Abstract: Glioblastoma (GBM) is the most aggressive primary brain tumor. Combination therapy with surgery, radiation, and chemotherapy is not curative at present and carries a significant risk of toxicity. Advancements in the knowledge of tumor biology and tumor microenvironment have led to the development of novel targeted therapies for glioblastoma. In the past 15 years, a vast amount of pre-clinical data has been generated for glioblastoma immunotherapy. Translating these promising results into the clinic is, however, still an evolving process. Early clinical trials have demonstrated the feasibility and safety of several such approaches in patients with recurrent as well as newly diagnosed glioblastoma. Both passive as well as active immunotherapeutic modalities have also shown potential clinical benefit in at least a subset of these patients. This brief review discusses 'why' and 'how' various types of immunotherapies are being employed to treat glioblastoma.
Glioblastoma (GBM) is the most common primary brain tumor in adults with the annual incidence of over 17,000 in the United States (Grossman et al., 2010; Omuro and DeAngelis, 2013). Despite the considerable improvements made in the conventional therapy for glioblastoma over the recent years, prognosis remains extremely poor with a median survival of 18 to 21 months (Finlay et al., 1995; Grossman et al., 2010; Johnson et al., 2012). Complete tumor resection is difficult owing to the diffusely infiltrative nature of the tumor (Grossman et al., 2010). Concomitant and adjuvant chemotherapy with the alkylating agent temozolomide along with radiation has only been shown to improve median survival by 2.5 months (Stupp et al., 2005). In the past decade, substantial amount of progress has been made in dissecting the glioblastoma biology in relation to its microenvironment as well as the host immune system. This has paved the way for researchers to explore novel targeted immunotherapeutic approaches that have the potential to improve cure rates with minimal toxicities, due to sparing of the surrounding normal brain structures. Here we review the advances made in some of the passive and active immunotherapeutic strategies for glioblastoma.
Targeted Immunotherapy with Monoclonal Antibodies (mAb)
Monoclonal antibodies (mAb) recognize specific antigens present on the tumor cell surface in a Major Histocompatibility Complex (MHC)-unrestricted manner and induce cell death by a host of immune and non-immune mediated mechanisms. Safe and effective anti-tumor therapy with monoclonal antibodies (mAb) requires that the target antigen be confined to the tumor and its microenvironment with absent or very low frequency of expression on normal tissues. Glioblastomas are known to be highly vascular tumors that secrete pro-angiogenic factors like vascular endothelial growth factor (VEGF) (Huang et al., 2005). VEGF is a key regulator of angiogenesis and is known to play a major role in tumor growth (Folkman, 1971; Hicklin and Ellis, 2005). VEGF production is increased under hypoxic conditions, e.g., in rapidly growing tumors with necrotic centers and its over-expression appears to correlate with poor prognosis (Carmeliet, 2005; Huang et al., 2005). VEGF receptors (VEGFR-1, VEGFR-2, and VEGFR-3) belong to a family of platelet derived growth factor tyrosine kinase receptors (PDGFR) that upon binding with its ligand activates downstream signaling leading to angiogenesis and increased vascular permeability (Karkkainen and Petrova, 2000; Petrova et al., 1999). Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody that neutralizes the biologic activity of isoform VEGF-A by blocking its binding to VGFR-1 and VGFR-2 on tumor endothelial cells (Ferrara et al., 2005). Bevacizumab, either as a single agent or in combination with irinotecan was shown to be effective for recurrent glioblastoma (Friedman et al., 2009; Kreisl et al., 2009). Multiple ongoing clinical trials are further testing the therapeutic efficacy of bevacizumab as a single agent as well as in combination with other cytotoxic agents and/or radiation (Table 1). Though recent evidence suggests the permeability of blood brain barrier (BBB) to intravenous bevacizumab (Friedman et al., 2009; Kreisl et al., 2009), the use of the intra-arterial route is being investigated as well (Table 1).
