IMR Press / JMCM / Volume 2 / Issue 4 / DOI: 10.31083/j.jmcm.2019.04.4201
Open Access Review
Molecular and immunological rationale for the use of tyrosine kinase inhibitors and immune checkpoint inhibitors in glioblastomas
Show Less
1 Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), Italy
J. Mol. Clin. Med. 2019, 2(4), 111–123; https://doi.org/10.31083/j.jmcm.2019.04.4201
Submitted: 30 August 2019 | Accepted: 13 December 2019 | Published: 20 December 2019
Abstract

Glioblastoma (GBM) is the most frequent and invasive tumor of the central nervous system. Maximal surgical resection followed by radiotherapy with concomitant and adjuvant chemotherapy with temozolamide is the standard of care first-line treatment used for GBM. However, increased patient survival based on this first-line treatment is limited, and tumors invariably recur. At recurrence, most common treatment options are further surgical resection, conventional chemotherapy, or the use of the anti-vascular endothelial growth factor (VEGF) agent, bevacizumab. The tumor microenvironment (TME), which is composed of the extracellular matrix, interstitial fluid and stromal cells, including astrocytes, macrophages and endothelial cells, is a key regulator of GBM progression and therapeutic drug resistance. A peculiar feature of the TME in GBM is the blood-brain-barrier (BBB), a semipermeable membrane of endothelial cells connected by tight junctions, capable of preventing the passage of the majority of the pharmaceutical compounds to the GBM tumor. The TME is characterized by an immunosuppressive state with few tumor-infiltrating lymphocytes (TILs) and other cells activating the immune system. The comprehensive characterization of the molecular landscape of somatic genomic alterations of GBM has lead to the identification of a plethora of mutated genes as well as of abnormal rearrangements of several receptors including the epidermal growth factor receptor and platelet derived growth factor receptor α. This has allowed the introduction of novel therapies, including the use of tyrosine kinase inhibitors (TKIs). Moreover, the use of immune checkpoint inhibitors (ICIs) has been successfully introduced in numerous advanced cancers, as well as encouraging results have been obtained that endorse the use of these antibodies in untreated brain metastases from malignant melanoma and from non-small cell lung cancer. Programmed cell death protein (PD-1) receptor/programmed death ligand 1 (PD-L1) inhibitors has been also proposed for GBM treatment. TME, mutational landscape and clonal evolution of GBM tumors are key factors of paramount importance for the efficacy of TKIs and ICIs used in the treatment of GBM. The current review summarizes the principal molecular and TME features of GBM providing the rationale for the use of TKIs and ICI immunotherapy. The main targeted therapies with TKIs and approaches using ICIs, that have been recently proposed, are also discussed.

Keywords
GBM
tumor microenvironment
tyrosine kinase inhibitors
immune checkpoint inhibitors
1. Introduction

Glioblastoma (GBM) is the most frequent and invasive tumor of the central nervous system (CNS) [1-3]. According to the recent update of the World Health Organization (WHO) [2], GBM belongs to the group of diffuse astrocytic and oligodendroglial tumors. Genetic alterations affecting neuroglial stem cells or progenitor cells seem to be involved in GBM pathogenesis [4-6]. The incidence of this tumor increases with age: median age at diagnosis is 65 years. GBM tumors affect 1.7-fold more often males than females. The WHO subdivides GBM into two major types according to the presence of mutations in the isocitrate dehydrogenase (IDH) 1 and IDH2 genes. GBM with wild type IDH accounts for > 90% of cases [2]. Clinically, the majority of patients present de novo grade IV lesions (i.e. primary GBM), while a minority of patients progresses from a less aggressive form of WHO grade II diffuse astrocytomas and WHO grade III anaplastic astrocytomas (i.e. secondary GBM) [2,7]. Prognosis and age of onset are different between primary GBM and secondary GBM. Primary GBM is typically diagnosed at older age with a worse prognosis in terms of overall survival (OS) [2,7]. In general, GBM patients display a median OS of about 15 months when undergoing to the canonical first-line treatment consisting of maximal surgical resection, followed by radiotherapy with concomitant and adjuvant chemotherapy, e.g. the oral alkylating agent, temozolomide (TMZ) [3,8-10]. The extension of patient survival after TMZ is limited with an average interval of about 2.5 months, and tumors invariably recur [3,8-10]. Following the first recurrence, treatment options are represented by further surgical resection when possible, or by conventional chemotherapy, e.g. TMZ (with different dosing schedules), nitrosoureas, and by treatment with the anti-vascular endothelial growth factor (VEGF) agent, bevacizumab [11,12]. However, these treatments have not shown any significant survival improvement in terms of patient survival [9,10,13]. The post-bevacizumab progression is often based on bevacizumab plus chemotherapy association, again without significant survival improvement [11,12,14]. Recently, the tyrosine kinase inhibitor (TKI) regorafenib has been introduced for the treatment of recurrent GBM [15].

A comprehensive molecular characterization of GBM tumors has allowed the proposal of novel therapies, such as TKIs [16-20]. Moreover, immune checkpoint inhibitors (ICIs) have been successfully proposed in several cancers including malignant melanoma [21,22] and non-small-cell lung carcinoma (NSCLC) [23-25], and encouraging results have emerged for their use in untreated brain metastases of the same tumors [26]. These results have lead to the introduction of programmed cell death protein (PD-1) receptor/programmed death ligand 1 (PD-L1) inhibitors for GBM treatment [27-34].

In the current review, we summarize the principal molecular and tumor microenvironment (TME) features of GBM providing the rationale for the use of novel targeted therapies and immunotherapy approaches using ICIs for the treatment of GBM-bearing patients. Moreover, the main targeted therapies and approaches using ICIs, that have been recently proposed, are also discussed.

2. Tumor microenvironment

GBM is characterized by a diffuse invasion pattern [35]. Microscopic tumor invasion frequently spreads beyond irradiated regions according to radiotherapy protocols [36]. These infiltrating tumor cells are generally enriched in the stem cell fraction of GBM tumor cells (GSCs) that can make propagation of the tumor easier [37]. The GSCs are characterized by a high refractoriness to chemotherapy, thus driving tumor recurrence and chemoresistance [37]. On the other hand, GBM tumors rarely metastasize in distant organs [38,39].

The tumor microenvironment (TME) is one of the main actor involved in tumor progression. GBM TME is characterized by the presence of an extracellular matrix (ECM), of an interstitial fluid and of various stromal cells including astrocytes, macrophages and endothelial cells [38,39]. Peculiar features of the TME in GBM are the blood-brain-barrier (BBB) and the presence of myelinated and interconnected axon tracts as well as specific features of the ECM [38-41]. Normal brain ECM is enriched in glycoproteins, glycosaminoglycans such as hyaluronic acid and proteoglycans [42,43]. Hyaluronic acid is mainly localized in the intraparenchymal region, and it is involved in tissue mechanics, organization and hydration. On the other hand, collagen and fibronectin are frequently distributed. In GBM tumors, there is an alteration of the ECM components with a 3-4-fold increment in the presence of glycosaminoglycans with respect to normal tissues. Astrocytes and oligodendrocytes are the major ECM producers in normal tissues. GBM cells can generate a pro-invasive matrix and induce the production of specific ECM components by stromal cells [44]. The BBB is a semipermeable membrane of endothelial cells of the capillary wall connected by tight junctions. While it allows the passage of factors crucial for the neural function, it is capable of preventing the passage of the majority of drugs to the tumor site, thus limiting the achievement of therapeutic drug concentrations [45,46]. Although during tumor progression the BBB can lose its integrity, it remains impassable for the majority of chemotherapeutic drugs, particularly in the still intact invading tumor regions [47,48]. Moreover, the presence of interconnected axon tracts represents one of the main limits for surgical resection [40,49,50].

GBM tumors are characterized by hypervascularity with an increment in angiogenesis with respect to normal brain tissues. The tumor neo-vasculature is not completely formed, with leaky vessels, augmented interstitial fluid pressure, and hypoxia [51-55]. GBM tumor cells are capable of invading parenchyma and remodel the surface of myelinated tracks. GBM tumor cells are also capable to rapidly invade vasculature. Invasion of GBM tumor cells can be driven by cellular signaling through the surface receptors CD44 and receptor for hyaluronan-mediated motility (RHAMM) that is activated by hyaluronic acid [56-60].

The CNS exhibits several peculiar features compatible with the condition of immune-isolation, such as the presence of tight junctions in the BBB and the absence of a classic lymphatic drainage system, nevertheless there is the presence of functional lymphatic vessels, and of different types of antigen-presenting cells (APCs), including microglia, macrophages, astrocytes and canonical APC such as dendritic cells (DCs) [60,61]. Moreover, activated T cells can invade the CNS. On the other hand, antigens can be presented locally or in the draining cervical lymph nodes (Fig. 1). However, with respect to other tumor types, GBM tumors display low numbers of tumor-infiltrating lymphocytes (TILs), frequently with an exhausted phenotype, as well as low numbers of the other immune stimulative cell types [60]. This reduced quantity and limited activity of T cells in GBM can be ascribed to the peculiar immune environment of the brain [38, 39, 62, 63], with a plethora of immunosuppressive mechanisms at both the molecular and cellular levels [64]. In particular, high levels of the immunosuppressive cytokines transforming growth factor β (TGFβ), interleukin-10 (IL-10) are produced by stromal cells of the brain in response to inflammatory stimuli, such as those from GBM tumor cells [65, 66]. Moreover, indolamine 2,3-dioxygenase (IDO) produced by tumor cells, stimulates the accumulation of regulatory T (Treg) cells. T cell proliferation and function can also be inhibited by microglia and tumor- infiltrating myeloid cells [67, 68].

Figure 1.

Interactions of immune checkpoint inhibitors (ICIs) in lymph nodes and in the GBM tumor microenvironment. Cytotoxic T lymphocyte protein 4 (CTLA-4), expressed on the surface of Tregs, is able to inhibit T cells activity by competing with CD28 for the binding of their shared ligands B7-1/2 (CD80/CD86). CTLA-4 blockade mainly acts by targeting CTLA-4-expressing Tregs in lymph nodes. Programmed cell death protein receptor (PD-1)/programmed death ligand 1 (PD-L1) blockade can overcome the T cell exhaustion and reverse the immunosuppression of the tumor microenvironment (TME) by blocking immune checkpoint molecules in the context of the TME of GBM. Abbreviations: Treg, regulatory T cell, DC, dendritic cell, CTLA-4, cytotoxic T lymphocyte protein 4, PD-1, programmed cell death protein receptor; PD-L1, programmed death ligand 1.

