**1. Introduction**

Primary malignant brain tumors remain one of the most lethal and clinically challenging of all cancers. Despite comprising only an estimated 1.3% of all new cancer cases, brain tumors represent one of the highest causes of cancer mortality with 18,600 (3.1%) deaths predicted in 2021 [1]. Glioblastoma (GBM) is one of the most common and aggressive of the primary malignant adult brain tumors with a median survival of less than 21 months despite standard of care which includes surgical resection, targeted radiation therapy, high-dose chemotherapy, and tumortreating fields [2–8].

Cancer immunotherapies have emerged as new therapeutic mainstays in a variety of cancers [9–14]. However, the unique characteristics of brain tumors pose extraordinary barriers that, thus far, have foiled efforts and the success of immunotherapeutic approaches. These characteristics include high tumor heterogeneity and relatively few coding mutations [15, 16], an immunosuppressive microenvironment [17–23], a relative lack of immune effector cell types [19, 24], and relative isolation from systemic circulation because of the blood-brain barrier [25–29]. This chapter will discuss some of the current immunotherapy types with emphasis on the prominent clinical trials for each and the limitations observed.

However, despite a lack of phase III trials demonstrating improved progressionfree survival (PFS) and/or overall survival (OS) in many of these immunotherapies, incremental progress continues to be made in brain malignancies in both the clinical and preclinical settings. Novel immunotherapeutic strategies and combinations are

currently being tested in the preclinical setting. This chapter will also discuss novel preclinical strategies to enhance immunotherapies, including modified chimeric antigen receptor (CAR) T cells, small molecular inhibitors that target immunologic pathways, and combinatorial checkpoint approaches.
