History and current state of immunotherapy in glioma and brain metastasis

Abstract

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.

Keywords: brain neoplasms; immunotherapy.

Figure 1.

Schematic of immune response to growing tumor and targets of immunotherapy. (1) Vaccines increase exposure of antigens to the antigen-presenting cells of the innate immune system like dendritic cells (DCs) and macrophages. (2) DC vaccines are antigen-presenting cells isolated from the patient’s whole blood and stimulated in vitro to recognize tumor antigens before being transfused back to the patient. DCs then migrate to lymphoid tissues where they present the antigens to T cells. (3) Activation of cytotoxic T cells requires costimulation by CD28 and CD80 (B7.1). CTLA-4 binds CD28 with higher affinity, acting as a negative regulator of this step and guiding immune tolerance. CTLA-4 antibodies inhibit CLTA-4 binding, favoring activation of cytotoxic T cells. (4) T-cell transfer involves infusing activated tumor-specific T cells that can recognize tumor antigens on MHC I and II molecules. (5) PD-L1 is expressed by tumor cells and binds PD-1 on T cells. This binding inhibits cell lysis, however, antibodies to PD-1 or PD-L1 prevents this binding and augments tumor eradication. APC, antigen-presenting cells; CTLA-4, Cytotoxic T-lymphocyte-associated antigen 4; DCs, dendritic cells; PD-1, programmed death -1; PD-L1, programmed death ligand-1; TCR, T-cell receptor.