The process of T cell-mediated immunity is defined by an interplay of stimulatory and inhibitory signals capable of promoting adaptive responses against foreign antigens but also of avoiding autoimmunity. By counteracting activating signaling, immune checkpoints exert a key role in central and peripheral tolerance [69]. In fact, under physiological conditions, immune checkpoint molecules represent a negative feedback to regulate inflammatory responses following T cell activation [70-74]. The expression of checkpoint molecules, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and PD1, represents a mechanism used by tumors, including GBM, to inhibit and escape the anti-tumor immune response. CTLA-4 is exclusively upregulated in T cells. CTLA-4 is capable of competing with the costimulatory molecule CD28 for the binding of the B7 ligands, with a negative regulatory effect in the early stages of T cell activation. PD-1 belongs to the B7/CD28 costimulatory receptor family expressed on DCs, natural killer (NK) cells, activated T cells, B cells, and monocytes. The main ligand of PD-1, PD-L1 is expressed on hematopoietic cells, microvascular endothelium cells and parenchyma cells of different organs [74-76]. PD-1 acts at multiple phases of the immune response modulating T cell activity in the peripheral tissues, including the tumor site [75-85].

3. Mutational landscape and clonal evolution of GBM

In the last years, the genomic landscape of untreated GBM tumors has been investigated. Several genes have been found mutated in GBM including phosphatase and tensin homolog (PTEN), tumor suppressor P53 (TP53), epidermal growth factor receptor (EGFR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1), neurofibromin 1 (NF1), retinoblastoma 1 (RB1), IDH1, platelet derived growth factor receptor alpha (PDGFRA), leucine zipper like transcription regulator 1 (LZTR1), spectrin alpha, erythrocytic 1 (SPTA1), ATRX chromatin remodeler (ATRX), gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6), kell metallo-endopeptidase (KEL), telomerase reverse transcriptase (TERT), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), mutL homolog 1 (MLH1), and PMS1 homolog 2 (PMS2) [16-20,86-95]. Moreover, several hotspot mutations have been found, including the IDH1 R132H mutation, the B-Raf proto-oncogene (BRAF) V600E mutation. More than 40% of GBM cases were found to harbor at least one nonsynonimous mutation in genes related to chromatin organization. Of note, these mutations of genes related to chromatin organization were found to be mutually exclusive thus suggesting a biological relevance of chromatin modification in GBM [16- 20,86,87].

A definition of a hypermutated profile has been proposed for GBM cases characterized by the presence of mutations in the DNA mismatch repair (MMR) genes, e.g. MSH2,MSH6,MLH1, and PMS2 [16,96-101]. Of note, acquired MMR deficiencies, particularly at the MSH6 gene, have been more frequently found in GBM cases at recurrence with respect to cases at the first diagnosis, presumably due to the chemotherapeutic treatments. Moreover, an association has been found between a high tumor mutational burden and the loss of MMR protein expression [16,96-99].

The EGFR gene is one of the most altered genes both at the DNA and RNA levels. Frequently, EGFR mutations have been found associated with regional gene amplification [16,96,114-117]. Moreover, a high concordance of mutations has been found between DNA and RNA transcript. Of note, in a relevant proportion of cases the aberrant exon 1-8 junction of epidermal growth factor receptor variant III (EGFRvIII) has been found expressed. Additional recurrent non-canonical EGFR transcript forms have been also detected [16,96,114,115,117,118]. Promoter DNA methylation profiles allowed to separate GBM cases in different clusters according to the DNA methylation status, with different enrichment in classical GBM subtype or mesenchymal GBM subtype. DNA methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter is a well-recognized marker of treatment response. In this context, the MGMT locus was found methylated in about 50% of GBM cases [16,96,114,119-128].

The clonal evolution of GBM is complex and treatment options are frequently implicated in the insurgence of a specific genomic alteration and of specific evolutionary patterns of genomic alterations. In particular, treatment failure is frequently associated with intratumoral heterogeneity [16,17,96]. Moreover, few driver alterations in GBM tumor cells, through a proliferation phase, seem to lead to a highly differentiated clonal population [14]. Of note, genes known to be implicated in GBM progression, such as TP53,EGFR,PDGFRA are frequently subjected to a process of mutational switching with different mutations of the same gene characterizing diagnosis or relapse [16,17,96]. Hypermutated tumors, accounting for 16% of cases, show the highest substitution rates [14]. They harbor mutations in MMR pathway genes, in the majority of the cases in the MSH6 gene. These MMR alterations have been supposed to be associated with putative mutagenic mechanisms of TMZ treatment [16,17,96-99].

Moreover, mutations in the latent transforming growth factor beta binding protein 4 (LTBP4) gene, encoding for the LTBP4 protein, capable of binding TGF-β and of activating TGF-β signaling pathway, have been found in 11% of relapse tumors. Of note, the binding of LTBP4 to TGF-β seems to promote tumor growth. A high LTBP4 expression in primary GBM samples with wild-type IDH1 has been associated with poor survival [16,17,96].

Primary GBM tumors more frequently present amplification/mutation of the EGFR gene, PTEN mutations and cyclin-dependent kinase inhibitor 2A (CDKN2A) deletions with respect to secondary GBM tumors [16,17,96]. On the other hand, TP53 mutations, MGMT promoter methylation and IDH1 mutations seem to be more frequent in secondary GBM tumors with respect to primary GBM tumors [16,17,96].

4. Mechanisms of chemoresistance

Standard first-line treatment of GBM consists of surgery followed by radiotherapy and chemotherapy with alkylating agents [3,5,6]. Alkylating agents such as TMZ but also carmustine (bichloroethyl nitrosurea) and lomustine (chloroethylnitrosourea) can readily cross the BBB and have shown cytotoxic activity by eliciting DNA damage and inducing apoptosis. In this context, MGMT is a DNA repair enzyme that plays a major role in resistance to TMZ and the other alkylating agents by removing the alkyl groups from the O6 position of guanine [129,130].

Notably, methylation of the MGMT promoter is associated with its epigenetic silencing resulting in loss of MGMT expression [120,130-132]. GBM tumors with methylated MGMT promoters have been demonstrated to be more sensitive to alkykating agents, whereas GBM tumors with unmethylated MGMT promoters express high levels of MGMT and therefore, are more resistant to alkylating agents [122,130,133,134]. A MGMT methylated status has been associated with longer progression free survival (PFS) and OS in GBM patients treated with alkylating agents. Moreover, patients with tumors with a methylated MGMT promoter have been shown to have survival benefit when treated with TMZ and radiotherapy, compared with those receiving only radiotherapy. On the other hand, patients with GBM tumors with an unmethylated MGMT promoter seem to not have any benefit from chemotherapy, regardless of the different administration schedules. This is in keeping with the activity of O6-methylguanine-DNA methyltransferase as a DNA repair enzyme capable of protecting cancer cells against alkylating agents [16,96,114,119-128,130,135].

The MMR pathway plays a key role in the modulation of the cytotoxic effect of O6-methylguanine. The MMR pathway, comprising MLH1, PMS2, MSH2, MSH3, and MSH6 proteins, is involved in the correction of errors in DNA base pairing which arises during DNA replication [135-139]. Resistance to TMZ can be caused by defects in this pathway that determine a tolerance to the mispairing of O6-methylguanine with thymine that can occur during DNA replication [135-139]. This mismatch triggers the MMR-dependent removal of the thymine, and this process can be repeated for various times. These repetitions can induce DNA double strand breaks with consequent TP53- dependent cell cycle arrest. GBM tumors with alterations in genes of the MMR pathway, such as mutations, exhibit resistance to alkylating agents such as TMZ [135-137,139].

The base excision repair (BER) pathway is involved in the repair of the N7-methylguanine and N3- methyladenine DNA adducts, that are the most common DNA adducts inflicted by TMZ, accounting for about 90% of all the methylation events [140-142]. The poly (ADP-ribose) polymerase (PARP-1) enzyme, belonging to the BER pathway, is expressed in GBM tumor cells and it is activated by DNA strand breaks. Inhibition of BER by using PARP inhibitors has been proposed in combination with TMZ treatment [140-142].

Besides the mechanisms involved in the DNA repair, chemoresistance in GBM can be influenced by the dysregulation of genes/proteins involved in the regulation of apoptosis [143]. Mutations of TP53, upregulation of B cell lymphoma -2 (BCL-2) and B-cell lymphoma-extra large (BCL-XL), or overexpression of EGFR can disrupt the apoptotic response of GBM cells to DNA damage [143-145].

TP53 in the wild type mutation status can interact with the promoter of a series of genes including EGFR,MDM2,MDM4 and BCL-2. TP53 dysregulation in GBM has been associated with BCL-2 upregulation. Moreover, upregulation of BCL-2 expression and EGFR expression has been associated with increased antitumor drug resistance [143-145].

5. Targeted therapies in GBM

The progresses in the knowledge of GBM-associated molecular signatures have led to the development of new treatment strategies using molecules targeting dysregulated pathways in GBM (Fig. 2).

Figure 2.

Candidate molecular pathways for targeted therapies in GBM. The introduction of next generation sequencing methods has led to the identification of specific molecular signatures in GBM. This detailed characterization of the GBM-associated molecular signatures has allowed a more personalized therapeutic approach with the development of novel therapies including those employing tyrosine kinase inhibitors (TKIs). Abbreviations: VEGFR, vascular endothelial growth factor receptor; NTRK, neutrophic tyrosine receptor kinases; MET, MET proto-oncogene; FGFR, fibroblast growth factor receptor; EGFR, epidermal growth factor receptor, EGFRvIII, epidermal growth factor receptor variant III; Ras, RAS protein; BRAF, B-Raf proto-oncogene; Raf, Raf protein; MEK/MAPK MAPK/ERK kinase, mitogen-activated protein kinase, extracellular signal-regulated kinase; PI3K, phosphatidylinositol 3-kinase; AKT, AKT Serine/Threonine Kinase 1; mTOR, mammalian target of rapamycin; PTEN, phosphatase and tensin homolog; CDK4/6; CDK9, CDK4/6; CDK9, cyclin dependent kinases 4/6, 9; Rb, retinoblastoma, CCND1, cyclin D1; E2F, E2F transcription factor, MDM2, mouse double minute 2 homolog; MDM4, mouse double minute 4 homolog; CDKN1B, cyclin-dependent kinase inhibitor 1B; CCNE1, cyclin E1; CDKN1B, cyclin-dependent kinase inhibitor 1A; TP53, tumor protein TP53.

GBM is a vascularized tumor, characterized by the expression of VEGF and other proangiogenic cytokines influencing tumor cell proliferation, migration and survival [60]. The TKI regorafenib has been approved in the treatment of GBM following the randomized multicentre open label phase 2 trial in which it has been compared with lomustine in patients with a relapsed GBM [15]. In this clinical trial the regorafenib treated GBM group showed a significantly improved OS survival when compared to the lomustine group [15].

Besides regorafenib, other TKIs targeting VEGF family components have been proposed for the treatment of GBM. In particular, cediranib and sunitinib showed promising results in reducing angiogenesis and normalizing vascularization [146,147].