Epidermal growth factor receptor (EGFR) gene mutation is a frequent finding in glioblastoma with a deletion mutation EGFRvIII (epidermal growth factor receptor variant III) being the most common (Aldape et al., 2004; Smith et al., 2001; Wong et al., 1992). Mutated EGFRvIII is a transmembrane glycoprotein that is expressed in 20 to 30% of GBMs (Moscatello et al., 1995) and has constitutive tyrosine kinase activity that plays an important role in tumorigenesis and development of chemoresistance (Nagane et al., 1996; Nishikawa et al., 1994). Recombinant human/mouse chimeric anti-EGFRvIII mAb cetuximab was found to be well tolerated when given intravenously in patients with recurrent GBM with encouraging results (Hasselbalch et al., 2010). However, combination therapy with cetuximab and bevacizumab/irinotecan was not found to be superior to bevacizumab and irinotecan alone (Hasselbalch et al., 2010). Safety and efficacy of intra-arterial infusion of cetuximab alone and in combination with bevacizumab is now being investigated (Table 1). Another anti-EGFRvIII antibody nimotuzumab has completed phase III trial and results are expected (NCT00753246). AMG 595, an immunoconjugate of anti-EGFRvIII human mAb with a cytotoxic agent maytansinoid DM1, is currently in a phase I trial (NCT01475006). Binding of the mAb to the EGFRvIII on tumor cell surface leads to internalization and disruption of the microtubule by maytansinoid DM1 resulting in inhibition of tumor cell proliferation. Nivolumab is a fully human mAb that blocks the activation of negative immunoregulatory cell surface receptor PD-1 (programmed death-1) by its ligands, PD-L1 and PD-L2, leading to activation of cytotoxic T-lymphocytes (CTLs) against tumor cells (Robert et al., 2013; Wolchok et al., 2013). Efficacy of nivolumomab is currently being tested in combination with ipilimumab (NCT02017717), a mAb that enhances T-cell activation by binding cytotoxic T-lymphocyte-associated antigen-4 (CTLA4; CD152) thus offsetting its inhibitory effect that is mediated through CD80 (B7-1) and CD86 (B7-2) (Robert et al., 2013; Wolchok et al., 2013).
Induction of In Vivo Anti-tumor Response Using Tumor Vaccines
For active specific immunotherapy of glioblastoma, autologous dendritic cells (DCs) are most commonly used as antigen presenting cells (APCs). In addition to being the most powerful activators of innate and adaptive immune system, DCs have been shown to activate Natural Killer (NK) cells and NK T cells (Dhodapkar et al., 2004; Rock et al., 1990; Vidard et al., 1996). Peripheral blood monocyte (PBMC)-derived DCs obtained from GBM patients by leukapheresis are pulsed ex vivo with tumor lysates or acid eluted membrane peptides, or by fusing the DCs with tumor cells (De Vleeschouwer et al., 2008; Liau et al., 2005; Wheeler et al., 2008; Yamanaka et al., 2005; Yu et al., 2001). Tumor antigen-loaded DCs are injected into the patient, most often intradermally, though other routes of administration (i.e., subcutaneous and intravenous) have been explored. Injected DCs then migrate to the lymph nodes to activate tumor antigen specific cytotoxic T lymphocytes (CTLs) in vivo, and induce sustained anti-tumor response in the host by forming immunological memory (de Vries et al., 2005; Morse et al., 1999).
