (poorly immunogenic, infiltrative but non-metastatic, expressing multiple mechanisms mediating immune escape) has yet to be discovered. In the meantime, we must use individual model tumours and limit the scope of the conclusions that we make from each system. Moreover, we must overcome the significant technical difficulties encountered as we strive to preserve brain integrity, whilst implanting tumours in this unique site. Or we can look to genetic models, in which there is the development of ‘spontaneous’ brain tumours (in some cases aided by the intracerebral delivery of a viral vector) incorporating many of the genetic features and heterogeneity typical of spontaneous human cancer.1 However, these models have generally been constructed to address genetic and pathological issues and they present a significant challenge for interpretable immunological studies. With these difficulties in mind, perhaps we need to accept that brain tumour models and clinical immunotherapies are currently in their first generation. To progress to a more successful second generation of therapies, there is a need to abandon the idea that an automatic one-way progression exists from rodent models to the clinic. We need better models to make better therapies, but how to choose and design the models can be greatly guided by data from clinical trials, if the trial design actually permits the generation of useful biological data. To date, most brain tumour immunotherapies have borrowed technologies and approaches already explored for tumours in other sites, principally melanoma. Thus, most of the now ‘classical’ tumour immunology approaches have been explored for brain tumour immunotherapy: cytokine immune enhancement, whole tumour cell vaccines, cytokine-modified tumour cell vaccines, gene therapies with immune bystander effects, dendritic cell therapies (reviewed in refs. 2–4). A few notable and exciting novel approaches unique to the CNS should not be passed aside, for example, exploiting the migratory properties of neural stem cells to deliver immunoactive molecules efficiently to the tumour site.5 The overall conclusions from these studies are that, depending upon the stringency of the models utilized, tumours that are pre-established in the brain are generally more difficult to eliminate than those in other sites, and may require different effector mechanisms. For example, studies in which multiple cytokines have been tested as modulators of immune responses gave different results according to the tumour model (SMA-560, B16) and site of implantation.6,7 Other attempts to create a cellular vaccine by overexpression of intercellular adhesion molecule-1 on a glioma cell line, resulted in growth inhibition of glioma cells implanted subcutaneously, but not in the CNS.8 Another recent study using a recombinant Listeria monocytogenes tumour vaccine revealed more stringent T-cell subset requirements for protection against an intracerebral challenge compared with the same tumour implanted by the subcutaneous route.9 These examples, together with the fact that no convincingly successful clinical brain tumour immunotherapy has been demonstrated to date, should force us to reassess what we understand about brain tumour immunology, rather than just brain tumour immunotherapy. It is from this perspective that we will discuss the issues pertinent to the problem by drawing from both clinical and experimental situations.