A targetable pathway in GBM is the PI3K/ mammalian target of rapamycin (mTOR) pathway. In this context, the mTOR inhibitor temsirolimus failed to demonstrate a treatment efficacy as single agent in recurrent GBM [148]. Likewise, the pan-PI3K inhibitor buparlisib failed to demonstrate a treatment efficacy probably due to an insufficient overall PI3K/mTOR pathway inhibition by tolerable doses of buparlisib [149]. mTOR pathway inhibitors also failed to reach efficacy in treatment combinations with radiotherapy and TMZ or in combination with radiotherapy only [150,151].

The most tested methods to target the TP53 pathway are represented by the neutralization of MDM2 and mouse double minute 4 homolog (MDM4) in GBM patients with a TP53 dysregulation. In fact, several studies have been proposed for GBM cases carrying MDM2 or MDM4 gene amplification [152].

In GBM, the RB pathway could be altered for the presence of a CDKN2A/B deletion, CDK4 or CDK6 amplification or RB1 gene alterations. In this context, a completed phase II trial using the CDK4/6 inhibitor palbociclib failed to demonstrate the efficacy of this treatment in GBM [153].

EGFR represents one of the main oncogenes in GBM. EGFR tyrosine kinase inhibitors employed as single agents failed to demonstrate significant activity for GBM treatment [154,155]. The potential use of MET as target for GBM treatment is still controversial. Several attempts have been made by using the TKIs crizotinib and cabozantinib, resulting in modest efficacy in recurrent GBM [156,157]. Three different genes encode for neutrophic tyrosine receptor kinases (NTRKs). Larotrectinib and entrectinib have been tested in NTRK fusion-positive GBM, but their efficacy is still to be confirmed [158]. Although fibroblast growth factor receptors (FGFRs) are frequently expressed in GBM, a relevance as potential therapy target seems to be restricted to GBM exhibiting FGFR-transforming acidic coiled-coil containing protein TACC fusions [159]. In this context, the pan-FGFR kinase inhibitor erdafitinib exhibited efficacy with a stable disease and a partial response in two patients with FGFR3-TACC3-positive recurrent GBM [160]. Regarding the possible targeting of the BRAFV600E mutations for GBM treatments, a modest treatment efficacy has been obtained in several studies [161]. Finally, eribulin has been proposed as an inhibitor of TERT activity in GBM cases [162].

6. Immunotherapy with ICIs for GBM treatment

Based on the results of using ICIs in other cancers, the use of PD-1/PDL1 inhibitors has been proposed for GBM cases. Clinical trial results have shown that nivolumab, as single agent, does not improve survival compared to bevacizumab in GBM patients with unresectable tumors [29]. Pembrolizumab monotherapy showed limited activity in GBMs with the evidence of only a few objective responses in the context of a compassionate treatment program. Moreover, the addiction of pembrolizumab did not improve the efficacy of bevacizumab monotherapy [29-34].

The use of nivolumab has been also recently tested in combination treatment regimens with surgery in patients with newly diagnosed or relapsed GBMs [27]. In particular, a single phase II clinical trial was conducted where the use of a pre-surgical dose of nivolumab followed by post-surgical nivolumab was tested in 30 patients, of which 3 were undergoing primary surgery for newly diagnosed GBM. No clinical benefit has been obtained following salvage surgery in the relapsed GBM, whereas 2 of the 3 patients undergoing primary surgery and treated with nivolumab were still alive 33 and 28 months later [27]. Another clinical trial evaluated the use of neoadjuvant and/or adjuvant pembrolizumab in 35 patients with recurrent, surgically resectable GBM tumors. In this context, the addiction of the neoadjuvant treatment with pembrolizumab to the surgery and the adjuvant treatment had significantly increased OS of GBM patients [28].

Mutations in the PTEN gene have been found to be enriched in GBM patients who are not responsive to ICIs [163]. The presence of PTEN mutations has been associated with an immunosuppressive TME [129,164,165].

Mutations of BRAF/protein tyrosine phosphatase non-receptor type 11 (PTPN11) were found to be enriched in tumors which are responsive to ICIs. In this context, given that mitogen-activated protein kinase (MAPK) pathway inhibition can significantly increase the efficacy of immunotherapy, a combination treatment of ICIs and MAPK inhibitors could be appropriate in GBM patients with BRAF/PTEN11 mutations [166,167].

Regarding the lack of responsiveness to ICIs, it has been shown that GBM cases which are not responsive to ICIs, are characterized by an enriched expression of genes associated with immunosuppression prior to the initiation of ICI treatment, whereas in GBM cases responsive to ICIs, the acquisition of an immunosuppressive condition seems to occur post-treatment [17,163]. This could be associated with an intrinsic resistance in non-responsive patients and in an acquired resistance by selective pressure in GBM tumors responsive to ICIs [17,163].

The use of the neoadjuvant antitumor agents nivolumab or pembrolizumab has been associated with an enhanced expression of chemokine transcripts, and a higher immune cell infiltration. Moreover, neoadjuvant administration of anti-PD-1 antibodies has been associated with a functional activation of TILs eliciting an interferon response within the TME. This T- cell-mediated interferon response seems to be related to a downregulation of the expression of cell cycle related genes with a decrease in tumor cell proliferation [27,28]. An increase in T cell receptor (TCR) clonal diversity among tumor-infiltrating T lymphocytes has also been detected following the treatment with neoadjuvant nivolumab. Treatment with nivolumab was also associated with long complementarity-determining region (CDR3) of TCR when compared with cases not treated with ICIs. Moreover, it has been suggested that treatment with nivolumab could prevent reduction of both adaptive and myeloid immune cell populations [27,28].

7. Proposed biomarkers for responsiveness to ICI treatment

The use of ICIs has demonstrated heterogeneous responses in GBM cases both in the clinical practice and in clinical trials, defining the need of identifying useful predictive biomarker of responsiveness. The first marker evaluated as predictor of a clinical response to ICIs was PD-L1 expression [168], that was correlated with specific histological and molecular features, demonstrating a possible correlation with IDH status. Specifically, a higher PD-L1 expression in gliomas has been related with a wild type IDH status, when compared with cases with an IDH mutated status, thus indicating a potentially higher responsiveness to ICIs in wild type IDH cases [169-171]. Of note, high PD-L1 expression have been found in mesenchymal GBM, thus suggesting an association with the aggressiveness of the tumors [172]. More recently, the tumor mutational load has been evaluated as a predictive marker of responsiveness to ICIs. In particular, a high mutational load could be associated with a higher presence of mutation-associated neo-antigens (MANAs) putatively capable of stimulating specific T cell clones, with a consequent increase in tumor immunogenicity. However, a putative cut-off to identify responsive cases seems to differ among the different cancer types. Moreover, a standardization of the protocol to determine the tumor mutational burden as well as of the adopted techniques for this determination has not yet been proposed. Evaluation of tumor mutational burden by whole genome sequencing has not been generally demonstrated to sufficiently predict long term clinical benefits [173-176]. Moreover, in recent studies higher somatic mutations and neoepitope loads have not been found in GBM cases responsive to ICIs [163]. On the other hand, a low mutational load does not appear to preclude the infiltration into the tumor of T cells responsive to specific MANAs, also in the context of the immunosuppressive TME characterizing GBM tumors [27,28,163]. Another proposed biomarker is the presence of MMR gene abnormalities, that has been related with a clinical response to ICIs in several clinical trials including in GBM patients [27,28]. An additional feature proposed as a biomarker of responsiveness to ICI is the expression of MHC class I molecules that has been found highly heterogeneous in GBM, with a higher expression in more responsive GBM cases [177].

8. CAR-T cell therapy for GBM treatment

The success of chimeric antigen receptor -T (CAR-T) cell therapy in hematological malignancies, with CAR-T cells targeting CD19 approved for B cell acute leukemia and lymphomas [178,179], has favored the introduction of this therapy approach also in solid tumors including GBM. In particular, for GBM treatment, CAR-T cells have been engineered mainly to target the following antigens EGFRvIII, human epidermal growth factor receptor 2, (HER2) and IL-13 receptor α2 (IL-13Rα2), for which clinical trials have been proposed. Results of the proposed clinical trials showed that the employment of CAR-T cell therapy for GBM is feasible, safe and potentially efficacious, although, as for other solid tumors, there are still several substantial obstacles [180-182]. In particular, the major challenges include tumor heterogeneity in terms of antigen expression, access of CAR-T cells to the tumor site as well as resistance of the TME to CAR-T therapy [183-186]. To overcome both antigen heterogeneity and antigen loss, one approach is to simultaneously target more than one tumor associated antigen with multi-specific CAR-T cells. In GBM tumors, there are several obstacles that a CAR-T cell must overcome to reach the tumor site, including abnormal vasculature capable to block T cell entry. One practical approach is represented by intracranial administration showing some promising results for anti-IL13Ra2 [181,182]. Different approaches have been introduced to overcome TME immune suppression in the context of CAR-T cell therapy. In particular, the concomitant use of ICIs has been proposed. Other strategies are represented by the introduction of several CAR-T modifications such as the knocking out of genes encoding T cell inhibitory receptors or signaling molecules (e.g. PD-1 or CTLA-4), or the co-expression of activating chimeric switch receptor (CSR), that combines the extracellular domain of an inhibitory receptor (PD-1 or CTLA-4) linked with the cytoplasmic co-stimulatory signaling domain of CD28 (Fig. 3) [187-191].

Figure 3.

Modified CAR-T cells to counteract immunosuppressive tumor microenvironment (TME). A strategy to improve chimeric antigen redirected T (CAR-T) cell efficacy in solid tumors including GBM is represented by the co-expression of an activating chimeric switch receptor (CSR), that combines the extracellular ligand-binding domain of an inhibitory receptor (PD-1 or CTLA-4) fused through a transmembrane domain with the cytoplasmic co-stimulatory signaling domain of CD28. The engagement of the CSR allows the transmission of an activating signal instead of the normal physiological inhibitory signal. Abbreviations: CSR, chimeric switch receptor; TCR, T cell receptor; PD-1, programmed cell death protein 1; CTLA-4, cytotoxic T-lymphocyte antigen 4.

9. Conclusions

In the last ten years, comprehensive genomic analyses have revealed that GBM tumors are highly heterogeneous with different tumor subgroups characterized by specific molecular features [16,17,96]. The high degree of heterogeneity makes tumor classification difficult as well as the designing of effective customized therapies capable of targeting dysregulated pathways. Moreover, the molecular pathways that can be targeted are often functionally synergic making the inhibition of a single particular molecular mechanism frequently useless [16,17,96]. In this context, a relevant role is also carried out by clonal selection that allows the propagation of drug resistant clones to a specific targeted therapy due to the presence of specific genomic alterations or pathway activations/dysregulations [16,17,96]. Another possible reason for the failure of targeted therapies is that several genomic alterations can drive only the early stages of progression, whereas their role is overridden in the later stages by other molecular mechanisms. Another relevant obstacle to an effective therapy is represented by the BBB which affects the targeting of chemotherapeutic drugs to the GBM tumor [45,46]. The TME can cause chemoresistance being capable of promoting tumor cell proliferation and of selecting aggressive cancer cells including GSCs. In a vicious circle, the interaction of TME with GSCs can further increase chemoresistance. The TME of GBM is largely immunosuppressive, this condition can strongly affect efficiency of ICI treatments [35,36,50-58]. Moreover, chemotherapeutic treatments can cause a reduction in the levels of circulating CD4+ and CD8+ lymphocytes [192,193]. On the other hand, the identification of immunological signatures capable to predict the responsiveness to ICIs is still an important clinical need [24-31].