Researchers have made considerable progress in translating the glioma vaccine therapy from the bench to the bedside. DC vaccines for glioblastoma have been well tolerated in early clinical trials with considerable efficacy (Bregy et al., 2013; Chang et al., 2011; Cho et al., 2012; Phuphanich et al., 2013; Yu et al., 2004; 2001). Most of the current clinical trials are designed to further test their efficacy and answer the key questions, such as ideal time interval between vaccines and the total duration of therapy required to sustain the host anti-tumor response (Table 2). As most immunotherapeutic approaches for cancer are known to be beneficial in the setting of minimal disease burden, post-operative adjuvant therapy with DC vaccines has been investigated. Improved PFS (progression free survival) and OS (overall survival) was reported following vaccination with autologous, mature, tumor lysate-loaded DC as an adjuvant therapy after reoperation (HGG-IMMUNO) in patients with relapsed GBM (n=56; 7 to 77 years of age) (De Vleeschouwer et al., 2008). Total resection and younger age were shown to be the predictors of better outcome with trend to improved PFS with faster DC vaccination schedule (De Vleeschouwer et al., 2008). A phase I study being conducted in collaboration with the HGG-IMMUNO group to investigate the anti-tumor immunity following intradermal injection of autologous DC vaccine with imiquimod (immune response modifier) after surgical resection is currently recruiting patients (NCT01808820). Rindopepimut, a peptide vaccine which evokes humoral and cellular immune response against EGFRvIII, has demonstrated improved PFS and OS with minimal side effects in adults with glioma (Heimberger et al., 2003; Sampson et al., 2009) and is currently being tested in a randomized phase III trial for adults with newly diagnosed GBM (NCT01480479). Recently, there has been a tremendous amount of interest in targeting cancer stem cells (CSCs) as they are believed to lead to tumorigenesis in the human brain and to play a key role in chemoresistance/radioresistance seen in glioblastoma, and in tumor recurrence (Altaner, 2008; Bao et al., 2006). Safety of autologous DC vaccine against CD133, the stem-like cell marker expressed in the glioblastoma cells, is currently being tested in a first-in-man trial (NCT02049489). Single antigen based vaccines carry the risk of creating target-antigen negative tumor cell variants (Sampson et al., 2010), whole tumor cell derived multi-peptide vaccines consisting of a panel of tumor-associated antigens (TAAs) along with some non-specific antigens are hence preferred (Van Gool et al., 2009). While the risk of inducing immune response against normal host tissues is a consideration with this strategy, none has been reported in GBM trials so far.
Passive Immunotherapy with Adoptive Cell Transfer
Adoptive cell transfer involves directly transferring effector immune cells to a host in order to induce anti-tumor activity. These ex vivo-generated effector cells may be innate immune cells or cells capable of more specific cell recognition. Nonspecific effector cells such as NK cells and lymphokine-activated killer (LAK) cells react innately as they recognize cell surface abnormalities, such as low expression of MHC class I molecules or carbohydrate abnormalities. T cells recognize foreign peptides presented on the cell surface by MHC molecules. While T cells specific for tumor antigens can be identified within the tumor tissues or elsewhere, most are present at a low frequency and many have receptors with low avidity for the tumor antigens, and are commonly anergic. An alternative strategy is to activate T cells ex vivo to circumvent these limitations and to overcome suppressive factors present in vivo, thus augmenting the anti-tumor activity (June, 2007). It is necessary to enrich for anti-tumor cells with the appropriate properties or to redirect the specificity of a non-tumor-specific population that can then be expanded to large numbers ex vivo for subsequent adoptive transfer. In addition, the host can be manipulated before adoptive cell transfer to provide an optimal environment for the transferred cells. In general, the transfer of ex vivo generated effectors could potentially overcome some of the current limitations of other targeted immunotherapies since T cells can expand, actively migrate through microvascular walls and penetrate the core of solid tumors to exert their antitumor activity (Marras et al., 2003; Plautz et al., 2000; Tsuboi et al., 2003).
Early work introduced NK cells, lymphokine activated killer cells (LAKs), and γδ T cells as ways to expand and activate the immune system and tip the balance towards an antitumor effector function in the face of a substantially immunosuppressive tumor microenvironment. LAK cells have been safely administered within the CNS resulting in improved long term survival in adult patients with recurrent glioma (Hayes et al., 1995). In a phase II trial of adult patients with GBM (n=33) treated with intralesional autologous LAK cells after initial primary treatment, those with higher doses of LAK cells had longer survival, and overall survival was encouraging compared to controls (Dillman et al., 2009). Ex vivo activation of tumor-draining lymph node cells induces potent effector function (Porter et al., 2011). This strategy has been used in patients with recurrent and newly diagnosed malignant glioma after surgery and radiation therapy. Several objective clinical responses were noted in both adult and pediatric patients with no significant toxicity (Plautz et al., 2000; Peres et al., 2008). Intracavitary administration of allogeneic mixed reactive T cells for recurrent gliomas (n=5) has shown promising results and the benefits of intra-tumoral administration is being studied (Kruse et al., 1997; Wang et al., 2008).
