Vaccine-Based Immunotherapeutics for the Treatment of Glioblastoma: Advances, Challenges, and Future Perspectives

Literature Review

Vaccine-Based Immunotherapeutics for the Treatment of Glioblastoma: Advances, Challenges, and Future Perspectives Joshua A. Cuoco1, Michael J. Benko2-5, Christopher M. Busch2-5, Cara M. Rogers2-5, Joshua T. Prickett2-5, Eric A. Marvin2-5

Key words Brain neoplasm - Clinical trials - Glioblastoma - Immunotherapeutic - Immunotherapy - Vaccine -

Abbreviations and Acronyms APC: Antigen-presenting cell APVAC: Actively personalized vaccination BBB: Bloodebrain barrier CMV: Cytomegalovirus CNS: Central nervous system CSF: Cerebrospinal fluid DC: Dendritic cell EGFRvIII: Epidermal growth factor receptor variant type III GAA: Glioma-associated antigen GBM: Glioblastoma GSC: Glioblastoma stemlike cells HLA-I: Human leukocyte antigen class I HSP: Heat-shock protein HSPPC-96: Heat-shock protein peptide complex-96 IDH1R132H: Isocitrate dehydrogenase 1 Arg132His IL-13Ra2: Interleukin-13 receptor subunit-a2 iRANO: Immunotherapy Response Assessment in Neuro-Oncology MHC: Major histocompatibility complex MRI: Magnetic resonance imaging Neovax: Neoantigen-based vaccine OS: Overall survival PFS: Progression-free survival pp65: Phosphoprotein 65 RANO: Response Assessment in Neuro-Oncology TAA: Tumor-associated antigen TGF-b: Transforming growth factor-b TMZ: Temozolomide T-regs: T-regulatory cells TSA: Tumor-specific antigen WT-1: Wilm’s tumor protein-1 From the 1New York Institute of Technology College of Osteopathic Medicine, Glen Head, New York, 2Carilion Clinic, Section of Neurosurgery and 3Virginia Tech Carilion School of Medicine, Roanoke, Virginia, 4Virginia Tech School of Neuroscience and 5Edward Via College of Osteopathic Medicine, Blacksburg, Virginia, USA To whom correspondence should be addressed: Joshua A. Cuoco, D.O., M.S. [E-mail: [email protected]] Citation: World Neurosurg. (2018) 120:302-315. https://doi.org/10.1016/j.wneu.2018.08.202 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.

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Glioblastoma is a highly aggressive neoplasm with an extremely poor prognosis. Despite maximal gross resection and chemoradiotherapy, these grade IV astrocytomas consistently recur. Glioblastoma cells exhibit numerous pathogenic mechanisms to decrease tumor immunogenicity while promoting gliomagenesis, which manifests clinically as a median survival of less than 2 years and few long-term survivors. Recent clinical trials of vaccine-based immunotherapeutics against glioblastoma have demonstrated encouraging results in prolonging progression-free survival and overall survival. Several vaccine-based treatments have been trialed, such as peptide and heat-shock proteins, dendritic cell-based vaccines, and viral-based immunotherapy. In this literature review, we discuss the immunobiology of glioblastoma, significant current and completed vaccinebased immunotherapy clinical trials, and broad clinical challenges and future directions of glioblastoma vaccine-based immunotherapeutics.

INTRODUCTION Glioblastoma (GBM) is an aggressive brain tumor with a dismal prognosis. The current standard of care for GBM, consisting of maximal safe resection, radiotherapy, and temozolomide (TMZ), translates into a median survival of 14.6 months and 2-year medial survival of 27%.1 The unfortunate survival rate of GBM has been attributed in part to intratumoral heterogeneity, GBM stem cells, and various mechanisms of glioblastoma-induced immunosuppression. As such, clinical trials of vaccine-based immunotherapeutics have emerged as a potential novel treatment modality intended to overcome GBM pathogenesis and improve patient outcomes. Contrary to the standard of care, immunotherapy is unique in being highly specific to both the patient and the tumor. Recently, clinical trials of vaccine-based immunotherapies against GBM have demonstrated promising results in prolonging progression-free survival (PFS) and overall survival (OS) and by exhibiting a favorable safety profile. Several types of vaccine-based immunotherapies have been trialed, including peptides, heatshock proteins, (DC)-based vaccines, and viral-based immunotherapies. Here, we provide a detailed discussion of GBM

immunobiology, and we review the significant current and completed GBM vaccine immunotherapy trials. Furthermore, clinical challenges and future directions of vaccinebased immunotherapies are considered. CENTRAL NERVOUS SYSTEM “IMMUNE PRIVILEGE” Historically, the central nervous system (CNS) was considered an immunoprivileged organ because of the presence of the bloodebrain barrier (BBB) and lack of classic lymphatic vessels. However, it has been known for decades that brain tumors can provoke an immune response against tumor antigens. Although the CNS is an immunologically unique organ, the immune system is still capable of surveying CNS antigens. This process initially entails antigens acquiring entrance into the cerebrospinal fluid (CSF) by one of several mechanisms such as disruption of the BBB, direct extension of the tumor into CSF spaces, or via glymphatic clearance.2 Subsequently, CSF antigens can be transported to cervical lymph nodes by 1 of 3 anatomic routes. First, CSF can enter recently described glymphatic vessels (i.e., meningothelial lymphatics of the dura) that drain into cervical lymph nodes.3-6 Second, CSF can traverse the

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Figure 1. Schematic diagram of the glioblastoma microenvironment; Glioblastoma tumors create a heterogeneous microenvironment rich in neoplastic glial cells, glioblastoma stem-like cells, non-neoplastic parenchymal cells (e.g., astrocytes), neurons, immunologic cells (e.g., microglia, macrophages, T-lymphocytes), and perivascular cells (e.g., endothelial, pericytes).

cribiform plate and enter the lymphatic vessels of the nasal mucosa, which also drain into cervical lymph nodes.7,8 The prior anatomic routes of CSF drainage are acquiescent to both antigens and immune cells. The last route to cervical lymph nodes, amendable only to CSF antigens, entails interstitial fluid transport through the basement membranes of arteries and capillaries within the brain parenchyma.9 Following antigen presentation and activation in cervical lymph nodes, T-cells may enter the CNS parenchyma through any of several routes. First, T-cells may pass through or between the BBB endothelial cell layer of postcapillary venules into perivascular spaces followed by infiltration of the glia limitans into the brain parenchyma.10-12 Second, T-cells may enter the CSF from subarachnoid leptomeningeal venules followed by possible entrance into the parenchyma after passing the glia limitans.13 Third, although not yet confirmed, experimental evidence suggests that T-cells within blood vessels may travel into the stroma of the choroid plexus and infiltrate its epithelium.14 In the choroid plexus, T-cells may enter the ventricular system, gain access to the subarachnoid space, and, ultimately, penetrate the parenchyma.14,15 Upon arrival at the site of the tumor (e.g., GBM), immune cells will encounter an extraordinary immunosuppressive microenvironment distinct from physiologic brain parenchyma.

