Brain Tumor Immunology and Immunotherapy

Introduction to Brain Tumor Immunology and Immunotherapy

In the mid- to late 19th century, physicians in Germany reported cases in which tumors in patients with concurrent infections were noted to shrink. Subsequently, there were many case reports of physicians attempting to use Streptococcus to treat malignant lesions. William B. Coley, in trying to determine a treatment for metastatic bone cancer, noted that there had been a patient at New York Hospital who recovered from an inoperable tumor in his neck after he contracted erysipelas caused by a streptococcal organism. This inspired Coley to induce Streptococcus infections in patients, but although he noted some success, he also encountered patient deaths from infection. This led him to the use of heat-inactivated Streptococcus together with a less virulent bacterium, giving rise to Coley’s toxin, which was used for the treatment of malignant disease. This was not without some controversy and, with the advent of radiation and chemotherapy, Coley’s toxin fell by the wayside. Despite this, Coley is widely known as the father of immunotherapy.

With the discovery and characterization of the immune system, such as dendritic cells (DCs), T cells, cytokines, and antibodies, research efforts have focused on the immune system, with immunotherapies being used as an adjunct in cancer therapy. Important contributions by Schreiber and colleagues demonstrated T-cell–mediated tumor-specific immune surveillance and antitumor immune responses but also presented evidence for tumor immune escape. ^, These contributions brought attention to the immune system as a possible armament in the battle against cancer and shed light on the emerging field of immuno-oncology. In 2010, the US Food and Drug Administration (FDA) approved and re-invigorated the field of immunotherapy with two immunotherapies: ipilimumab, a monoclonal antibody (mAb) inhibitor for cytotoxic T-lymphocyte–associated protein type 4 (CTLA-4) for the treatment of stage IV melanoma, and sipuleucel-T (Provenge), a DC vaccine, for the treatment of stage IV metastatic castrate-resistant prostate cancer. ^, The following year, chimeric antigen receptor T cells (CAR-Ts) revolutionized the treatment for hematologic cancers, particularly for B-cell malignancies. CD19-directed CAR-T therapy for patients with B-cell lymphoma led to a complete and durable remission in a pediatric patient with treatment-refractory chronic lymphocytic leukemia (CLL) following adoptive transfer of construct-transduced autologous T cells.

We can exploit the immune system’s impressive ability to select and eliminate “foreign” cells through innovative therapies ( Fig. 134.1 ). When a microbe penetrates the external barriers of the body (i.e., skin), macrophages and related cells recognize certain features of the microbe that are not normally present in or on normal host cells, such as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) for damaged cells. These signals allow the macrophages to phagocytose the invader and recruit other cells, such as neutrophils and natural killer cells, to clear the infection. Natural killer cells, closely related to T lymphocytes but lacking cluster of differentiation 3 (CD3, part of the T-cell receptor), can lyse cells that show signs of being infected or neoplastic without needing the stimulation of a major histocompatibility complex (MHC) molecule. Dendritic cells (DCs), together with macrophages, can act as antigen-presenting cells (APCs) to present antigens as well as stimulate the adaptive immune system by secreting cytokines, which are proteins that drive immunoreactivity.

Whereas the innate immune system is activated simply on the recognition of any antigen it notes to be pathogenic, the adaptive immune system is more targeted in its function and responds to nonself pathogens in an antigen- and sequence-specific manner. The primary response is generated by circulating lymphocytes, separated into B and T lymphocytes, which have defined specificity for a given antigen. B lymphocytes, on binding to an antigen that is recognized by immunoglobulins on their surface, respond by proliferating and secreting antigen-specific antibodies to that pathogen. T lymphocytes, in contrast, must have antigen presented to their T-cell receptor in the context of an MHC molecule on an APC. T cells are further subdivided into two major CD ⁺ classes: CD8 ⁺ T cells, which primarily differentiate into cytotoxic T lymphocytes that directly lyse target cells, and CD4 ⁺ helper T cells, which secrete cytokines that drive the immune response. CD4 ⁺ T cells are activated by MHC class II receptors on APCs, which present antigens derived from material the cell has taken in from endocytosis and lysed, meaning they primarily recognize extracellular proteins. APCs directly cross prime naïve CD8 ⁺ cells through MHC class I antigen presentation, stimulating production of cytotoxic T cells. CD8 ⁺ T cells, in contrast, are activated by MHC class I receptors that present a sampling of antigens produced within nucleated cells, such as those produced by a virus or by a neoplastic cell. These are reviewed in Fig. 134.1 .