Over time, adoptive cell therapies for the treatment of glioblastoma have evolved from being relatively non-specific to tumor-specific, and most current clinical trials utilize targeted approaches such as virus specific cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR)-modified T cells (Table 3). T cells recognize targets through an antigen-specific T-cell receptor (TCR) and engage with their target when presented in the context of a matching MHC molecule. Developing successful CTL therapies depends on the availability of tumor-associated antigens (TAAs) as targets, their successful processing and presentation by professional APCs, and efficient methods for T-cell activation and expansion. Both viral antigens and TAAs can be used as such targets. Several TAAs have been validated as therapeutic targets in GBM and are actively being studied for potential clinical application (Saikali et al., 2007; Wykosky et al., 2008; Zhang et al., 2008). CD133 is one such TAA of interest in CTL therapy for glioblastoma; CD133+ CTLs have been shown to be cytotoxic to glioma stem cells (Hua et al., 2011). A large percentage of GBM have been shown to express the cytomegalovirus (CMV) immunodominant proteins pp65 and IE1-72 as well as CMV nucleic acid has been detected in GBM cells by in situ hybridization (Cobbs et al., 2002; Mitchell et al., 2008; Scheurer et al., 2008). CMV-specific CTLs expanded ex vivo from CMV seropositive GBM patients have been shown to recognize and kill CMV-expressing autologous tumor cells (Louis and Brenner, 2009). This has prompted the use of CMV specific CTLs as a therapeutic modality in phase I trials (NCT00693095; NCT01205334; NCT01109095).
Genetic modification of T cells with chimeric antigen receptors (CARs) can also be employed as highly targeted therapies using adoptive cell transfer (Figure 1). CARs are artificial molecules custom made by fusing an extracellular variable domain usually derived from a high-affinity monoclonal antibody specific for a TAA of interest to an intracellular signaling domain derived from the ζ-signaling chain of the TCR (Eshhar et al., 1993). The intracellular signaling domain is responsible for activating the T cell upon encountering the specific antigen. CARs recognize antigens in an HLA-independent manner and hence are able to circumvent some mechanisms by which tumors evade immune-recognition, such as down regulation of MHC molecules (Sadelain et al., 2003). CAR T cells have been shown to be effective even when target antigens are modestly expressed on tumor cells likely because they can multiply in response to antigen encounter and can recruit other effectors as well as additional components of the immune system amplifying the antitumor immune response (Ahmed et al., 2009). In addition, they broaden the range of antigens recognizable by T cells to include carbohydrate and glycolipid antigens. T cells expressing CARs can be reliably generated in a relatively short time for clinical usage, typically 10-15 days (Pule et al., 2003). CAR-modified T cells have been effectively generated against some of the glioma-associated antigens including IL-13 receptor alpha 2 (IL13Rα2), human epidermal growth factor receptor 2 (HER2), ephrin type A receptor 2 (EphA2), and epidermal growth factor receptor variant III (EGFRvIII) (Choi et al., 2014; Liu et al., 2004; Jarboe et al., 2007; Morgan et al., 2012; Wang et al., 2008). HER2-specific CAR T cells generated from GBM patients recognized autologous HER2-positive tumor cells, including their CD133-positive stem cells in vitro, and had potent antitumor activity against autologous xenografts in orthotopic models of human glioblastoma (Ahmed et al., 2010). A clinical trial of CMV-specific CTLs modified to express HER2-specific CARs is currently underway (NCT01109095). T cells engineered to target IL13Rα2 have also shown tumor recognition and anti-tumor effector function (Kahlonn et al., 2004; NCT00730613). IL13Rα2 is currently being explored in a clinical trial by infusion of autologous CAR T cell clones into resection cavities of adult GBM (NCT01082926). Further, a phase I/II trial is investigating the safety and effectiveness of autologous CARs targeting EGFRvIII in adults with glioblastoma (NCT01454596).
