Brain Tumor Immunology and Immunotherapy


We would like to thank Gena S. Behnke for her expertise and graphic design skills for assistance in constructing the figures for this work.

This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Key Concepts

  • The CNS is immunocompetent with lymphatic vessels that drain to cervical lymph nodes, allowing for sampling of the CNS with peripheral immune response that can pass the blood-brain barrier.

  • Several single targeted immunotherapies, such as EGFRvIII, IL13-Rα2, and HER-2, have demonstrated success in eliciting a response and eliminating their targets; however, there was no significant effect on overall survival, potentially because of the heterogenous nature of glioblastoma and its escape capability.

  • Dendritic cells are designed to prompt responses against a variety of antigens; a current phase 3 trial with a dendritic cell–based vaccine is under way.

  • Recent data indicate that neoadjuvant immune-checkpoint inhibitors (ICIs) may improve overall survival in recurrent glioblastoma patients; this contrasts with the lack of survival benefit from adjuvant PD-1 inhibitor monotherapy.

  • Immunotherapies for metastatic brain tumors (melanoma and non–small cell lung cancer) treated with ICIs as either monotherapy or combination therapy have shown efficacy with mild toxicity.

  • Multiple therapies are being combined with ICIs or the treatment of brain tumors.

  • CAR-T and TCR therapies have been shown to be potentially effective against metastatic brain tumors.

  • Early-phase trials are under way for oncolytic viral immunotherapy approaches that utilize the lysogenic properties of the virus to generate an immune response against cellular content.

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.

Figure 134.1, Immunology background on humoral and cell-mediated immune response.

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 ).

Figure 134.2, Peptide and heat shock protein vaccine.

Peptide Vaccines

The first target for a peptide vaccine in gliomas was epidermal growth factor receptor class III variant (EGFRvIII), an extracellular protein uniquely expressed on cancer tissue. EGFRvIII is a frame deletion mutation of exons 2 to 7 in the extracellular domain of EGFR resulting in a unique glycine residue between exons 1 and 8 and the therapeutic target. The EGFRvIII gene has been thought to reside on extra chromosome 7 or small circular extrachromosomal fragments known as double-minute chromosomes. , It is an attractive target for a peptide vaccine because it is absent in normal tissue but expressed in malignancies such as breast, ovarian, and lung cancers, as well as in approximately 24% to 67% of GBM cases. The EGFRvIII peptide vaccine targets EGFRvIII + GBM cells in patients. Phase 1/2 trials of CDX-110 (rindopepimut), which targets EGFRvIII through a 14-mer peptide conjugated to the keyhole limpet hemocyanin (KLH, an immunostimulatory carrier protein) peptide vaccine, demonstrated safety and tumor-specific immune response with improved survival compared with matched control patients. However, the phase 3 double-blind randomized controlled trial (ACT IV) unfortunately showed no significant difference between the control group and the vaccine group, and the trial was discontinued ( Table 134.1 ). In the vaccine group, patients expressed increased EGFRvIII antibody production, and the majority of resected recurrent tumors were negative for EGFRvIII. This data suggested that the EGFRvIII peptide vaccine successfully targeted EGFRvIII + tumor cells but in the process selected for EGFRvIII-negative or low-expressing tumor cells. Therefore in a heterogenous tumor such as GBM, single-antigen therapy may have very limited success rate despite measurable positive immune response.

TABLE 134.1
Past and Active Phase 3 Clinical Trials
Immunotherapy Therapy Disease Addition Control Phase, Design N = Results
Rindopepmiut NCT01480479 (ACT IV) EGFRvIII KHL Peptide Newly diagnosed glioblastoma GM-CSF + TMZ KLH + TMZ 3, RCT, blind 745 Terminated early: mOS 20.1 months vs. 20.0 months
Dendritic Cell NCT02546102 (STING) Peptide-pulsed DC Newly diagnosed glioblastoma TMZ TMZ + placebo 3, RCT 414 Suspended as a result of finances
Dendritic cell NCT00045968 (DC-VaxL) Tumor lysate– pulsed DC Newly diagnosed glioblasotoma None Unpulsed PBMC 3, RCT, blind 348 Closed: Results still blinded
Immune-Checkpoint inhibitor NCT02017717 (checkmate 143) Nivolumab (anti–PD-1) First-recurrence glioblastoma after radiation/TMZ None Bevacizumab 3, RCT 369 Completed nivo: mOS 9.8 vs. bevacizumab: 10.0; 12-month OS rate 42% in both arms. PFS medians were 1.5 mo (nivo) vs. 3.5 mo (bevacizumab)
Adenovirus NCT02511405 (globe) Ofranergene obadenovec (vb-111) Recurrent glioblastoma Bevacizumab Bevacizumab 3, RCT 252 Completed: Median OS was 6.8 vs. 7.9 mo
Retrovirus NCT02414165 Toca 5 (Toca 511 + FC) Recurrent high-grade gliomas None TMZ vs. lomustine vs. bevacizumab 2,3, RCT 403 Active
Immune-Checkpoint inhibitor NCT02667587 (Checkmate 548) Nivolumab Newly diagnosed glioblastoma TMZ + RT TMZ + RT + placebo 3, RCT, blind 603 Active
Immune-checkpoint inhibitor NCT02617589 (Checkmate 498) Nivolumab Newly diagnosed glioblastoma RT TMZ + RT 3, RCT 550 Recruiting
Immune-Checkpoint inhibitor NCT02460068 (NIBIT-M2) Ipilimumab Metastatic melanoma Fotemustine +/–nivolumab Fotemustine 3, RCT 168 Recruiting
DC, Dendritic cell; KLH, keyhole limpet hemocyanin; mo, months; mOS, median overall survival; OS, overall survival; PBMC, peripheral blood mononuclear cells; RCT, randomized controlled trial; RT, radiation therapy; TMZ, temozolomide.

Another target for peptide vaccination is survivin, a membrane inhibitor of apoptosis and regulator of cell cycle. Its expression is absent in terminally differentiated tissues but present in various cancer types including GBM. A peptide vaccine targeting survivin is currently under investigation. The vaccine utilizes a 15-mer survivin peptide linked to KLH (SurVaxM) to stimulate an immunogenic response. An early phase 2 trial is under way for newly diagnosed GBM patients with restricted HLA types (HLA-A∗02/03/11/24 haplotype) ( NCT02455557 ). The data so far are optimistic, with a 12-month overall survival (OS) of 94.2%.

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