10. Future perspectives

GBM remains an incurable and lethal disease despite the continuous attempts to increase the survival of GBM affected cases. Although TKI use has been so far associated with a limited response in terms of survival increases of GBM treated cases, further efforts could be made in the definition of combination treatment approaches to include their use in the canonical well-established therapeutic modalities.

The data collected so far regarding the ICI employment in GBMs are modest and still incomplete to propose them as a standard therapeutic approach for GBM affected patients [24-34] . However, results of the use of nivolumab and pembrolizumab administered as adjuvant and neoadjuvant treatments in the context of chemo-radio immuno-combinations seem to be more promising, at least for a certain fraction of patients. Several candidate biomarkers have been proposed to predict responsiveness to ICI treatment for GBM patients. Nevertheless, a strong correlation has not yet been found between the proposed biomarkers and clinical and radiological response to ICIs. In this context, further analyses remain necessary within both pre-clinical and clinical studies regarding different aspects encompassing somatic features of tumor cells, mutational landscapes, deficiency in DNA mismatch repair, transcription factors, immune-related gene expression miRNA signatures, and association with neoantigens. Additional information could be obtained by using computational/mathematical models useful to reach a better understanding of the molecular complexity generated by the differences in genomic, transcriptomic and immune-related features.

An ever increasing knowledge of this molecular complexity could also provide the rationale for the introduction of the use of CAR-T cells, in combination with ICIs or TKIs, in the treatment paradigm of GBM.

Conflict of interest statement

There are no conflicts of interest to disclose.