THE MICROENVIRONMENT OF GLIOBLASTOMA Tumors are unable to thrive independently; rather, they are closely intertwined and are reliant on their proximate cellular environment. Tumor cells demonstrate the ability to adjust to their surrounding environment and alter it to their own advantage. Indeed, such a task requires complex interactions between the tumor progeny with various supporting cells. This microenvironment is a focused nook composed of neoplastic cells, immune cells, blood vessels, and stroma intertwined through an extracellular matrix (ECM).16 The brain microenvironment is unique from peripheral environments such that the brain is largely secluded by the BBB.16,17 Even though the CNS is not as immunologically privileged as once alleged, GBMs prefer to proliferate within its local microenvironment as even highly aggressive CNS tumors rarely metastasize outside of the brain parenchyma.18 To create efficacious immunotherapeutics against GBM, it is imperative to understand the molecular basis of the tumor microenvironment and how this niche supports gliomagenesis. Glioblastoma creates a heterogeneous microenvironment rich in neoplastic glial cells, glioblastoma stemlike cells (GSCs), nonneoplastic parenchymal cells (e.g., astrocytes), neurons, immunologic cells (e.g., microglia, macrophages, Tlymphocytes), and perivascular cells (e.g., endothelial, pericytes) (Figure 1).19-21 Each

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cell type serves a purpose in supporting the tumor microenvironment and promoting gliomagenesis. Tumor initiating cells, known as GSCs, demonstrate the capability to maintain the malignant features of GBM, such as tumor cell inception, angioneogenesis, and proliferation as well as acquiring resistance to chemotherapeutics.20-24 Interestingly, GSCs have recently been shown to secrete extracellular vesicles containing vascular endothelial growth factor from ex vivo cultured patient-derived GSCs, which elicited an angiogenic reaction within the microenvironment.20 Nonneoplastic astrocytes are the most prevalent glial cell within the GBM perivascular niche. Upon activation, astrocytes can encompass and shield tumors from the gliotoxic effects of chemotherapeutics.25 Furthermore, histologic analysis has demonstrated that infiltrating microglia composes 5% to 20% of GBM tumor mass.26 Microglial cells actively recruit peripheral macrophages and increase neoplastic migration as well as tumor evasion.27,28 To meet their metabolic requirements, these tumors use numerous mechanisms of neovascularization such as angioneogenesis,29 vasculogenic mimicry30 (tumor synthesis of vessel-like entities), or vessel co-option31 (tumor sequestering of physiologic vessels). Each mechanism is dependent on pericyte and endothelial recruitment, which can occur through GBM secretion of vascular endothelial growth factor.32,33 Remarkably, GBM cells have been shown to transdifferentiate into vascular endothelial cells34 and to generate vascular pericytes35 in vivo to further angioneogenesis. The extracellular matrix, consisting of fibrous proteins and several other biomolecules (e.g., hyaluronic acid, glycosaminoglycans, proteoglycans), interweaves the heterogeneous microenvironment together and also relays biochemical and mechanical signals to tumor cells.36,37 Last, neoplastic glial cells refine their microenvironment and drive pathogenesis through a multitude of immunologic mechanisms. MECHANISMS OF IMMUNOSUPPRESSION IN GLIOBLASTOMA Patients with GBM can become significantly immunosuppressed. Translational research

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overexpression of these ligands on GBM cells may represent viable targets for confronting immunosuppression on the molecular level. Glioblastoma cells can also evade the host immune system by decreasing the expression of human leukocyte antigen class I (HLA-I) molecules on their cell surface.53,54 Downregulation of HLA-I reduces tumor immunogenicity while permitting tumor cell evasion of T-lymphocyte cytotoxic responses.55 Nonetheless, the upregulation of nonclassic HLA-I molecules, such as HLA-E and HLA-G, can inhibit T-lymphocyte cytotoxicity and natural killer cell function, contributing to immunologic escape from its host.56,57 Figure 2. Mechanisms of glioblastoma-induced immunosuppression of the tumor microenvironment. Left, T cells expressing Fas undergo apoptosis upon binding to GBM Fas-L. T cell CTLA-4 and PD-1 binding to GBM B7 and PD-L1, respectively, suppresses T cell function within the microenvironment. Center, Secretion of CCL-2 and TGF-b recruits T regulatory cells, which inhibits T cell function. IL-10 also constrains host responses by inhibiting antigen-presenting cells. Right, HLA-G inhibits NK and T cell function. Downregulation of HLA-I reduces tumor immunogenicity and permits tumor cell evasion of T-lymphocyte cytotoxic responses. GBM, glioblastoma; Fas-L, Fas ligand; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand; CCL-2, chemokine C-C ligand 2; TGF-b, transforming growth factor-b; IL-10, interleukin 10; HLA, human leukocyte antigen; NK, natural killer.

has shown that this patient population exhibits an increased fraction of T-regulatory cells (T-regs) with a diminishing proportion of CD4þ T-cells.38 Glioblastoma-derived chemokine C-C ligand 2 attracts T-regs to its microenvironment whereby these cells function to suppress or downregulate the propagation of effector T-cells.39,40 Nevertheless, T-reg infiltration is not an absolute mechanism of systemic immunosuppression because T-reg influx is not demonstrated in all GBM patients.41 This suggests that GBM exhibits other mechanisms of systemic immunosuppression induction. Additional systemic immunologic abnormalities found in GBM patients include a decrease in antigen presentation and cytokine synthesis and a weakening of leukocyte function, including diminished T-cell cytotoxicity, Bcell antibody synthesis, or T-cell and B-cell propagation.42,43 Glioblastoma is classified as an immunologically “cold” tumor in that there is a scarcity of immunologic effector cells within the GBM microenvironment.44 As such, there is a diminished probability for “cold” tumors, including GBM, to respond to immunotherapies.44 Moreover, GBM exhibits a relatively low tumor mutational

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load compared with “hot” tumors, such as melanoma, which exhibit an inflamed microenvironment with a surplus of infiltrating immune effector cells.44 Locally at the tumor site, GBM cells are active constituents in creating and sustaining an immunosuppressed microenvironment (Figure 2). Local immunosuppression is dependent on T-regs secreting antiinflammatory cytokines, such as transforming growth factor-b (TGF-b) and interleukin-10, which stimulates T-reg function and also reduces antigenpresenting cell (APC) utility and T-cell effector responses.23 Additionally, tumorassociated macrophages and myeloidderived suppressor cells penetrate the tumor niche, sustain tumor evolution, and diminish antitumor immunologic responses.45-47 Glioblastoma cells can also express negative regulators of T-cell function, including programmed cell death protein,44 Fas-ligand,48 T-cell immunoglobulin and mucin domain 3,49 lymphocyte-activation gene 3,50 lectin-like transcript 1,51 and cytotoxic T-lymphocyte-associated protein 4 receptor.52 These proteins inhibit Tcell activation and function while promoting T-reg immunosuppression. The

