Introduction to immunotherapy for brain tumor patients: challenges and future perspectives

Abstract

Malignant gliomas, including glioblastoma (GBM) as the most aggressive type of adult CNS tumors, are notoriously resistant to current standard of care treatments, including surgery, systemic chemotherapy, and radiation therapy (RT). This lack of effective treatment options highlights the urgent need for novel therapies, including immunotherapies. The overarching goal of immunotherapy is to stimulate and activate the patient's immune system in a targeted manner to kill tumor cells. The success of immunotherapeutic interventions in other cancer types has led to interest in and evaluation of various experimental immunotherapies in patients with malignant gliomas. However, these primary malignant brain tumors present a challenge because they exist in a vital and sensitive organ with a unique immune environment. The challenges and current status of experimental immunotherapeutic approaches, including vaccines, immune-checkpoint blockade, chimeric antigen receptor T-cell therapy, and oncolytic viruses will be discussed, as well as the potential for combinatorial therapies.

Keywords: checkpoint; glioblastoma; glioma; immunotherapy; vaccine.

Fig. 1

Immunotherapy concepts for glioblastoma (GBM). A, Vaccines can be peptide/DNA based or cell based. Their goal is to promote antigen presentation and T-cell infiltration. Shown here is a peptide vaccine, which may encompass both broad GBM antigens and patient-specific antigens. B, Checkpoint inhibitor therapy relies on antibodies to inhibit immune-checkpoint molecules. Programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) are expressed on T cells and promote self-tolerance in healthy tissues. In GBM, this mechanism is exploited by tumor cells that express programmed death ligand 1 (PD-L1). Immune-checkpoint inhibitors bind to these molecules and limit T-cell inhibition. C, Chimeric antigen receptor (CAR) T-cell therapy uses genetically engineered T cells to target tumor-specific or associated antigens. CAR T-cell activation does not rely on MHC-dependent antigen presentation, and efficiently targets surface antigens, such as epidermal growth factor receptor variant III (EGFRvIII). D,) Viral therapies use both lytic and nonlytic viruses to kill tumor cells and induce an immune response. These viruses may directly kill tumors cells by lysis or encode enzymes that convert prodrugs into cytotoxic chemotherapies. Figures were created with BioRender.com.