**Application**

**Chapter 4**

**Provisional chapter**

**Impact of Immunotherapy in the Treatment of**

**Impact of Immunotherapy in the Treatment of** 

DOI: 10.5772/intechopen.78603

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Despite the efforts developed in the respective treatment, consisting of maximal surgical resection followed by adjuvant radiotherapy and chemotherapy, the prognosis remains very poor. This may be partly related to the resistance of GBM cells and their infiltrative and invasive nature into the surrounding brain tissue. Therefore, newer and challenging alternative approaches for the treatment have emerged, including immunotherapy. This anticancer therapy, based on the stimulation of the host's immune system, has been currently investigated and several advances in the clinical trial stage have already been reached. Immunotherapeutic strategies comprise a set of modalities, including vaccines (cell-free and cell-based), chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, monoclonal antibodies (mAbs), and oncolytic viruses (OVs). In this chapter, we will review the principal concepts and the recent prog-

**Keywords:** glioblastoma multiforme, immunotherapy, vaccine, antigen, dendritic cell,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Glioblastoma multiforme (GBM), histologically a World Health Organization (WHO) grade IV glioma, is the most common and aggressive malignant brain tumor, accounting for approximately 45–50% of all primary malignant brain tumors. Despite the efforts developed by its current standard therapy (maximal surgical tumor resection followed by concomitant

**Glioblastoma**

and Carla Vitorino

**Abstract**

clinical trial

**1. Introduction**

**Glioblastoma**

Jessica Silva, Ana Miranda, João Sousa,

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Jessica Silva, Ana Miranda, João Sousa, Alberto Pais

Alberto Pais and Carla Vitorino

http://dx.doi.org/10.5772/intechopen.78603

ress in immunotherapy for GBM.

#### **Impact of Immunotherapy in the Treatment of Glioblastoma Impact of Immunotherapy in the Treatment of Glioblastoma**

DOI: 10.5772/intechopen.78603

Jessica Silva, Ana Miranda, João Sousa, Alberto Pais and Carla Vitorino Jessica Silva, Ana Miranda, João Sousa, Alberto Pais and Carla Vitorino

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.78603

#### **Abstract**

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Despite the efforts developed in the respective treatment, consisting of maximal surgical resection followed by adjuvant radiotherapy and chemotherapy, the prognosis remains very poor. This may be partly related to the resistance of GBM cells and their infiltrative and invasive nature into the surrounding brain tissue. Therefore, newer and challenging alternative approaches for the treatment have emerged, including immunotherapy. This anticancer therapy, based on the stimulation of the host's immune system, has been currently investigated and several advances in the clinical trial stage have already been reached. Immunotherapeutic strategies comprise a set of modalities, including vaccines (cell-free and cell-based), chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, monoclonal antibodies (mAbs), and oncolytic viruses (OVs). In this chapter, we will review the principal concepts and the recent progress in immunotherapy for GBM.

**Keywords:** glioblastoma multiforme, immunotherapy, vaccine, antigen, dendritic cell, clinical trial

#### **1. Introduction**

Glioblastoma multiforme (GBM), histologically a World Health Organization (WHO) grade IV glioma, is the most common and aggressive malignant brain tumor, accounting for approximately 45–50% of all primary malignant brain tumors. Despite the efforts developed by its current standard therapy (maximal surgical tumor resection followed by concomitant

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

radiotherapy plus temozolomide (TMZ) chemotherapy), GBM remains an incurable disease with a poor prognosis that attains a median survival of 14.6 months and a mean survival rate of 0.05–4.7% at 5 years, which is partially due to its heterogeneous and invasive nature as well as to the tumor resistance [1–3]. In addition, it is well-known that the protective nature of the blood–brain barrier (BBB) limits the entry of therapeutic agents into the brain and consequently hampers the success of therapies [4].

multipeptide, and heat-shock protein (HSP) vaccines, whose applicability has already been

Impact of Immunotherapy in the Treatment of Glioblastoma

http://dx.doi.org/10.5772/intechopen.78603

67

Cancer peptide vaccines take advantage of peptides to trigger a pharmacological activity through the mobilization of the immune system against tumor antigens [13]. Investigating the expression profile of antigens in human GBM thus becomes the most important step in the process of developing vaccine-directed immunotherapy [14]. In fact, multiple glioma-related antigens have been identified and even tested in vaccine trials over the last years, but only a few reached promising results given the known variable expression patterns of proteins/ antigen among GBM patients [14, 15]. These vaccines may incorporate a single or multiple, long or short peptides acting as tumor antigens, which are often coupled to carrier proteins in order to potentiate their immunogenicity [15, 16]. Although being a recent treatment modality in oncology, GBM has already a varied range of successfully proven vaccines, many of them