EXPERIMENTAL VACCINATION THERAPIES A vaccine is a biologic preparation administered to a person or animal with the intention of producing long-term immunity by triggering an adaptive immune response against specific antigens. Traditionally, vaccinations are dispensed as a prophylactic measure to prevent disease pathogenesis. Nevertheless, in the context of diagnosed cancer, the objective of a vaccine is to induce an immunologic response against tumor antigens and, ultimately, to provide the host’s immune cells the ability to eradicate tumor cells. A diverse variety of experimental GBM vaccination therapies have been studied in the clinical setting, including peptide vaccines, heat-shock protein peptide complex-96, DC-based therapy, and immunovirotherapy. Here, we provide a literature review of recent advancements, clinical challenges, and future directions of vaccination therapies in the treatment of GBM. A summary of completed clinical trials of GBM vaccine therapies can be found in Table 1. Current clinical trials can be found in Table 2. Epidermal Growth Factor Receptor Variant Type III GBM cells exhibit significant aberrations on the molecular level that increase their pathogenicity. Indeed, GBM cells increase their pathogenicity and reduce their immunogenicity by modifying their genomic,99 epigenomic,100 transcriptomic,101 proteomic,102 and metabolomic profiles.103 Although nearly 10,000 possible GBM targets have been recognized, a limited

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Table 1. Completed Vaccine-Based Immunotherapy Trials for Glioblastoma Trial

Year Published

Experimental Treatment Arm

Phase Sample Size

Primary Endpoint(s)

Results Reference

EGFRvIII ACTIVATE

2010

Rindopepimut, TMZ/RT, GR

II

18

ACT-II

2011

Rindopepimut, TMZ/RT, GR

II

22

ACT-III

2015

Rindopepimut, TMZ/RT, GR

II

65

OS, PFS

Positive

58

Positive

59

PFS

Positive

60

Differences in immune responses with two distinct TMZ regimens

ACT-IV

2017

Rindopepimut, TMZ/RT, GR

III

745

OS

Negative

61

ReACT

2015

Rindopepimut, Bevacizumab

II

72

PFS, OS, ORR, Safety

Positive

62

WT-1 vaccine

2008

Modified 9-mer WT-1 peptide

II

21

Safety, Clinical response

Positive

63

WT-1 vaccine

2015

Modified 9-mer WT-1 peptide, TMZ/RT, Variable resection

I

7

Safety

Positive

64

WT-1 vaccine

2016

Modified 9-mer WT-1 peptide

II

59

Humoral response

Positive

65

2016

SurVaxM

I

9

Safety, Immunogenicity

Positive

66

Multipeptide Vaccine

2014

Survivin, EphA2, IL-13Ra2, TMZ/RT

N/A

26

Safety, T-cell responses

Positive

67

IMA950

2016

IMA950, TMZ/RT, GR

I

45

Safety, Tolerability

Positive

68

2018

APVAC 1 & 2, TMZ/RT, GR

I

16

Safety, Feasibility, Biological Activity

Positive

69

HSPPC-96

2013

Autologous HSPPC-96, GR

I

12

Safety, OS

Positive

70

HSPCC-96

2014

Autologous HSPPC-96, GR

II

41

OS

Positive

71

HeatShock

2018

Autologous HSPPC-96, TMZ/RT, GR

II

46

Safety, ST

Pending

72

HSPCC-96

2017

Autologous HSPPC-96, TMZ/RT, GR

I

20

PFS

Pending

73

DC vaccine

2005

Autologously pulsed DCs, TMZ/RT, GR

I

12

Safety

Positive

74

DC vaccine

2011

Autologously pulsed DCs, TLR agonist, TMZ/RT, GR

I

23

Safety

Positive

75

DC vaccine

2011

DCs pulsed with synthetic gliomaassociated peptides, TMZ/RT, GR

I/II

22

DLT, TTP

Positive

76

ICT-107

2013

DCs pulsed with 6 synthetic class I tumor peptides, TMZ/RT, GR

I

21

Safety, Immunogenicity

Positive

77

ICT-107

2014

DCs pulsed with 6 synthetic class I tumor peptides, TMZ/RT, GR

II

124

Safety, OS

Negative

78

GBMVax

2015

Trivax, TMZ/RT, GR

II

87

PFS

Pending

79

ATTAC

2015

DCs pulsed with CMV pp65, Td, TMZ/RT, GR

I

6

Efficacy of pre-conditioning with Td

Positive

80

ATTAC

2017

DCs pulsed with CMV pp65, TMZ/RT, GR

I

11

Safety

Positive

81

Wilm’s Tumor Protein-1

Survivin SurVaxM Multipeptide Vaccines

Personalized Peptide Vaccines GAPVAC-101 HSPPC-96

Dendritic Cell-Based

Immunovirotherapy

EGFRvIII, epidermal growth factor receptor variant III; TMZ, temozolomide; RT, radiation therapy; GR, gross resection; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; WT-1, Wilm’s tumor protein-1; EphA1, Ephrin type-A receptor 1 precursor; IL-13Ra2, interleukin-13 receptor subunita2; N/A, not applicable; HSPPC-96, heat-shock protein peptide complex 65; ST, survival time; DC, dendritic cell; TLR, toll-like receptor; DLT, dose-limiting toxicity; TTP, time to progression; CMV pp65, cytomegalovirus phosphoprotein 65; Td, tetanus/ diphtheria toxoid.