References
[1]
Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. Cbtrus statistical report: Primary brain and other central nervous system tumors diagnosed in the united states in 2012-2016. Neuro Oncol, 2019; 21(Supplement_5): v1-v100.
[2]
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol, 2016; 131(6): 803-820. 27157931https://www.ncbi.nlm.nih.gov/pubmed/27157931
[3]
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med, 2005; 352(10): 987-996. 10.1056/NEJMoa04333015758009https://www.ncbi.nlm.nih.gov/pubmed/15758009
[4]
Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell, 1999; 97(6): 703-716. 10.1016/s0092-8674(00)80783-710380923https://www.ncbi.nlm.nih.gov/pubmed/10380923
[5]
Levine JH, Simonds EF, Bendall SC, Davis KL, Amir el AD, Tadmor MD, et al. Data-driven phenotypic dissection of aml reveals progenitor-like cells that correlate with prognosis. Cell, 2015; 162(1): 184-197. 10.1016/j.cell.2015.05.04726095251https://www.ncbi.nlm.nih.gov/pubmed/26095251
[6]
Canoll P, Goldman JE. The interface between glial progenitors and gliomas. Acta Neuropathol, 2008; 116(5): 465-477. 10.1007/s00401-008-0432-918784926https://www.ncbi.nlm.nih.gov/pubmed/18784926
[7]
Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res, 2013; 19(4): 764-772. 10.1158/1078-0432.CCR-12-300223209033https://www.ncbi.nlm.nih.gov/pubmed/23209033
[8]
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase iii study: 5-year analysis of the eortc-ncic trial. Lancet Oncol, 2009; 10(5): 459-466. 10.1016/S1470-2045(09)70025-719269895https://www.ncbi.nlm.nih.gov/pubmed/19269895
[9]
Stupp R, Hegi ME. Brain cancer in 2012: Molecular characterization leads the way. Nat Rev Clin Oncol, 2013; 10(2): 69-70. 10.1038/nrclinonc.2012.2401d7a4167-1c6b-46b2-b83b-d4206744f3a5http://dx.doi.org/10.1038/nrclinonc.2012.240
[10]
Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, et al. Novottf-100a versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase iii trial of a novel treatment modality. Eur J Cancer, 2012; 48(14): 2192-2202. 10.1016/j.ejca.2012.04.011a5231e7b-461b-4039-8e83-bca2ea592eeahttp://dx.doi.org/10.1016/j.ejca.2012.04.011
[11]
Chamberlain MC. Salvage therapy with lomustine for temozolomide refractory recurrent anaplastic astrocytoma: A retrospective study. J Neurooncol, 2015; 122(2): 329-338. 25563816https://www.ncbi.nlm.nih.gov/pubmed/25563816
[12]
Chamberlain MC, Johnston SK. Salvage therapy with single agent bevacizumab for recurrent glioblastoma. J Neurooncol, 2010; 96(2): 259-269. 10.1007/s11060-009-9957-619593660https://www.ncbi.nlm.nih.gov/pubmed/19593660
[13]
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol, 2009; 27(28): 4733-4740. 10.1200/JCO.2008.19.872119720927https://www.ncbi.nlm.nih.gov/pubmed/19720927
[14]
Quant EC, Norden AD, Drappatz J, Muzikansky A, Doherty L, Lafrankie D, et al. Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro Oncol, 2009; 11(5): 550-555. 10.1215/15228517-2009-00619332770https://www.ncbi.nlm.nih.gov/pubmed/19332770
[15]
Lombardi G, De Salvo GL, Brandes AA, Eoli M, Ruda R, Faedi M, et al. Regorafenib compared with lomustine in patients with relapsed glioblastoma (regoma): A multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol, 2019; 20(1): 110-119. 10.1016/S1470-2045(18)30675-230522967https://www.ncbi.nlm.nih.gov/pubmed/30522967
[16]
Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell, 2013; 155(2): 462-477. 24120142https://www.ncbi.nlm.nih.gov/pubmed/24120142
[17]
Wang J, Cazzato E, Ladewig E, Frattini V, Rosenbloom DI, Zairis S, et al. Clonal evolution of glioblastoma under therapy. Nat Genet, 2016; 48(7): 768-776. 10.1038/ng.359027270107https://www.ncbi.nlm.nih.gov/pubmed/27270107
[18]
Kessler T, Sahm F, Sadik A, Stichel D, Hertenstein A, Reifenberger G, et al. Molecular differences in idh wildtype glioblastoma according to mgmt promoter methylation. Neuro Oncol, 2018; 20(3): 367-379. 10.1093/neuonc/nox16029016808https://www.ncbi.nlm.nih.gov/pubmed/29016808
[19]
Stathias V, Jermakowicz AM, Maloof ME, Forlin M, Walters W, Suter RK, et al. Drug and disease signature integration identifies synergistic combinations in glioblastoma. Nat Commun, 2018; 9(1): 5315. 10.1038/s41467-018-07659-z30552330https://www.ncbi.nlm.nih.gov/pubmed/30552330
[20]
Eder K, Kalman B. Molecular heterogeneity of glioblastoma and its clinical relevance. Pathol Oncol Res, 2014; 20(4): 777-787. 10.1007/s12253-014-9833-325156108https://www.ncbi.nlm.nih.gov/pubmed/25156108
[21]
Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-ctla-4 treatment (checkmate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol, 2015; 16(4): 375-384. 25795410https://www.ncbi.nlm.nih.gov/pubmed/25795410
[22]
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med, 2015; 373(1): 23-34. 10.1056/NEJMoa150403026027431https://www.ncbi.nlm.nih.gov/pubmed/26027431
[23]
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase i study of single-agent anti-programmed death-1 (mdx-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol, 2010; 28(19): 3167-3175. 10.1200/JCO.2009.26.760920516446https://www.ncbi.nlm.nih.gov/pubmed/20516446
[24]
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for pd-l1-positive non-small-cell lung cancer. N Engl J Med, 2016; 375(19): 1823-1833. 27718847https://www.ncbi.nlm.nih.gov/pubmed/27718847
[25]
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med, 2015; 373(19): 1803-1813. 26406148https://www.ncbi.nlm.nih.gov/pubmed/26406148
[26]
Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: Early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol, 2016; 17(7): 976-983. 27267608https://www.ncbi.nlm.nih.gov/pubmed/27267608
[27]
Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, Lopez-Janeiro A, Porciuncula A, Idoate MA, et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med, 2019; 25(3): 470-476. 10.1038/s41591-018-0339-530742120https://www.ncbi.nlm.nih.gov/pubmed/30742120
[28]
Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, et al. Neoadjuvant anti-pd-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med, 2019; 25(3): 477-486. 10.1038/s41591-018-0337-730742122https://www.ncbi.nlm.nih.gov/pubmed/30742122
[29]
Reiss SN, Yerram P, Modelevsky L, Grommes C. Retrospective review of safety and efficacy of programmed cell death-1 inhibitors in refractory high grade gliomas. J Immunother Cancer, 2017; 5(1): 99. 10.1186/s40425-017-0302-x29254497https://www.ncbi.nlm.nih.gov/pubmed/29254497
[30]
Schwartz LH, Litiere S, de Vries E, Ford R, Gwyther S, Mandrekar S, et al. Recist 1.1-update and clarification: From the recist committee. Eur J Cancer, 2016; 62: 132-137. 10.1016/j.ejca.2016.03.08127189322https://www.ncbi.nlm.nih.gov/pubmed/27189322
[31]
Reardon DA, Nayak L, Peters KB, Clarke JL, Jordan JT, Groot JFD, et al. Phase ii study of pembrolizumab or pembrolizumab plus bevacizumab for recurrent glioblastoma (rgbm) patients. Journal of Clinical Oncology, 2018; 36(15_suppl): 2006-2006. 10.1200/JCO.2018.78.8240http://ascopubs.org/doi/10.1200/JCO.2018.78.8240
[32]
Reardon DA, Omuro A, Brandes A, Rieger J, Wick A, Sepulveda J, et al. Os10.3 randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: Checkmate 143. Neuro-Oncology, 2017; 19(Suppl 3): iii21.
[33]
Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res, 2016; 4(2): 124-135. 10.1158/2326-6066.CIR-15-015126546453https://www.ncbi.nlm.nih.gov/pubmed/26546453
[34]
Reardon DA, Freeman G, Wu C, Chiocca EA, Wucherpfennig KW, Wen PY, et al. Immunotherapy advances for glioblastoma. Neuro Oncol, 2014; 16(11): 1441-1458. 25190673https://www.ncbi.nlm.nih.gov/pubmed/25190673
[35]
Young RM, Jamshidi A, Davis G, Sherman JH. Current trends in the surgical management and treatment of adult glioblastoma. Ann Transl Med, 2015; 3(9): 121. 10.3978/j.issn.2305-5839.2015.05.1026207249https://www.ncbi.nlm.nih.gov/pubmed/26207249
[36]
Sherriff J, Tamangani J, Senthil L, Cruickshank G, Spooner D, Jones B, et al. Patterns of relapse in glioblastoma multiforme following concomitant chemoradiotherapy with temozolomide. Br J Radiol, 2013; 86(1022): 20120414. 23385995https://www.ncbi.nlm.nih.gov/pubmed/23385995
[37]
Eyler CE, Rich JN. Survival of the fittest: Cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol, 2008; 26(17): 2839-2845. 10.1200/JCO.2007.15.182918539962https://www.ncbi.nlm.nih.gov/pubmed/18539962
[38]
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med, 2013; 19(11): 1423-1437. 10.1038/nm.339424202395https://www.ncbi.nlm.nih.gov/pubmed/24202395
[39]
Quail DF, Joyce JA. The microenvironmental landscape of brain tumors. Cancer Cell, 2017; 31(3): 326-341. 10.1016/j.ccell.2017.02.00928292436https://www.ncbi.nlm.nih.gov/pubmed/28292436
[40]
Gritsenko PG, Ilina O, Friedl P. Interstitial guidance of cancer invasion. J Pathol, 2012; 226(2): 185-199. 10.1002/path.303122006671https://www.ncbi.nlm.nih.gov/pubmed/22006671
[41]
Nakasone ES, Askautrud HA, Kees T, Park JH, Plaks V, Ewald AJ, et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell, 2012; 21(4): 488-503. 10.1016/j.ccr.2012.02.0176aee850d-abc0-4665-b5af-63c2bc132085http://dx.doi.org/10.1016/j.ccr.2012.02.017
[42]
Mahesparan R, Read TA, Lund-Johansen M, Skaftnesmo KO, Bjerkvig R, Engebraaten O. Expression of extracellular matrix components in a highly infiltrative in vivo glioma model. Acta Neuropathol, 2003; 105(1): 49-57. 10.1007/s00401-002-0610-012471461https://www.ncbi.nlm.nih.gov/pubmed/12471461
[43]
Novak U, Kaye AH. Extracellular matrix and the brain: Components and function. J Clin Neurosci, 2000; 7(4): 280-290. 10938601https://www.ncbi.nlm.nih.gov/pubmed/10938601
[44]
Kim Y, Kang H, Powathil G, Kim H, Trucu D, Lee W, et al. Role of extracellular matrix and microenvironment in regulation of tumor growth and lar-mediated invasion in glioblastoma. PLoS One, 2018; 13(10): e0204865. 10.1371/journal.pone.020486530286133https://www.ncbi.nlm.nih.gov/pubmed/30286133
[45]
Chen Y, Liu L. Modern methods for delivery of drugs across the blood-brain barrier. Adv Drug Deliv Rev, 2012; 64(7): 640-665. 10.1016/j.addr.2011.11.01022154620https://www.ncbi.nlm.nih.gov/pubmed/22154620
[46]
Miura Y, Takenaka T, Toh K, Wu S, Nishihara H, Kano MR, et al. Cyclic rgd-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier. ACS Nano, 2013; 7(10): 8583-8592. 24028526https://www.ncbi.nlm.nih.gov/pubmed/24028526
[47]
de Vries NA, Beijnen JH, Boogerd W, van Tellingen O. Blood-brain barrier and chemotherapeutic treatment of brain tumors. Expert Rev Neurother, 2006; 6(8): 1199-1209. 10.1586/14737175.6.8.119916893347https://www.ncbi.nlm.nih.gov/pubmed/16893347
[48]
van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat, 2015; 19: 1-12. 10.1016/j.drup.2015.02.00225791797https://www.ncbi.nlm.nih.gov/pubmed/25791797
[49]
Giese A, Westphal M. Glioma invasion in the central nervous system. Neurosurgery, 1996; 39(2): 235-250; discussion 250-232.
[50]