As a check against unrestricted proliferation of the immune system, the immune system naturally generates immunosuppressive cells such as regulatory T cells, regulatory B cells, immunosuppressive monocytes, and myeloid-derived suppressive cells (MDSCs). These cells secrete immunosuppressive cytokines, keeping the immune system from unchecked activation. Cytokines such as transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), prostaglandin E ₂ , (PGE ₂ ), and interleukin-10 (IL-10) are secreted by these cells to regulate immunoreactivity. Immune-checkpoint proteins such as cytotoxic T-lymphocyte–associated protein type 4 (CTLA-4) and programmed cell death protein 1 (PD-1) bind to their ligands and reduce T-cell activation or induce apoptosis, respectively. These immunosuppressive features contribute to the mechanism by which tumor cells evade immune recognition, destruction, and therapies. Cancer cells evade therapies through clonal selection, tumor-specific antigen downregulation, and immunosuppressive environment creation.

The central nervous system (CNS) has been historically viewed as an immune-privileged organ system with limited immune function and penetration as a result of the selective permeable blood-brain barrier (BBB), presumed absence of a lymphatic system, and lack of traditional APCs. In 1948, classic allografting experiments into rat brains failed to reject foreign cells that were normally eliminated when implanted in peripheral tissues. Cell types such as microglia, astrocytes, endothelial cells, and cells within the choroid plexus were later identified in the CNS to have properties of APCs but were unable to effectively prime T cells. Despite these findings, evidence of immune response in the CNS from autoimmune CNS diseases such as multiple sclerosis and Alzheimer disease hinted at the possibility of immunosurveillance within the CNS. Recently, lymphatic vessels were identified that run parallel to the dural sinuses and drain into the deep cervical lymph nodes. There, DCs can uptake antigens and stimulate T cells, which migrate back to the CNS and mount an immune response. ^, In the CNS, microglia primarily take up the role of the macrophages, constantly sampling the immune microenvironment of the brain for pathogens that can be phagocytosed and presented to circulating immune cells to create an effector response. Further, the peripheral immune system can generate an immune response that is able to infiltrate the BBB and interact with the CNS, refuting the notion of “immune privilege.” T-cell infiltration of patient tumors, which may have intact BBBs, correlated with improved patient survival.

The success of immunotherapies in multiple systemic cancer types over the past decade has generated increasing interest for developing immunotherapies for CNS tumors. By exploiting these understood mechanisms and cellular roles, we aim to harness the potential of these intricate and adaptive systems to eliminate tumor cells. In this chapter, we summarize past hallmark and current emerging immunotherapies. Notably, peptide vaccines, CAR-T therapy, DC vaccines, heat shock protein vaccines, viral therapies, and immune-checkpoint inhibitors (IHIs) have been studied as immunotherapies against brain tumors.

Antigen-Driven Therapies

Cancer-specific mutations are attractive for targeted therapy purposes. Although glioblastoma multiforme (GBM) has a relatively low tumor mutational burden (TMD, the total number of nonsynonymous mutations per coding area of a tumor genome) compared with other cancers, unique cancer-associated or cancer-specific epitopes can be targeted for GBM therapy. Cancer-specific epitopes are antigens that are unique only to cancer cells, while cancer-associated epitopes are genes that are present in cancer cells but may also be present in healthy tissue. Focused treatment against specific antigens can be achieved by priming the immune system against specific antigens through innate and adaptive immunity or through isolation and stimulation of patient cells ex vivo via adoptive measures ( Fig. 134.2 ).