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number of these antigens are capable of demonstrating both immunogenicity and activating a host immune response.104 Tumor antigens that fulfill both conditions are divided into tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs). TAAs are molecules that may be expressed in both physiologic and malignant tissue. Examples of TAAs include overexpression of homeostatic proteins, viral proteins, and antigens primarily expressed in germ cells. TSAs

are expressed only in malignant tissue and include mutated gene products such as GBMspecific epidermal growth factor receptor variant type III (EGFRvIII) or isocitrate dehydrogenase 1 Arg132His (IDH1R132H). The EGFR gene is overexpressed in nearly 40% of IDH wild-type GBM tumors.105 Tumors with EGFR gene overexpression often demonstrate gene rearrangements, with the most common mutation being a deletion of exons 2e7 in the EGFR gene.106

This mutation, known as EGFRvIII, creates a ligand-independent, constitutively active tyrosine kinase that drives oncogenecity by promoting tumor motility and proliferation, inhibiting apoptosis, and awarding tumor resistance to radiation.106 Importantly, this deletion results in a novel 14 amino-acid peptide sequence restricted to EGFRvIII. More than 50% of primary GBMs exhibit an EGFRvIII mutation and with lower percentages found in

Table 2. Ongoing Vaccine-Based Immunotherapy Trials for Glioblastoma Phase

Sample Size

Primary Endpoint(s)

ClinicalTrials.gov Identifier

Reference

Live-attenuated, L. monocytogenes encoding EGFRvIII þ NY-ESO-1

I

11

MTD

NCT01967758

82

NOA-16

20-mer IDHR132H peptide, TMZ/RT

I

39

RLT, Immunogenicity

NCT02454634

83

RESIST

PEPIDH1M, Td, TMZ/RT

I

28

RLT

NCT02193347

84

DSP-7888

I

96

Safety, DLT

NCT02498665

85

DSP-7888

DSP-7888

I/II

30

DLT, OS

NCT02750891

86

WIZARD201G

DSP-7888, Bevacizumab

II

200

DLT, OS

NCT03149003

87

SurVaxM, TMZ

II

64

PFS

NCT02455557

88

IMA950

IMA950 with Poly-ICLC, TMZ/RT, GR

I/II

19

Safety, Tolerability

NCT01920191

89

SL-701

SL-701, Bevacizumab

I/II

74

Safety, Tolerability, OS, ORR

NCT02078648

90

NeoVax, TMZ/RT, Pembrolizumab

I

46

Safety, Tolerability

NCT02287428

91

ALLIANCE IND#15380

HSPPC-96 plus bevacizumab or HSPPC96 plus bevacizumab at progression, GR

II

90

OS

NCT01814813

92

HSPPC-96

HSPPC-96, Pembrolizumab, TMZ/RT

II

108

OS

NCT03018288

93

HSPPC-96

HSPCC-96, RT, GR

I

20

MTD, RP2D

NCT02722512

94

STING

ICT-107, TMZ/RT, GR

III

414

OS

NCT02546102

95

ICT-121

ICT-121

I

20

Safety, Tolerability

NCT02049489

96

DCVax-L

DCVax, TMZ/RT, GR

III

348

PFS

NCT00045968

97

CMV pp65-pulsed DCs, Td, TMZ/RT, GR

II

150

OS

NCT02465268

98

Trial

Experimental Treatment Arm

EGFRvIII ADU-623 IDHR132H

Wilm’s tumor protein-1 DSP-7888

Survivin SurVaxM Multipeptide vaccines

Personalized peptide vaccines NeoVax HSPPC-96

Dendritic cellebased

Immunovirotherapy ATTAC-II

EGFRvIII, epidermal growth factor receptor variant III; NY-ESO-1, cancer-testis antigen; MTD, maximum tolerated dose; IDH, isocitrate dehydrogenase; TMZ, temozolomide; RT, radiation therapy; RLT, rate-limiting toxicity; Td, tetanus/diphtheria toxoid; DLT, dose-limiting toxicity; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; HSPPC-96, heat-shock protein peptide complex 96; GR, gross resection; RP2D, recommended phase II dose; CMV pp65, cytomegalovirus phosphoprotein 65; DC, dendritic cell.

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prostate, colorectal, breast, and lung cancer.107-109 As such, EGFRvIII is the classic TSA studied in GBM cells and a promising molecular target for vaccine-based immunotherapy against these tumors. A vaccine against EGFRvIII, known as rindopepimut, was created by conjugating the novel 14 amino acid sequence of EGFRvIII to the carrier protein keyhole limpet hemocyanin.110 Three uncontrolled phase II trials investigating the immunogenicity and efficacy of rindopepimut against GBM tumors demonstrated a substantial increase in PFS and OS.58-60 Notably, these trials had rigorous inclusion criteria, including gross total tumor resection and lack of disease progression on imaging after chemoradiotherapy.58-60 The first trial, known as the ACTIVATE trial, studied patients with EGFRvIII-positive newly diagnosed GBM. Compared with matched historical control individuals, vaccinated patients demonstrated a median OS of 26 months.58 Remarkably, 9 of the 11 patients who experienced recurrence had lost EGFRvIII expression.58 The second and third trials, known as ACT-II and ACT-III, respectively, evaluated vaccination plus TMZ. These two trials further demonstrated that recurrent tumors exhibit a loss of EGFRvIII expression in response to vaccination and standard therapy.59,60 The ensuing double-blinded, randomized phase III trial (ACT IV) was prematurely discontinued because interim analysis revealed that increased OS in the experimental group was unlikely to occur. Although the outcomes of ACT-IV were negative, various lessons were learned from the results, including the following: 1) historical controls are not optimal for vaccine trials, 2) patients with EGFRvIII loss of expression require controls, 3) the host humoral response to rindopepimut is not a reliable predictor of outcomes, and 4) vaccine therapy against GBM may require more than 1 molecular target to elicit sufficient immunogenicity.61,111 Despite the negative outcome of ACT-IV, a smaller randomized phase II study, known as the ReACT trial, investigated bevacizumab with or without rindopepimut in patients with recurrent GBM. With an increase in OS from 9.3 months in the control arm to 11.3 months in the experimental arm, the ReACT study demonstrated an increase in OS.62 Currently, the only ongoing trial studying EGFRvIII vaccination in GBM patients is the phase I ADU-623 trial (NCT01967758).82

VACCINE-BASED IMMUNOTHERAPEUTICS FOR GLIOBLASTOMA

This trial is investigating the safety profile and immunogenicity of a live-attenuated, double-deleted strain of gram-positive Listeria monocytogenes encoding EGFRvIII plus the cancer antigen NY-ESO-1 in patients with newly diagnosed and recurrent GBM.82