Nimsky C, Ganslandt O, Hastreiter P, Wang R, Benner T, Sorensen AG, et al. Preoperative and intraoperative diffusion tensor imaging-based fiber tracking in glioma surgery. Neurosurgery, 2005; 56(1): 130-137; discussion 138. 15617595https://www.ncbi.nlm.nih.gov/pubmed/15617595
[51]
Hambardzumyan D, Bergers G. Glioblastoma: Defining tumor niches. Trends Cancer, 2015; 1(4): 252-265. 27088132https://www.ncbi.nlm.nih.gov/pubmed/27088132
[52]
Persano L, Rampazzo E, Della Puppa A, Pistollato F, Basso G. The three-layer concentric model of glioblastoma: Cancer stem cells, microenvironmental regulation, and therapeutic implications. ScientificWorldJournal, 2011; 11: 1829-1841. 10.1100/2011/73648022125441https://www.ncbi.nlm.nih.gov/pubmed/22125441
[53]
Chen Z, Hambardzumyan D. Immune microenvironment in glioblastoma subtypes. Front Immunol, 2018; 9: 1004. 10.3389/fimmu.2018.0100429867979https://www.ncbi.nlm.nih.gov/pubmed/29867979
[54]
Brat DJ, Castellano-Sanchez AA, Hunter SB, Pecot M, Cohen C, Hammond EH, et al. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res, 2004; 64(3): 920-927. 10.1158/0008-5472.can-03-207314871821https://www.ncbi.nlm.nih.gov/pubmed/14871821
[55]
Brat DJ, Van Meir EG. Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest, 2004; 84(4): 397-405. 10.1038/labinvest.370007014990981https://www.ncbi.nlm.nih.gov/pubmed/14990981
[56]
Zimmermann DR, Dours-Zimmermann MT. Extracellular matrix of the central nervous system: From neglect to challenge. Histochem Cell Biol, 2008; 130(4): 635-653. 18696101https://www.ncbi.nlm.nih.gov/pubmed/18696101
[57]
Dicker KT, Gurski LA, Pradhan-Bhatt S, Witt RL, Farach-Carson MC, Jia X. Hyaluronan: A simple polysaccharide with diverse biological functions. Acta Biomater, 2014; 10(4): 1558-1570. 10.1016/j.actbio.2013.12.01924361428https://www.ncbi.nlm.nih.gov/pubmed/24361428
[58]
Akiyama Y, Jung S, Salhia B, Lee S, Hubbard S, Taylor M, et al. Hyaluronate receptors mediating glioma cell migration and proliferation. J Neurooncol, 2001; 53(2): 115-127. 10.1023/a:101229713204711716065https://www.ncbi.nlm.nih.gov/pubmed/11716065
[59]
Ponta H, Sherman L, Herrlich PA. Cd44: From adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol, 2003; 4(1): 33-45. 10.1038/nrm100412511867https://www.ncbi.nlm.nih.gov/pubmed/12511867
[60]
Schiffer D, Annovazzi L, Casalone C, Corona C, Mellai M. Glioblastoma: Microenvironment and niche concept. Cancers (Basel), 2018; 11(1): 5.
[61]
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature, 2015; 523(7560): 337-341. 10.1038/nature1443226030524https://www.ncbi.nlm.nih.gov/pubmed/26030524
[62]
Gajewski TF, Corrales L, Williams J, Horton B, Sivan A, Spranger S. Cancer immunotherapy targets based on understanding theT cell-inflamed versus non-t cell-inflamed tumor microenvironment. Adv Exp Med Biol, 2017; 1036: 19-31. 10.1007/978-3-319-67577-0_229275462https://www.ncbi.nlm.nih.gov/pubmed/29275462
[63]
Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. Neoantigen vaccine generates intratumoralT cell responses in phase ib glioblastoma trial. Nature, 2019; 565(7738): 234-239. 10.1038/s41586-018-0792-930568305https://www.ncbi.nlm.nih.gov/pubmed/30568305
[64]
Perng P, Lim M. Immunosuppressive mechanisms of malignant gliomas: Parallels at non-cns sites. Front Oncol, 2015; 5: 153. 26217588https://www.ncbi.nlm.nih.gov/pubmed/26217588
[65]
Gong D, Shi W, Yi SJ, Chen H, Groffen J, Heisterkamp N. Tgfbeta signaling plays a critical role in promoting alternative macrophage activation. BMC Immunol, 2012; 13: 31. 10.1186/1471-2172-13-3122703233https://www.ncbi.nlm.nih.gov/pubmed/22703233
[66]
Vitkovic L, Maeda S, Sternberg E. Anti-inflammatory cytokines: Expression and action in the brain. Neuroimmunomodulation, 2001; 9(6): 295-312. 12045357https://www.ncbi.nlm.nih.gov/pubmed/12045357
[67]
Wainwright DA, Balyasnikova IV, Chang AL, Ahmed AU, Moon KS, Auffinger B, et al. Ido expression in brain tumors increases the recruitment of regulatoryT cells and negatively impacts survival. Clin Cancer Res, 2012; 18(22): 6110-6121. 10.1158/1078-0432.CCR-12-213022932670https://www.ncbi.nlm.nih.gov/pubmed/22932670
[68]
Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med, 2003; 9(10): 1269-1274. 10.1038/nm93414502282https://www.ncbi.nlm.nih.gov/pubmed/14502282
[69]
Xu F, Jin T, Zhu Y, Dai C. Immune checkpoint therapy in liver cancer. J Exp Clin Cancer Res, 2018; 37(1): 110. 10.1186/s13046-018-0777-429843754https://www.ncbi.nlm.nih.gov/pubmed/29843754
[70]
Chambers CA, Kuhns MS, Egen JG, Allison JP. Ctla-4-mediated inhibition in regulation of T cell responses: Mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol, 2001; 19: 565-594. 10.1146/annurev.immunol.19.1.56511244047https://www.ncbi.nlm.nih.gov/pubmed/11244047
[71]
Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, et al. The interaction properties of costimulatory molecules revisited. Immunity, 2002; 17(2): 201-210. 10.1016/S1074-7613(02)00362-Xf65ae3bb-5267-47fa-83e6-3f6cd6629248http://www.sciencedirect.com/science/article/pii/S107476130200362X
[72]
Inarrairaegui M, Melero I, Sangro B. Immunotherapy of hepatocellular carcinoma: Facts and hopes. Clin Cancer Res, 2018; 24(7): 1518-1524. 10.1158/1078-0432.CCR-17-028929138342https://www.ncbi.nlm.nih.gov/pubmed/29138342
[73]
Krummel MF, Allison JP. Ctla-4 engagement inhibits il-2 accumulation and cell cycle progression upon activation of restingT cells. J Exp Med, 1996; 183(6): 2533-2540. 10.1084/jem.183.6.25338676074https://www.ncbi.nlm.nih.gov/pubmed/8676074
[74]
Stone JD, Chervin AS, Kranz DM. T-cell receptor binding affinities and kinetics: Impact on T-cell activity and specificity. Immunology, 2009; 126(2): 165-176. 10.1111/j.1365-2567.2008.03015.x19125887https://www.ncbi.nlm.nih.gov/pubmed/19125887
[75]
Bhandaru M and Rotte A. Blockade of programmed cell death protein-1 pathway for the treatment of melanoma. J Dermatol Res Ther, 2017; 1(3): 1-11.
[76]
Cheng X, Veverka V, Radhakrishnan A, Waters LC, Muskett FW, Morgan, SH, et al. Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem, 2013; 288(17): 11771-11785. 10.1074/jbc.M112.44812623417675https://www.ncbi.nlm.nih.gov/pubmed/23417675
[77]
Francisco LM, Sage PT, Sharpe AH. The pd-1 pathway in tolerance and autoimmunity. Immunol Rev, 2010; 236: 219-242. 10.1111/j.1600-065X.2010.00923.x20636820https://www.ncbi.nlm.nih.gov/pubmed/20636820
[78]
Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, et al. T cell costimulatory receptor cd28 is a primary target for pd-1-mediated inhibition. Science, 2017; 355(6332): 1428-1433. 10.1126/science.aaf129228280247https://www.ncbi.nlm.nih.gov/pubmed/28280247
[79]
Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol, 2020; 20(1): 25-39. 31570880https://www.ncbi.nlm.nih.gov/pubmed/31570880
[80]
Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol, 2018; 29(1): 71-83. 10.1093/annonc/mdx68629069302https://www.ncbi.nlm.nih.gov/pubmed/29069302
[81]
Sharma P, Allison JP. Dissecting the mechanisms of immune checkpoint therapy. Nat Rev Immunol, 2020; 20(2): 75-76. 10.1038/s41577-020-0275-831925406https://www.ncbi.nlm.nih.gov/pubmed/31925406
[82]
Wei SC, Anang NAS, Sharma R, Andrews MC, Reuben A, Levine JH, et al. Combination anti-ctla-4 plus anti-pd-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc Natl Acad Sci U S A, 2019; 116(45): 22699-22709. 10.1073/pnas.182121811631636208https://www.ncbi.nlm.nih.gov/pubmed/31636208
[83]
Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov, 2018; 8(9): 1069-1086. 10.1158/2159-8290.CD-18-036730115704https://www.ncbi.nlm.nih.gov/pubmed/30115704
[84]
Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang NAS, Andrews MC, et al. Distinct cellular mechanisms underlie anti-ctla-4 and anti-pd-1 checkpoint blockade. Cell, 2017; 170(6): 1120-1133 e.17. 10.1016/j.cell.2017.07.02428803728https://www.ncbi.nlm.nih.gov/pubmed/28803728
[85]
Wei SC, Sharma R, Anang NAS, Levine JH, Zhao Y, Mancuso JJ, et al. Negative co-stimulation constrainsT cell differentiation by imposing boundaries on possible cell states. Immunity, 2019; 50(4): 1084-1098 e.10. 10.1016/j.immuni.2019.03.00430926234https://www.ncbi.nlm.nih.gov/pubmed/30926234
[86]
Kloosterhof NK, Bralten LB, Dubbink HJ, French PJ, van den Bent MJ. Isocitrate dehydrogenase-1 mutations: A fundamentally new understanding of diffuse glioma? Lancet Oncol, 2011; 12(1): 83-91. 10.1016/S1470-2045(10)70053-X20615753https://www.ncbi.nlm.nih.gov/pubmed/20615753
[87]
Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in idh1 dominantly inhibit idh1 catalytic activity and induce hif-1alpha. Science, 2009; 324(5924): 261-265. 10.1126/science.117094419359588https://www.ncbi.nlm.nih.gov/pubmed/19359588
[88]
D'Angelo F, Ceccarelli, M, Tala, Garofano L, Zhang, J, Frattini, V, et al. The molecular landscape of glioma in patients with neurofibromatosis 1. Nat Med, 2019; 25(1): 176-187. 10.1038/s41591-018-0263-830531922https://www.ncbi.nlm.nih.gov/pubmed/30531922
[89]
Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell, 2016; 164(3): 550-563. 10.1016/j.cell.2015.12.02826824661https://www.ncbi.nlm.nih.gov/pubmed/26824661
[90]
Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone h3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 2012; 482(7384): 226-231. 10.1038/nature10833f35c3229-92af-4536-a531-461f1f16fb73http://dx.doi.org/10.1038/nature10833
[91]
Kannan K, Inagaki A, Silber J, Gorovets D, Zhang J, Kastenhuber ER, et al. Whole-exome sequencing identifies atrx mutation as a key molecular determinant in lower-grade glioma. Oncotarget, 2012; 3(10): 1194-1203. e4c15ece-67fb-48c6-953a-edb2ebea8656WOS:000312410800017
[92]
Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA, Fontebasso AM, et al. Frequent atrx mutations and loss of expression in adult diffuse astrocytic tumors carrying idh1/idh2 and tp53 mutations. Acta Neuropathol, 2012; 124(5): 615-625. 10.1007/s00401-012-1031-3b35c6896-1adb-43b5-84c1-af24f3b4dc43http://link.springer.com/article/10.1007/s00401-012-1031-3
[93]
Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol, 2007; 170(5): 1445-1453. 10.2353/ajpath.2007.07001117456751https://www.ncbi.nlm.nih.gov/pubmed/17456751
[94]
Dolecek TA, Propp JM, Stroup NE, Kruchko C. Cbtrus statistical report: Primary brain and central nervous system tumors diagnosed in the united states in 2005-2009. Neuro Oncol, 2012; Suppl 5(Suppl 5):v1-49. 28475809https://www.ncbi.nlm.nih.gov/pubmed/28475809
[95]
Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev, 2012; 26(8): 756-784. 10.1101/gad.187922.11222508724https://www.ncbi.nlm.nih.gov/pubmed/22508724
[96]
TCGA Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 2008; 455(7216): 1061-1068. 10.1038/nature0738518772890https://www.ncbi.nlm.nih.gov/pubmed/18772890
[97]
Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, et al. Loss of the mismatch repair protein msh6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res, 2007; 13(7): 2038-2045. 10.1158/1078-0432.CCR-06-214917404084https://www.ncbi.nlm.nih.gov/pubmed/17404084
[98]