Developing an Effective Immunotherapy for Glioblastoma: Challenges Involved
Though the pre-clinical data for adoptive glioblastoma immunotherapy has been largely promising, several obstacles, some posed by glioma cells or their microenvironment and others intrinsic to the immunotherapy products, limit their clinical efficacy. Glioblastoma cells are considered to be poor APCs. They have inadequate phosphorylation and cytoskeletal rearrangements which are required for appropriate APC to T-cell contacts and stimulation of an immune response. T cells obtained from patients with gliomas do not make sufficient contact with APCs and consequently are not appropriately stimulated (Dix et al., 1999). Tumor cells can, directly or by influencing the tumor microenvironment to play a protumoral role, manipulate the host’s immune response for tumor-protective effects. T cells in the microenvironment and their impact on tumor growth may depend heavily upon the particular tumor infiltrating lymphocyte (TIL) subset. It is fairly agreed upon that the majority of CD4+ T cells favor tumor progression, while CD8+ T cells favor tumor rejection in GBM (Byrd et al., 2012). Regulatory T cells inhibit the effect of T cells against tumor antigens (Heimberger et al., 2003). Cytokines produced by tumors stimulate increased helper T-cell and decreased regulatory T-cell function that decreases natural tumor immunity (Sonabend et al., 2012). Secretion of inhibitory factors such as transforming growth factor beta (TGFβ) by the tumor microenvironment can have inhibitory effects on the immune system and can allow cancers to proliferate and become more invasive (Grauer et al., 2007; Heimberger et al., 2008; Kuppner et al., 1989; Nakano et al., 2006; Platten et al., 2001; Siepl et al., 1988). The in vivo induction of antigen-specific T cells using antigen loaded DC is often not reproducible, because tumor-specific T cells are either present at very low frequency due to relatively weak immunogenicity of TAAs or are anergized (Marras et al., 2003; Plautz et al., 2000; Tsuboi et al., 2003). Down-regulation of MHC molecules may limit the effectiveness of tumor vaccine induced cellular immune response as well (Dunn et al., 2004). Problems such as limited in vivo expansion following infusion of cellular products are being resolved by optimizing the cellular product (for example including enhanced signaling domains in CAR T cells or infusion of more naïve phenotypes of effectors) and/or optimizing the host by strategies such as lymphodepletion or co-administration of immuno-stimulatory cytokines.
In addition to having variable antigen expression between patients, glioblastoma cells in any individual patient exhibit great heterogeneity and targeted therapies can become ineffective over time as tumors develop antigen escape variants. This could develop because of the high mutation rate in glioblastoma, but might be intrinsic to the tumor cell or induced by selective survival of target negative tumor cells after therapy. Overcoming this mechanism of resistance will be necessary to improve response in patients. There are strategies in the development that could offset antigen escape by co-targeting multiple TAAs, such as use of whole tumor cell derived DC vaccines and using cellular products grafted with multiple CARs (Hegde et al., 2013) or TanCAR, a bispecific CAR molecule that can simultaneously target two TAAs (Grada et al., 2013). The presence of BBB provides challenges in using systemically administered immunotherapy strategy for the treatment of glioblastoma. This barrier also provides immune privilege that makes utilizing host immune responses in treatment of these malignancies challenging (Doolittle et al., 2005). While many studies utilize direct injection of cells to the tumor site to bypass BBB, intravenous, intra-arterial, intranodal, intradermal, and intranasal injections are other options. Investigative comparison of these delivery strategies should be performed to reach the optimal delivery route for effective GBM immunotherapy modalities.
Developing an effective targeted immunotherapy for glioblastoma has been a considerable challenge due to disease heterogeneity and hostile environment the tumor creates for the immune system. Despite the obstacles, remarkable progress has been made in the field in the past decade. While early clinical trials of these targeted approaches have shown encouraging results in terms of efficacy and safety, substantial testing needs to be undertaken before these novel treatment modalities can be made available as standard therapies across the centers that treat patients with glioblastoma.
Authors have funding support from the Alliance for Cancer Gene Therapy (ACGT, Inc.), Alex’s Lemonade Stand Pediatric Cancer Foundation (ALSF), CureSearch for Children’s Cancer, Children’s Cancer Research Fund, and the Stand Up to Cancer (SU2C)-St. Baldrick’s Pediatric Cancer Dream Team Grant.
The Center for Cell and Gene Therapy (CAGT) has research collaboration with Celgene Inc., to develop chimeric antigen receptor (CAR)-based therapeutics that is administered by Baylor College of Medicine. M.H. and N.A. have patent applications in the field of T-cell and gene-modified T-cell therapy for cancer.
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