Isocitrate Dehydrogenase R132H The most common IDH1 mutation identified in GBM results in an arginine-tohistidine amino acid substitution at position 132. Although IDHR132H have been reported in >70% of lower-grade gliomas and secondary GBMs, this mutation has been observed only in approximately 5% of primary GBMs.112 Nevertheless, this mutation alters the active site of IDH, resulting in differential production of the oncometabolite D-2-hydroxyglutarate, epigenetic hypermethylation, genetic instability, and gliomagenesis.103,113 Preclinical data have demonstrated that IDHR132H constitutes an immunogenic epitope targetable by mutation-specific vaccines. In fact, peptide vaccination of mice lacking murine major histocompatibility complex (MHC) and transgenic for human MHC class I and II with the IDHR132H mutation resulted in an efficient MHC class II-restricted mutationspecific antitumor response dependent on interferon-g CD4þ T-helper cells.113 Importantly, wild-type IDH1 did not induce T-cell activity, confirming the tumor specificity of IDHR132H. This study established that a mutation-specific antiIDHR132H vaccine might be a feasible novel immunotherapy for IDHR132Hpositive tumors. Currently, 2 phase I trials are investigating the safety and immunogenic profile of IDHR132H vaccination in patients harboring GBM. The NOA-16 trial (NCT02454634) is the first human trial of a 20-mer IDHR132H peptide vaccination in 39 patients with GBM.83 Experimental groups are subdivided into 3 groups. Experimental group 1 will receive only vaccination treatment 4 to 6 weeks after radiation treatment. Experimental groups 2 and 3 will receive vaccination treatment in conjunction with TMZ, beginning on day 10 of the fourth or first TMZ cycle, respectively. The RESIST trial (NCT02193347) is another phase I trial investigating the safety of the PEPIDH1M vaccine (a peptide that spans the region of

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IDHR132H) with or without TMZ in patients with grade II recurrent gliomas.84 Wilm’s Tumor Protein-1 Wilm’s tumor protein-1 (WT-1), a zinc finger DNA-binding protein, is expressed in most GBMs. This transcription factor has significant oncogenic potential in part by regulating GBM proliferation and apoptosis.114 A phase II trial including 21 patients with WT-1/HLA-A*2402-positive recurrent GBM investigated the safety and clinical response of immunotherapy targeting WT-1.63 Patients received intradermal injections of an HLA-A*2402restricted modified 9-mer WT-1 peptide once per week for 3 months. This trial demonstrated a median PFS of 20 weeks and an overall response rate of 9.5%.63 Although it was a small uncontrolled nonrandomized trial, the study demonstrated that targeting WT-1 is safe and can induce a clinical response. Subsequently, the same group investigated the safety of combined WT-1 plus standard-ofcare treatment in 7 patients with newly diagnosed GBM in a phase I trial.64 A PFS from histologic diagnosis was reported to be 5.2 to 49.1 months.64 Five of 7 patients experienced lymphocytopenia, which was attributable to TMZ administration. Moreover, this group then investigated whether the WT-1 peptide vaccine is capable of inducing a humoral response in 59 GBM patients and whether such a response is associated with clinical outcomes.65 Compared with sera measured before WT-1 vaccination, 50.8% of patients reached the predetermined cutoff for a WT-1 IgG antibody-positive response after vaccination.65 These results demonstrated that WT-1 specific humoral responses can be induced by a WT-1 peptide vaccination and lead to a significant rise in WT-1 IgG antibody concentration. The PFS and OS in patients with WT-1 IgG antibody production were found to be significantly longer than in the group who did not demonstrate a WT-1 IgG antibody positive response.65 Currently, numerous trials are examining the safety and efficacy of WT-1 vaccine against primary and recurrent GBM. The vaccine under trial, known as DSP-7888, is derived from WT-1 peptides. These trials include a phase I dose-escalation trial of DSP-7888 in adult patients with primary GBM (among other patients with advanced malignancies) (NCT02498665),85 a phase I/II

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uncontrolled, open-label trial of DSP-7888 in pediatric patients with recurrent and relapsed diffuse intrinsic pontine glioma, GBM, or anaplastic astrocytoma (NCT02750891),86 and a phase II open-label, parallel-groups trial of DSP-7888 plus bevacizumab versus bevacizumab alone in patients with recurrent GBM (NCT03149003).87 Survivin Survivin, also known as baculoviral inhibitor of apoptosis repeat-containing 5, is a member of the inhibitor of apoptosis family. Functionally, it inhibits the activation of caspases and negatively regulates apoptosis. Survivin is overexpressed in many cancers, including GBM.66 Moreover, survivin expression has been correlated with degree of tumor proliferation.115 These factors have highlighted survivin as an attractive molecular target for immunotherapy. A phase I trial, known as SurVaxM, investigated the safety, immunogenicity, and clinical effects of a survivin vaccine in 9 patients with survivin-positive recurrent GBM.66 SurVaxM was well tolerated, with no serious adverse events reported. Six patients experienced cellular and humoral responses to the administered vaccine. Median PFS was 17.6 weeks, and median OS was 86.6 weeks, with 7 patients surviving longer than 1 year.66 In a subsequent phase II trial, the SurVaxM is currently being studied in combination with TMZ in 64 patients with newly diagnosed GBM (NCT02455557).88 Several trials of multipeptide vaccines containing survivin have also been published or are currently ongoing, as discussed below. Multipeptide Vaccines To decrease immune tolerance and disease recurrence associated with singlepeptide vaccines, numerous studies have begun to investigate the efficacy of multipeptide vaccines that combine several glioma-associated antigens (GAA). A recently completed trial investigated the safety and T-cell response of GAA epitope peptides (Ephrin type-A receptor 1 precursor, interleukin-13 receptor subunit alpha 2 [IL-13Ra2], and survivin) plus standard of care in 26 pediatric patients with newly diagnosed high-grade glioma or diffused brainstem glioma.67 The multipeptide vaccine was well tolerated and induced anti-GAA immune responses in 13 of 21 evaluable patients. Five

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children experienced symptomatic pseudoprogression, which was associated with prolonged survival, compared with patients who did not demonstrate pseudoprogression.67 Pseudoprogression in these cases was indicative of immune cell penetration into tumors, resulting in edema. However, no conclusions about efficacy could be derived from the study because it was uncontrolled and pooled 2 different disease entities. IMA950 is a multipeptide vaccine developed to treat GBM. It contains 11 TAAs identified on HLA surface receptors in primary GBM samples, including brevican, baculoviral inhibitor of apoptosis protein repeat-containing 5 (survivin), chondroitin sulfate proteoglycan 4, fatty acid-binding protein 7, hepatitis B virus core antigen, insulin-like growth factor-2 mRNA-binding protein 3, met proto-oncogene, neuroligin 4 X-linked, neuronal cell adhesion molecule, protein tyrosine phosphatase receptor-type Z polypeptide 1, and tenascin C.68 A phase I trial was conducted to assess the safety and immunogenicity in 45 patients with newly diagnosed GBM using IMA950 plus standard of care.68 Adverse effects were mild but included 2 patients who experienced anaphylaxis. Ninety percent of patients demonstrated an immune response to at least 1 TAA, and 50% of patients responded to 2 TAAs.68 The PFS was reported to be 74% at 6 months and 31% at 9 months after treatment.68 A phase I/II trial of IMA950 adjuvanted with Poly-ICLC (Hiltonol) in combination with standard of care in 19 patients with newly diagnosed GBM has recently been completed (NCT01920191).89 Interim analysis demonstrated that IMA950 adjuvanted to poly-ICLC is well tolerated and immunogenic, with an encouraging preliminary median OS of 21.2 months.116 SL-701 is a multivalent class I-restricted, peptide vaccine composed of survivin, IL13Ra2, and EphA2.90,117 A phase I/II trial of the GAA vaccine SL-701 plus bevacizumab for the treatment of 74 patients with recurrent GBM has recently been completed (NCT02078648).90 Although final results are pending, interim analysis demonstrated that SL-701 was well tolerated and demonstrated antitumor activity.117 Personalized Peptide Vaccines Personalized vaccine therapy considers the genetic diversity, tumor biomarkers, and