Hunter C, Smith R, Cahill DP, Stephens P, Stevens C, Teague J, et al. A hypermutation phenotype and somatic msh6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res, 2006; 66(8): 3987-3991. 16618716https://www.ncbi.nlm.nih.gov/pubmed/16618716
[99]
Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K, Nutt CL, et al. Msh6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res, 2009; 15(14): 4622-4629. 10.1158/1078-0432.CCR-08-301219584161https://www.ncbi.nlm.nih.gov/pubmed/19584161
[100]
Daniel P, Sabri S, Chaddad A, Meehan B, Jean-Claude B Rak J, et al. Temozolomide induced hypermutation in glioma: Evolutionary mechanisms and therapeutic opportunities. Front Oncol, 2019; 9: 41. 10.3389/fonc.2019.0004130778375https://www.ncbi.nlm.nih.gov/pubmed/30778375
[101]
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, et al. Patterns of somatic mutation in human cancer genomes. Nature, 2007; 446(7132): 153-158. 17344846https://www.ncbi.nlm.nih.gov/pubmed/17344846
[102]
Kuttler F, Mai S. Formation of non-random extrachromosomal elements during development, differentiation and oncogenesis. Semin Cancer Biol, 2007; 17(1): 56-64. 10.1016/j.semcancer.2006.10.00717116402https://www.ncbi.nlm.nih.gov/pubmed/17116402
[103]
Sanborn JZ, Salama SR, Grifford M, Brennan C, Mikkelsen T, Jhanwar S, et al. Double minute chromosomes in glioblastoma multiforme are revealed by precise reconstruction of oncogenic amplicons. Cancer Res. 2013; 73(19): 6036-6045. 10.1158/0008-5472.CAN-13-018623940299https://www.ncbi.nlm.nih.gov/pubmed/23940299
[104]
Zheng S, Fu J, Vegesna R, Mao Y, Heathcock LE, Torres-Garcia W, et al. A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival. Genes Dev 2013; 27(13): 1462-1472. 10.1101/gad.213686.11323796897https://www.ncbi.nlm.nih.gov/pubmed/23796897
[105]
Furgason JM, Koncar RF, Michelhaugh SK, Sarkar FH, Mittal S, Sloan AE, et al. Whole genome sequence analysis links chromothripsis to egfr, mdm2, mdm4, and cdk4 amplification in glioblastoma. Oncoscience 2015; 2(7): 618-628. 26328271https://www.ncbi.nlm.nih.gov/pubmed/26328271
[106]
Parsons W, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321(5897): 1807-1812. 10.1126/science.116438218772396https://www.ncbi.nlm.nih.gov/pubmed/18772396
[107]
Chen AJ, Paik JH, Zhang H, Shukla S.A, Mortensen R, Hu J. et al. Star rna-binding protein quaking suppresses cancer via stabilization of specific mirna. Genes Dev, 2012; 26(13): 1459-1472. 10.1101/gad.189001.11222751500https://www.ncbi.nlm.nih.gov/pubmed/22751500
[108]
Mizoguchi M, Yoshimoto K, Ma X, Guan Y, Hata N, Amano T, et al. Molecular characteristics of glioblastoma with 1p/19q co-deletion. Brain Tumor Pathol 2012; 29(3): 148-153. 10.1007/s10014-012-0107-z2273623494e04e46-4b4c-46e0-adee-58d8222fbaa7https://www.ncbi.nlm.nih.gov/pubmed/22736234
[109]
Kamiryo T, Tada K, Shiraishi S, Shinojima S, Nakamura H, Kochi M, et al. Analysis of homozygous deletion of the p16 gene and correlation with survival in patients with glioblastoma multiforme. J Neurosurg 2002; 96(5): 815-822. 10.3171/jns.2002.96.5.081512005388https://www.ncbi.nlm.nih.gov/pubmed/12005388
[110]
Tabouret E, Labussière M, Alentorn A, Schmitt Y, Marie Y, Sanson M, et al. Lrp1b deletion is associated with poor outcome for glioblastoma patients. J Neurol Sci, 2015; 358(1-2): 440-443. 10.1016/j.jns.2015.09.34526428308https://www.ncbi.nlm.nih.gov/pubmed/26428308
[111]
Moreira F, Kiehl T, So K, Ajeawung N, Honculada A, Gould P, et al. Npas3 demonstrates features of a tumor suppressive role in driving the progression of astrocytomas. Am J Pathol, 2011; 179(1): 462-476. 10.1016/j.ajpath.2011.03.04421703424https://www.ncbi.nlm.nih.gov/pubmed/21703424
[112]
Yang D, Zhang W, Padhiar A, Yue Y, Shi Y, Zheng T, et al. Npas3 regulates transcription and expression of vgf: Implications for neurogenesis and psychiatric disorders. Front Mol Neurosci 2016; 9: 109. 10.3389/fnmol.2016.0010927877109https://www.ncbi.nlm.nih.gov/pubmed/27877109
[113]
Nobusawa S, Hirato J, Kurihara H, Ogawa A, Okura N, Nagaishi M, et al. Intratumoral heterogeneity of genomic imbalance in a case of epithelioid glioblastoma with braf v600e mutation. Brain Pathol 2014; 24(3): 239-246. 10.1111/bpa.1211424354918https://www.ncbi.nlm.nih.gov/pubmed/24354918
[114]
Cominelli M, Grisanti S, Mazzoleni S, Branca C, Buttolo L, Furlan D, et al. Egfr amplified and overexpressing glioblastomas and association with better response to adjuvant metronomic temozolomide. J Natl Cancer Inst, 2015; 107(5):djv041. 10.1093/jnci/djv04025780062https://www.ncbi.nlm.nih.gov/pubmed/25780062
[115]
Jaros E, Perry RH, Adam L, Kelly PJ, Crawford PJ, Kalbag RM, et al. Prognostic implications of p53 protein, epidermal growth factor receptor, and ki-67 labelling in brain tumours. Br J Cancer 1992; 66(2): 373-385. 10.1038/bjc.1992.2731503912https://www.ncbi.nlm.nih.gov/pubmed/1503912
[116]
Schlegel J, Stumm G, Brändle K, Merdes A, Mechtersheimer G, Hynes NE, et al. Amplification and differential expression of members of the erbb-gene family in human glioblastoma. J Neurooncol, 1994; 22(3): 201-207. 10.1007/BF010529207760096https://www.ncbi.nlm.nih.gov/pubmed/7760096
[117]
Ekstrand AJ, James CD, Cavenee WK, Seliger B, Pettersson RF, Collins VP. Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res, 1991; 51(8): 2164-2172. 2009534https://www.ncbi.nlm.nih.gov/pubmed/2009534
[118]
Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA 1994; 91(16): 7727-7731. 10.1073/pnas.91.16.77278052651https://www.ncbi.nlm.nih.gov/pubmed/8052651
[119]
Paz MF, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L, et al. Cpg island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res, 2004; 10(15): 4933-4938. 10.1158/1078-0432.CCR-04-039215297393https://www.ncbi.nlm.nih.gov/pubmed/15297393
[120]
Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, et al. Inactivation of the DNA-repair gene mgmt and the clinical response of gliomas to alkylating agents. N Engl J Med, 2000; 343(19): 1350-1354. 10.1056/NEJM20001109343190111070098https://www.ncbi.nlm.nih.gov/pubmed/11070098
[121]
Zawlik I, Vaccarella S, Kita D, Mittelbronn M, Franceschi S, Ohgaki H. Promoter methylation and polymorphisms of the mgmt gene in glioblastomas: A population-based study. Neuroepidemiology, 2009; 32(1): 21-29. 10.1159/00017008818997474https://www.ncbi.nlm.nih.gov/pubmed/18997474
[122]
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. Mgmt gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med, 2005; 352(10): 997-1003. 10.1056/NEJMoa04333115758010https://www.ncbi.nlm.nih.gov/pubmed/15758010
[123]
Armstrong TS, Wefel JS, Wang M, Gilbert MR, Won M, Bottomley A, et al. Net clinical benefit analysis of radiation therapy oncology group 0525: A phase iii trial comparing conventional adjuvant temozolomide with dose-intensive temozolomide in patients with newly diagnosed glioblastoma. J Clin Oncol, 2013; 31(32): 4076-4084. 10.1200/JCO.2013.49.606724101048a15ce303-2629-40d8-99be-42cca2c8f6a4https://www.ncbi.nlm.nih.gov/pubmed/24101048
[124]
Wiestler B, Claus R, Hartlieb SA, Schliesser MG, Weiss EK, Hielscher T, et al. Malignant astrocytomas of elderly patients lack favorable molecular markers: An analysis of the noa-08 study collective. Neuro Oncol, 2013; 15(8): 1017-1026. 23595628https://www.ncbi.nlm.nih.gov/pubmed/23595628
[125]
Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: The nordic randomised, phase 3 trial. Lancet Oncol, 2012; 13(9): 916-926. 10.1016/S1470-2045(12)70265-6230adc4b-082b-4254-aab5-174a9bebecc6http://dx.doi.org/10.1016/S1470-2045(12)70265-6
[126]
Reifenberger G, Hentschel B, Felsberg J, Schackert G, Simon M, Schnell O, et al. Predictive impact of mgmt promoter methylation in glioblastoma of the elderly. Int J Cancer, 2012; 131(6): 1342-1350. 10.1002/ijc.2738522139906https://www.ncbi.nlm.nih.gov/pubmed/22139906
[127]
Wick W, Weller M, van den Bent M, Sanson M, Weiler M, von Deimling A, et al. Mgmt testing--the challenges for biomarker-based glioma treatment. Nat Rev Neurol 2014; 10(7): 372-385. 10.1038/nrneurol.2014.10024912512https://www.ncbi.nlm.nih.gov/pubmed/24912512
[128]
Wick W, Osswald M, Wick A, Winkler F. Treatment of glioblastoma in adults. Ther Adv Neurol Disord, 2018; 11:1756286418790452. 10.1177/175628641879376630147750https://www.ncbi.nlm.nih.gov/pubmed/30147750
[129]
Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, et al. Loss of pten promotes resistance to T cell-mediated immunotherapy. Cancer Discov, 2016; 6(2): 202-216. 10.1158/2159-8290.CD-15-028326645196https://www.ncbi.nlm.nih.gov/pubmed/26645196
[130]
Erasimus H, Gobin M, Niclou S, Van Dyck E. DNA repair mechanisms and their clinical impact in glioblastoma. Mutat Res Rev Mutat Res 2016; 769: 19-35. 27543314https://www.ncbi.nlm.nih.gov/pubmed/27543314
[131]
Qian, XC, and Brent, TP. Methylation hot spots in the 5’ flanking region denote silencing of the o6-methylguanine-DNA methyltransferase gene. Cancer Res 1997; 57(17): 3672-3677. 9288770https://www.ncbi.nlm.nih.gov/pubmed/9288770
[132]
van Nifterik KA, van den Berg J, van der Meide WF, Ameziane N, Wedekind LE, Steenbergen RDM, et al. Absence of the mgmt protein as well as methylation of the mgmt promoter predict the sensitivity for temozolomide. Br J Cancer 2010; 103(1): 29-35. 10.1038/sj.bjc.660571220517307https://www.ncbi.nlm.nih.gov/pubmed/20517307
[133]
Chen ZP, Yarosh D, Garcia Y, Tampieri D, Mohr G, Malapetsa A, et al. Relationship between o6-methylguanine-DNA methyltransferase levels and clinical response induced by chloroethylnitrosourea therapy in glioma patients. Can J Neurol Sci 1999; 26(2): 104-109. 10352868https://www.ncbi.nlm.nih.gov/pubmed/10352868
[134]
Jaeckle KA, Eyre HJ, Townsend JJ, Schulman S, Knudson HM, Belanich M, et al. Correlation of tumor o6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: A southwest oncology group study. J Clin Oncol, 1998; 16(10): 3310-3315. 10.1200/JCO.1998.16.10.33109779706https://www.ncbi.nlm.nih.gov/pubmed/9779706
[135]
Christmann M, Kaina B. Epigenetic regulation of DNA repair genes and implications for tumor therapy. Mutat Res, 2019; 780: 15-28. 10.1016/j.mrfmmm.2015.07.00926258283https://www.ncbi.nlm.nih.gov/pubmed/26258283
[136]
Bobola MS, Tseng SH, Blank A, Berger MS, Silber JR. Role of o6-methylguanine-DNA methyltransferase in resistance of human brain tumor cell lines to the clinically relevant methylating agents temozolomide and streptozotocin. Clin Cancer Res, 1996; 2(4): 735-741. 9816224https://www.ncbi.nlm.nih.gov/pubmed/9816224
[137]
Middlemas DS, Stewart CF, Kirstein MN, Poquette C, Friedman HS, Houghton PJ, et al. Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models. Clin Cancer Res, 2000; 6(3): 998-1007. 10741727https://www.ncbi.nlm.nih.gov/pubmed/10741727
[138]
Sun Q, Pei C, Li Q, Dong T, Dong Y, Xing W, et al. Up-regulation of msh6 is associated with temozolomide resistance in human glioblastoma. Biochem Biophys Res Commun 2018; 496(4): 1040-1046. 10.1016/j.bbrc.2018.01.09329366782https://www.ncbi.nlm.nih.gov/pubmed/29366782