Considering the frequent amplification of epidermal growth factor receptor (EGFR) and its active mutant EGFRvIII in GBM, many researchers have focused their works on developing EGFRvIII vaccines with remarkable clinical results. For instance, rindopepimut (also called Rintega® and CDX-110) was subjected to a number of phase I/II CT since its introduction (VICTORI, pediatric pontine glioma pilot study (NCT01130077), ACTIVATE (NCT00643097), ACT II, ACT III (NCT00458601), and ReACT (NCT01498328)), where its clinical efficacy was clearly shown in patients with GBM. Such vaccination resulted in prolonged progressionfree and overall survival (OS) with no safety concerns. However, a phase III CT (ACT IV (NCT01480479)) with rindopepimut was discontinued since the study failed to meet its primary OS endpoint [7, 17, 18]. Another example is a live attenuated *Listeria*-based vaccine (ADU-623) expressing both EGFRvIII and NY-ESO-1 antigens, which is currently being tested

Despite the increased interest in EGFRvIII, other antigens have been considered for the investigation of immunotherapy in GBM, with emphasis on SurVaxM, PEPIDH1M, and DSP-7888 vaccines. SVN53-67/M57 (SurVaxM), a peptide vaccine derived from survivin, not only has revealed promising results in preclinical studies with GL261-bearing mice but has also been investigated in CT (phase II so far (NCT02455557)) [11, 18, 19]. Since isocitrate dehydrogenase 1 (IDH1) is an enzyme commonly mutated in GBM, it has been developed IDH1 peptide vaccines for patients with glioma positive for IDH1 R132H mutation (presented in 5–12% of GBMs). Currently, two phase I CT are being conducted for that purpose, called RESIST trial (NCT02193347) with PEPIDH1M vaccine and NOA-16 (NCT02454634), both of which target patients with IDH1R132H-mutated gliomas [15, 20]. Another developing peptide vaccine uses the tumor-associated antigens (TAA) Wilm's tumor protein-1 (WT-1), recognized as an oncogene expressed in GBM responsible for tumor growth. WT1 peptide vaccination has been investigated through several phases I/II CT, alone or in combination with other therapeutics, including TMZ. Overall, the results of these WT1 based vaccines have been positive, confirming their safety profile along with good clinical

in patients with recurrent GBM through a phase I CT (NCT01967758) [11, 18].

developed for GBM [11–13].

*2.1.1. Peptide and multipeptide vaccines*

peptide/multipeptide vaccines [11].

Recently, new and promising immunotherapeutic approaches have emerged and evidenced a great impact in GBM treatment, harnessing the ability of the host's immune system to induce or enhance antitumor responses [2, 5]. These immunotherapeutic strategies are related with both active immunotherapy, such as vaccines (cell-free and cell-based), and passive immunotherapy, namely monoclonal antibodies (mAbs), immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy and oncolytic viruses (OVs). Despite the presence of the BBB, such strategies can be successful by considering some key points. If immunotherapy is intended to be given intravenously, the BBB is effectively a problem, but likely to be exceeded. On the one hand, it is noteworthy that patients with GBM tend to have a fenestrated endothelium with BBB disruption, which will possibly facilitate the passage of immunotherapeutic cells. On the other hand, there are already mechanisms to induce a reversible BBB opening with a transiently increase in the respective permeability. Nonetheless, there is currently an easier and more effective approach, which consists of direct intracranial injection of immunotherapeutic agents, thus overcoming the problems associated with the BBB [4, 6].

Regardless the low number of clinical trials (CT) that are completed to date, the early results reached for all of these strategies are generally related with positive patient outcomes, which has increased the interest in proceeding with the investigations. This chapter provides a brief description and the currently ongoing CT of all of these therapies, with particular emphasis on vaccines. In fact, vaccination represents a valuable therapeutic option in cancer since it can induce widespread and sustained antitumor effects, with less toxicity than standard chemotherapy [7, 8].