clinical profiles of each patient to create individualized targetable therapies. The ultimate endpoint of this strategy is to develop patient-specific therapies that increase anticancer immunity while reducing off-target interactions and minimizing adverse effects. The recently completed GAPVAC-101 trial was the firstin-human phase I trial to investigate the safety and immunogenicity of the actively personalized vaccination (APVAC) concept in 16 patients with newly diagnosed GBM (NCT02149225).118 Two APVAC vaccines with poly-ICLC were administered with standard of care. The vaccines consisted of 2 novel peptide-based APVAC vaccines per patient based on whole-exome sequence and HLA-ligandome analyses.69 The APVAC 1 vaccine consisted of 9 peptides selected from a library of proteins obtained by means of tumor expression profiling. The peptides that were highly associated with the tumor expression profile were chosen for each patient to amplify the maximum number of potential antitumor immune responses. APVAC 2 consisted of 2 de novo antigens per patient based on mutation status, HLA presentation, and immunogenicity. Although the final results have yet to be published, recent abstract data indicated that the GAPVAC101 trial demonstrated high biologic activity, with a median PFS and OS of 14.2 and 29 months, respectively.69 Another phase I trial is currently evaluating the safety and efficacy of neoantigen-based vaccines (NeoVax) with radiotherapy in 46 methylguanine methyltransferaseunmethylated newly diagnosed GBM patients (NCT02287428).91 This study has multiple cohorts, including radiotherapy followed by NeoVax, pembrolizumab plus radiotherapy followed by NeoVax, and pembrolizumab plus chemoradiotherapy followed by NeoVax. Heat-Shock Protein Peptide Complex-96 Heat-shock proteins (HSPs) are ubiquitous intracellular chaperones that function to facilitate protein folding and transport. These proteins are differentially expressed based on the presence of cellular stressors, such as heat, infection, hypoxia, and malignancy. Physiologic HSPs are unable to elicit an immune response; however, the complex of HSP with a tumor antigen is capable of provoking a response. This

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occurs when endoplasmic reticular chaperone HSP-96 binds TSAs, forming HSP-9 protein complex (HSPPC-96).119,120 Intracellular and extracellular HSPs, then coordinate the internalization of HSPPC-96 into APCs for class I and II MHCemediated presentation of tumor-associated peptides, eliciting a hosteimmune response.119,120 In a small phase I trial, 12 patients with recurrent high-grade gliomas were immunized with an autologous HSPPC-96 vaccine derived from surgically resected tumor.70 No significant toxicities were reported. Peripheral blood leukocyte assays before and after vaccine administration demonstrated a significant immune response in 11 of the 12 patients. Brain biopsy specimens from immune responders demonstrated an increase in CD3þ, CD4/CD8-double positive, and CD56þ T-cell populations.70 Immune responders experienced a median OS of 47 weeks, compared with 16 weeks for the nonresponder.70 This study was the first evidence in humans to establish personalized patient-specific immune responses against autologous tumor-derived peptides complexed to HSPCC-96. In a subsequent open-label phase II trial, 41 patients with recurrent GBM underwent gross total resection followed by immunization with autologous HSPCC-96 vaccine.71 In that trial, 90.2% of patients were alive at 6 months, and 29.3% were alive at 12 months, with a median OS of 42.6 weeks.71 There were 37 serious adverse effects reported, of which 17 were attributable to the vaccine. Interestingly, 66% of patients who were lymphopenic before vaccine administration demonstrated a significant decrease in OS, with a hazard ratio of 4.0 (95% CI: 1.4e11.8; P ¼ 0.012).71 This trial emphasized that significant lymphopenia before vaccination may influence the outcomes of immunotherapy. There are 2 additional HSPPC-96 completed trials with data pending publication. The first is a phase II trial (NCT00905060) investigating autologous HSPPC-96 vaccine in adults with newly diagnosed GBM undergoing standard-ofcare therapy.72 The second is a phase I trial (NCT02122822) studying HSPPC-96 in patients with newly diagnosed supratentorial gliomas.73 Furthermore, there are 3 ongoing trials, including a phase II randomized trial (NCT01814813)92 comparing the efficacy

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of HSPPC-96 vaccine administered with bevacizumab or bevacizumab given at progression, a randomized double-blind phase II trial (NCT03018288)93 measuring the efficacy of radiotherapy plus TMZ and pembrolizumab with and without HSPCC96 in newly diagnosed GBM, and a phase I trial (NCT02722512)94 evaluating the safety of HSPPC-96 in pediatric patients with newly diagnosed GBM. Dendritic Cell-Based Therapy DCs are essential APCs within the adaptive immune system. These cells engulf and process tumor antigens and express them on their cell surface for presentation to CD8þ and CD4þ T-lymphocytes via MHC I and II, respectively. Interactions between antigenexpressing DCs and T-cells induce a molecular cascade, resulting in a tumor antigen specific immune response. DCs have been used extensively to generate vaccines for experimental use in patients with GBM.74-77 In an early phase I trial, DCs pulsed with autologous tumor peptides were administered to 12 patients with diagnoses of GBM.74 Although a systemic cytotoxic T-lymphocyte response was measurable in 6 patients, this did not translate into increased survival.74 Interestingly, the extent of T-cell infiltration into tumor parenchyma was inversely correlated with TGF-b2 expression and directly correlated with clinical survival (P ¼ 0.047).74 A subsequent phase I trial studied autologous tumor lysate-pulsed DC vaccination in combination with toll-like receptor agonists in 23 patients with GBM.75 Tumor with a mesenchymal gene expression profile demonstrated a greater proportion of CD3þ and CD8þ tumorinfiltrating lymphocytes with respect to GBMs than with other gene expression profiles (P ¼ 0.006).75 Importantly, patients with this genomic signature experienced increased survival compared with historical controls.75 These data suggest that GBMs with a mesenchymal gene expression signature might be more susceptible to immunotherapy. Another phase I/II trial evaluated the immunogenicity of a novel vaccination therapy of a-type 1 polarized DCs attached to synthetic peptides for GAA epitopes (e.g., EphA2, IL-13Ra2, YLK-40), glycoprotein 100 in patients expressing the HLA-A*02 serotype.76 The trial consisted of 22 patients, with 13 GBM patients. Of the GBM patients who were treated with

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this therapy, 58% demonstrated multiple CD8þ T-cell responses.76 After therapy, 4 patients with GBM remained progression free for >12 months.76 More recently, a double-blinded randomized phase I DC-based vaccine trial, known as ICT-107, evaluated the safety and immunogenicity of an autologous DC vaccine pulsed with 6 synthetic class I peptides expressed by gliomas and overexpressed by GSCs.77 This study consisted of 21 patients, including 17 with new diagnoses of GBM, 3 with recurrent GBM, and 1 with brainstem glioma.77 The stem cell antigens included melanoma-associated antigen 1, absent in melanoma 2 protein, tyrosinase related protein-2, gp100, human epidermal growth factor receptor 2, and IL-13Ra2.77 Median PFS and OS in patients with newly diagnosed GBM were 16.9 and 38.4 months, respectively.77 Furthermore, expression of melanoma-associated antigen 1 and absent in melanoma 2 protein in tumors before vaccination correlated with prolonged survival. These promising results led to a phase II trial of ICT-107; however, this trial did not demonstrate improved OS.78 Although currently suspended for financial reasons, a phase III trial of ICT107 (NCT02546102), known as STING, will evaluate the efficacy of combining standard-of-care chemoradiation with autologous DCs pulsed with glioma and GSC-expressed peptides in 414 GBM patients.95 Following a method similar to that used in the ICT-107 trials, the phase I ICT121 trial (NCT02049489) is investigating the safety of using autologous DC pulsed with purified peptides from cluster of differentiation 133 (a known protein essential for GSC maintenance) in treating recurrent GBM.96,121 Recently completed, the GBMVax trial (NCT01213407) is a phase II study that compared the efficacy of autologous DC vaccines with chemoradiation.79 Results of this study are pending. Currently in phase III, the DCVax-L trial (NCT00045968) is the most advanced trial to date in studying autologous DC vaccine therapy for the treatment of GBM.97 The study consists of 331 patients randomized (2:1) after completing surgery and chemoradiotherapy receiving DCVax-L plus TMZ (n ¼ 223) or TMZ alone (n ¼ 99).122 Patients who experienced GBM recurrence were permitted to receive the DCVax-L

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vaccine. Owing to the crossover trial design, approximately 90% of the intent-to-treat study population (n ¼ 331) received the DCVax-L vaccine. Although still ongoing, the first results on survival from the DCVaxL trial have recently been published. For the intent-to-treat population, the median OS was 23.1 months from the date of surgery, which is considerably greater than the median OS of 15 to 17 months typically attained with standard-of-care therapy.122 Remarkably, the median OS for patients with methylated methylguanine methyltransferase was 34.7 months from surgery.122 Moreover, DCVax-L was well tolerated; 2.1% of patients reported having a grade IIIeIV adverse effect.122 Overall, these interim data indicate that the DCVax-L vaccine may significantly prolong OS compared with the current standard of care. Further results are eagerly awaited.

Immunovirotherapy Cytomegalovirus (CMV), a herpes virus, infects 50% to 80% of the adult population; however, it causes clinical consequences in only immunocomprised patients and fetuses.123 Several groups have established that >90% of GBMs express human CMV proteins.124-126 Remarkably, homeostatic brain parenchyma surrounding virusinfected GBM does not express CMV proteins, which suggests that CMV proteins may be TSAs.127,128 Although it is unclear whether CMV plays a role in GBM oncogenesis, basic science data have shown that CMV proteins can induce angioneogenesis, cellular proliferation, and immunologic escape.129 The CMV phosphoprotein 65 (pp65) is expressed in 50% to 70% of GBMs, making this dominant CMV epitope a possible target for antitumor vaccination therapy.127 A small randomized pilot phase I trial in patients with recently diagnosed GBM investigated the efficacy of targeting GBM pp65 as measured by survival outcomes.80 Six patients were administered pulsed DCs with CMV pp65 in combination with tetanus-diphtheria toxoid preconditioning compared with tetanus-diphtheria toxoid alone. Patients who were given tetanusdiphtheria toxoid demonstrated enhanced migration of DCs and a significantly improved median PFS and OS of 10.8 and 18.5 months, respectively, compared with

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controls.80 Furthermore, the experimental group demonstrated 50% survival at 40 months, whereas the control group demonstrated 0% survival.80 Recently, the same group of investigators published the results of a second phase I trial. This trial examined pp65-specific cellular responses in 11 patients who received standard of care (i.e., gross total resection, radiotherapy, dose-intensified TMZ) plus pp65-pulsed DCs, and they evaluated the consequences of long-term PFS and OS.81 The experimental group demonstrated an increase in fraction of T-regs after treatment.81 Survival among the experimental group exceeded that of matched historical controls, with a median PFS and OS of 25.3 and 41.1 months, respectively.81 Four patients remained progression free 59 to 64 months from the time of diagnosis.81 This study demonstrated that in light of an increased T-reg fraction after treatment, patients who received pp65-pulsed DCs experienced long-term PFS and OS. Moreover, this study confirmed previous data signifying GBMexpressed CMV pp65 as a viable antitumor vaccination therapy. The ATTAC-II trial (NCT02465268) is a current phase II trial investigating the efficacy of using pp65pulsed DCs plus standard of care in 150 patients with newly diagnosed GBM.98

Despite highly promising results of phase II trials, no single completed phase III trial to date has demonstrated clinical efficacy of vaccine therapy for GBM in comparison with standard of care. However, interim analysis of the ongoing phase III trial DCVax-L demonstrated favorable results, with a median OS of 23.1 months compared with an average median OS of 15 to 17 months observed in patients treated with standard of care.122 As such, the lack of successful phase III trials may be attributed to a multitude of factors, including intrinsic properties of the vaccine, immunologic status of the host, degree of tumor resection, radiologic imaging dilemmas (e.g., tumor pseudoprogression), and adverse effects of immunotherapy.

imaging (MRI) (with contrast material), whereas chemotherapeutic efficacy, vasogenic edema, and gliosis are preferably visualized with spin-spin relaxation time (T2)weighted MRI (without contrast material).130 Criteria for radiographic response to current standard-of-care treatment of GBM is specified by the Response Assessment in NeuroOncology (RANO) Working Group. This organization has established an international multidisciplinary effort intended to generate endpoint criteria for GBM clinical trials.131 Although such expert guidelines have been put forth, accurate interpretation of posttreatment imaging is still challenging. For example, approximately 20% to 30% of GBM patients may show high contrast on MRI 3 months after treatment; however, such findings may not signify true disease progression but rather a phenomenon known as tumor pseudoprogression.132 In the context of immunotherapy, this phenomenon occurs as a result of immunotherapeutic recruitment of the host’s immune system as a mechanism for targeting GBM cells. An inflammatory response and disruption of the BBB ensues, which manifests radiologically as lesion enhancement suggesting disease progression.132 Identifying true tumor progression from pseudoprogression is essential because true tumor progression leads to the premature termination of immunotherapy. To properly distinguish disease progression from immunotherapyinduced pseudoprogression, experts developed the immunotherapy RANO (iRANO) criteria based on immune-related response criteria and original RANO guidelines (Table 3).133 It should be noted that in cases of tumor pseudoprogression within 6 months after initiation of immunotherapy in neurologically stable patients, the disease should be classified as stable even if restricted viable neoplastic tissue with predominance of gliosis or inflammation is demonstrated on brain biopsy.132,133 The iRANO guidelines serve to assist clinicians in interpreting initial imaging findings suggestive of disease progression with the intention of reducing the premature discontinuation of immunotherapy.

Tumor Pseudoprogression Radiographic assessment of GBM progression is currently based on nuclear spin-lattice time (T1)-weighted magnetic resonance

Adverse Effects of Immunotherapy The majority of GBM immunotherapy trials have shown a favorable safety profile, with

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Table 3. iRANO Criteria: Distinguishing True Disease Progression from ImmunotherapyInduced Pseudoprogression Tumor progression may be confirmed on repeated imaging 3 months after initial imaging if: 1. There are no new or worsening neurologic deficits not attributable to a comorbid event or medication AND 2. It is less than 6 months from the start of immunotherapy If repeated imaging confirms tumor progression, then the date of actual tumor progression must be dated back to the initial date of radiographic progression The advent of new lesions does not necessarily indicate tumor progression less than 6 months from the start of immunotherapy

minimal adverse effects reported. Although each type of immunotherapy can hypothetically exhibit a unique adverse effect profile, several common adverse effects are observed in most trials, most of which are not attributable to the vaccine. Commonly reported adverse effects include fever, malaise, myalgias, arthralgia, diaphoresis, rash, pruritus, flushing, headache, nausea, and vomiting.58,71,75,81 However, significant neurotoxicity resulting from vaccine administration has also been reported. In trials by Rutkowski et al.134 and De Vleeschouwer et al.,135 adjuvant DC-based tumor vaccination caused peritumoral edema, resulting in significant neurologic deficits. Neurologic symptoms were controlled with administration of steroids in both trials. Furthermore, several exceedingly rare adverse effects have been reported, including epididymitis, pneumonia, cerebrovascular accident, and metastasis of GBM to the lungs and lumbar spine, among others.2 The majority of GBM patients in vaccine trials receive both immunotherapy plus standard of care, which includes radiotherapy. Although no GBM vaccine trial to date has reported a higher rate of symptomatic radiation necrosis in the immunotherapy arm, similar trials for the treatment of brain metastases have reported this association.136-138 In fact, Martin et al.136 recently described a significant association between patients receiving immunotherapeutic checkpoint inhibitors and symptomatic radiation necrosis in patients receiving stereotactic radiation for brain metastases (e.g., melanoma, nonesmall-cell lung cancer, renal cell carcinoma). Indeed, if a similar association is found between vaccine-based immunotherapeutics for the treatment of GBM, it may dramatically

change the current treatment paradigm used in GBM immunotherapy trials. FUTURE PERSPECTIVES Immunotherapy is a viable, efficacious approach in treating GBM because of its robust antitumor activity and specific response against neoplastic cells. Nevertheless, neurotoxicity is a significant concern of immunotherapy. Trials have reported patients in whom peritumoral edema develops, triggering varying degrees of neurotoxicity after vaccination.134,135 Nonspecific autoimmune toxicity may be an obligatory yet temporary consequence of activating a host immune response to treat GBM; however, preclinical data have not been able to accurately predict the incidence of neurotoxicity. Indeed, work aimed at anticipating specific patient populations susceptible to the development of neurotoxicity may be beneficial. Clinical trials could use such information for patient selection and to create novel exclusion criteria, reducing morbidity and mortality. By contrast, there are subgroups of patients who experience a greater response to immunotherapy. For example, as detailed earlier, Prins et al.75 established that tumor with a mesenchymal gene expression profile exhibit a greater proportion of CD3-positive and CD8-positive tumorinfiltrating lymphocytes with respect to GBMs with other gene expression profiles. Importantly, patients with this genomic signature experienced increased survival compared with historical controls.67 Furthermore, Liau et al.74 determined that the extent of T-cell infiltration into tumor parenchyma was inversely correlated with TGF-b2 expression and directly correlated with clinical survival (P ¼ 0.047).74 These

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data suggest that a mesenchymal gene expression signature and low TGF-b2 expression could be potential predictors of immunogenic subgroups of GBM patients who are more responsive to immunotherapy.74,75 The ability to predict patient subgroups who are either more responsive to immunotherapy or more susceptible to the development of neurotoxicity will be a significant yet necessary advancement in the field of GBM immunotherapy. There are numerous obstacles in developing vaccine-based immunotherapeutics for GBM, including 1) identifying immunotherapies that are capable of penetrating the BBB, 2) finding highly immunogenic TSAs in GBM, 3) discovering biomarkers to track treatment response, and 4) ensuring that therapies have a high safety profile. Moreover, the constant evolution of the GBM microenvironment and systemic immunosuppression induced by GBM further challenge the development of efficacious immunotherapies. Combining different vaccine therapies with each other and/or with an immune checkpoint inhibitor may improve results compared with single vaccines by offsetting the systemic and local immunosuppression induced by GBM. For example, combining multipeptide vaccines with DC vaccines or multipeptide vaccine with an immune checkpoint inhibitor may be worth further investigation in the future. Personalized peptide vaccinations represent a novel avenue of treatment to increase anticancer immunity while reducing off-target interactions and minimizing adverse effects. Indeed, personalized peptide vaccinations may be the future of GBM immunotherapy. The results of the GAPVAC-101 and NeoVax trials are eagerly awaited. CONCLUSIONS Vaccine-based immunotherapy for GBM is a novel modality that has shown promising results in recent trials. In contrast to current standard-of-care therapeutics, the high specificity of these vaccines permits a safe and effective method for targeting GBM cells. As current clinical trials are seen to completion and additional tumorspecific targets are discovered, we will gain a clearer understanding of the clinical benefits of, and indications for, GBM immunotherapy.

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Conflict of interest statement: The author declares (or authors declare) that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 11 June 2018; accepted 27 August 2018 Citation: World Neurosurg. (2018) 120:302-315. https://doi.org/10.1016/j.wneu.2018.08.202 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.

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