[139]
Walker MC, Masters JR, Margison GP. O6-alkylguanine-DNA-alkyltransferase activity and nitrosourea sensitivity in human cancer cell lines. Br J Cancer 1992; 66(5): 840-843. 10.1038/bjc.1992.3701419626https://www.ncbi.nlm.nih.gov/pubmed/1419626
[140]
Bryant HE, Helleday T. Inhibition of poly (adp-ribose) polymerase activates atm which is required for subsequent homologous recombination repair. Nucleic Acids Res 2006; 34(6): 1685-1691. 10.1093/nar/gkl10816556909https://www.ncbi.nlm.nih.gov/pubmed/16556909
[141]
Gupta SK, Smith EJ, Mladek AC, Tian S, Decker PA, Kizilbash SH, et al. Parp inhibitors for sensitization of alkylation chemotherapy in glioblastoma: Impact of blood-brain barrier and molecular heterogeneity. Front Oncol 2018; 8: 670. 10.3389/fonc.2018.0067030723695https://www.ncbi.nlm.nih.gov/pubmed/30723695
[142]
Helleday T, Bryant HE, Schultz N. Poly(adp-ribose) polymerase (parp-1) in homologous recombination and as a target for cancer therapy. Cell Cycle 2005; 4(9): 1176-1178. 10.4161/cc.4.9.203116123586https://www.ncbi.nlm.nih.gov/pubmed/16123586
[143]
Zhang Y, Dube C, Gibert M, Cruickshanks N, Wang B, Coughlan M, et al. The p53 pathway in glioblastoma. Cancers (Basel) 2018; 10(9): 297. 10.3390/cancers10090297http://www.mdpi.com/2072-6694/10/9/297
[144]
Hafner A, Bulyk ML, Jambhekar A, Lahav G. The multiple mechanisms that regulate p53 activity and cell fate. Nat Rev Mol Cell Biol, 2019; (4): 199-210. 10.1038/s41580-019-0110-x30824861https://www.ncbi.nlm.nih.gov/pubmed/30824861
[145]
Mantovani F, Collavin L, Del Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ 2019; 26(2): 199-212. 10.1038/s41418-018-0246-930538286https://www.ncbi.nlm.nih.gov/pubmed/30538286
[146]
Grisanti S, Ferrari VD, Buglione M, Agazzi GM, Liserre R, Poliani L, et al. Second line treatment of recurrent glioblastoma with sunitinib: Results of a phase ii study and systematic review of literature. J Neurosurg Sci, 2019; 63(4): 458-467. 10.23736/S0390-5616.16.03874-127680966https://www.ncbi.nlm.nih.gov/pubmed/27680966
[147]
Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, et al. Phase iii randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol, 2013; 31(26): 3212-3218. 10.1200/JCO.2012.47.246423940216https://www.ncbi.nlm.nih.gov/pubmed/23940216
[148]
Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, et al. Phase ii study of cci-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs, 2005; 23(4): 357-361. 10.1007/s10637-005-1444-016012795https://www.ncbi.nlm.nih.gov/pubmed/16012795
[149]
Wen PY, Touat M, Alexander BM, Mellinghoff IK, Ramkissoon S, McCluskey CS, et al. Buparlisib in patients with recurrent glioblastoma harboring phosphatidylinositol 3-kinase pathway activation: An open-label, multicenter, multi-arm, phase ii trial. J Clin Oncol, 2019; 37(9): 741-750. 10.1200/JCO.18.0120730715997https://www.ncbi.nlm.nih.gov/pubmed/30715997
[150]
Wick W, Gorlia T, Bady P, Platten M, van den Bent MJ, Taphoorn MJ, et al. Phase ii study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without mgmt promoter hypermethylation (eortc 26082). Clin Cancer Res, 2016; 22(19): 4797-4806. 10.1158/1078-0432.CCR-15-315327143690https://www.ncbi.nlm.nih.gov/pubmed/27143690
[151]
Ma DJ, Galanis E, Anderson SK, Schiff D, Kaufmann TJ, Peller PJ, et al. A phase ii trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: Ncctg n057k. Neuro Oncol, 2015; 17(9): 1261-1269. 10.1093/neuonc/nou32825526733https://www.ncbi.nlm.nih.gov/pubmed/25526733
[152]
Wick W, Dettmer S, Berberich A, Kessler T, Karapanagiotou-Schenkel I, Wick A, et al. N2m2 (noa-20) phase i/ii trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-mgmt hypermethylated glioblastoma. Neuro Oncol, 2019; 21(1): 95-105. 10.1093/neuonc/noy16130277538https://www.ncbi.nlm.nih.gov/pubmed/30277538
[153]
Taylor JW, Parikh M, Phillips JJ, James CD, Molinaro AM, Butowski NA, et al. Phase-2 trial of palbociclib in adult patients with recurrent rb1-positive glioblastoma. J Neurooncol, 2018; 140(2): 477-483. 10.1007/s11060-018-2977-330151703https://www.ncbi.nlm.nih.gov/pubmed/30151703
[154]
Lassman AB, Rossi MR, Raizer JJ, Abrey LE, Lieberman FS, Grefe CN, et al. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: Tissue analysis from north american brain tumor consortium trials 01-03 and 00-01. Clin Cancer Res, 2005; 11(21): 7841-7850. 10.1158/1078-0432.CCR-05-042116278407https://www.ncbi.nlm.nih.gov/pubmed/16278407
[155]
Hegi ME, Diserens AC, Bady P, Kamoshima Y, Kouwenhoven MC, Delorenzi M, et al. Pathway analysis of glioblastoma tissue after preoperative treatment with the egfr tyrosine kinase inhibitor gefitinib--a phase ii trial. Mol Cancer Ther, 2011; 10(6): 1102-1112. 10.1158/1535-7163.MCT-11-004821471286dfed9c20-110e-4463-b0d5-f55b4d1564d9http://dx.doi.org/10.1158/1535-7163.MCT-11-0048
[156]
Wen PY, Drappatz J, de Groot J, Prados MD, Reardon DA, Schiff D, et al. Phase ii study of cabozantinib in patients with progressive glioblastoma: Subset analysis of patients naive to antiangiogenic therapy. Neuro Oncol, 2018; 20(2): 249-258. 29016998https://www.ncbi.nlm.nih.gov/pubmed/29016998
[157]
Project ICGCPT. Recurrent met fusion genes represent a drug target in pediatric glioblastoma. Nat Med, 2016; 22(11): 1314-1320. 27748748https://www.ncbi.nlm.nih.gov/pubmed/27748748
[158]
Ferguson SD, Zhou S, Huse JT, de Groot JF, Xiu J, Subramaniam DS, et al. Targetable gene fusions associate with the idh wild-type astrocytic lineage in adult gliomas. J Neuropathol Exp Neurol, 2018; 77(6): 437-442. 10.1093/jnen/nly02229718398https://academic.oup.com/jnen/article/77/6/437/4989444
[159]
Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, et al. Transforming fusions of fgfr and tacc genes in human glioblastoma. Science 2012; 337(6099): 1231-1235. 10.1126/science.122083422837387https://www.ncbi.nlm.nih.gov/pubmed/22837387
[160]
Di Stefano AL, Fucci A, Frattini V, Labussiere M, Mokhtari K, Zoppoli P, et al. Detection, characterization, and inhibition of fgfr-tacc fusions in idh wild-type glioma. Clin Cancer Res, 2015; 21(14): 3307-3317. 10.1158/1078-0432.CCR-14-219925609060https://www.ncbi.nlm.nih.gov/pubmed/25609060
[161]
Kaley T, Touat M, Subbiah V, Hollebecque A, Rodon J, Lockhart AC, et al. Braf inhibition in braf(v600)-mutant gliomas: Results from the ve-basket study. J Clin Oncol, 2018; 36(35): JCO2018789990. 10.1200/JCO.18.0121930343620https://www.ncbi.nlm.nih.gov/pubmed/30343620
[162]
Takahashi M, Miki S, Fujimoto K, Fukuoka K, Matsushita Y, Maida Y, et al. Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts. Cancer Sci, 2019; 110(7): 2247-2257. 10.1111/cas.1406731099446https://www.ncbi.nlm.nih.gov/pubmed/31099446
[163]
Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, et al. Immune and genomic correlates of response to anti-pd-1 immunotherapy in glioblastoma. Nat Med, 2019; 25(3): 462-469. 10.1038/s41591-019-0349-y30742119https://www.ncbi.nlm.nih.gov/pubmed/30742119
[164]
George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ, Shukla S, et al. Loss of pten is associated with resistance to anti-pd-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity, 2017; 46(2): 197-204. 10.1016/j.immuni.2017.02.00128228279https://www.ncbi.nlm.nih.gov/pubmed/28228279
[165]
Lastwika KJ, Wilson W 3rd, Li QK, Norris J, Xu H, Ghazarian SR, et al. Control of pd-l1 expression by oncogenic activation of the akt-mtor pathway in non-small cell lung cancer. Cancer Res, 2016; 76(2): 227-238. 10.1158/0008-5472.CAN-14-336226637667https://www.ncbi.nlm.nih.gov/pubmed/26637667
[166]
Ebert PJR, Cheung J, Yang Y, McNamara E, Hong R, Moskalenko M, et al. Map kinase inhibition promotesT cell and anti-tumor activity in combination with pd-l1 checkpoint blockade. Immunity, 2016; 44(3): 609-621. 10.1016/j.immuni.2016.01.02426944201https://linkinghub.elsevier.com/retrieve/pii/S1074761316300115
[167]
Toso A, Revandkar A, Di Mitri D, Guccini I, Proietti M, Sarti M, et al. Enhancing chemotherapy efficacy in pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep, 2014; 9(1): 75-89. 10.1016/j.celrep.2014.08.04425263564https://www.ncbi.nlm.nih.gov/pubmed/25263564
[168]
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. Pd-1 blockade with nivolumab in relapsed or refractory hodgkin's lymphoma. N Engl J Med, 2015; 372(4): 311-319. 10.1056/NEJMoa141108725482239https://www.ncbi.nlm.nih.gov/pubmed/25482239
[169]
Berghoff AS, Preusser M. In search of a target: Pd-1 and pd-l1 profiling across glioma types. Neuro Oncol, 2016; 18(10): 1331-1332. 10.1093/neuonc/now16227534576https://www.ncbi.nlm.nih.gov/pubmed/27534576
[170]
Berghoff AS, Kiesel B, Widhalm G, Wilhelm D, Rajky O, Kurscheid S, et al. Correlation of immune phenotype with idh mutation in diffuse glioma. Neuro Oncol, 2017; 19(11): 1460-1468. 10.1093/neuonc/nox05428531337https://www.ncbi.nlm.nih.gov/pubmed/28531337
[171]
Garber ST, Hashimoto Y, Weathers SP, Xiu J, Gatalica Z, Verhaak RG, et al. Immune checkpoint blockade as a potential therapeutic target: Surveying cns malignancies. Neuro Oncol, 2016; 18(10): 1357-1366. 10.1093/neuonc/now13227370400https://www.ncbi.nlm.nih.gov/pubmed/27370400
[172]
Qiu XY, Hu DX, Chen WQ, Chen RQ, Qian SR, Li CY, et al. Pd-l1 confers glioblastoma multiforme malignancy via ras binding and ras/erk/emt activation. Biochim Biophys Acta Mol Basis Dis, 2018; 1864(5 Pt A): 1754-1769. 10.1016/j.bbadis.2018.03.00229510196https://www.ncbi.nlm.nih.gov/pubmed/29510196
[173]
Schumacher TN, Kesmir C, van Buuren MM. Biomarkers in cancer immunotherapy. Cancer Cell, 2015; 27(1): 12-14. 25584891https://www.ncbi.nlm.nih.gov/pubmed/25584891
[174]
Champiat S, Ferte C, Lebel-Binay S, Eggermont A, Soria JC. Exomics and immunogenics: Bridging mutational load and immune checkpoints efficacy. Oncoimmunology, 2014; 3(1): e27817. 10.4161/onci.2781724605269https://www.ncbi.nlm.nih.gov/pubmed/24605269
[175]
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to pd-1 blockade in non-small cell lung cancer. Science, 2015; 348(6230): 124-128. 25765070https://www.ncbi.nlm.nih.gov/pubmed/25765070
[176]
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to pd-1 blockade. Science, 2017; 357(6349): 409-413. 10.1126/science.aan673328596308https://www.ncbi.nlm.nih.gov/pubmed/28596308
[177]
Indraccolo S, Lombardi G, Fassan M, Pasqualini L, Giunco S, Marcato R, et al. Genetic, epigenetic, and immunologic profiling of mmr-deficient relapsed glioblastoma. Clin Cancer Res, 2019; 25(6): 1828-1837. 10.1158/1078-0432.CCR-18-189230514778https://www.ncbi.nlm.nih.gov/pubmed/30514778
[178]
Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. N Engl J Med, 2018; 378(5): 439-448. 10.1056/NEJMoa170986629385370https://www.ncbi.nlm.nih.gov/pubmed/29385370
[179]
Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel car t-cell therapy in refractory large b-cell lymphoma. N Engl J Med, 2017; 377(26): 2531-2544. 10.1056/NEJMoa170744729226797https://www.ncbi.nlm.nih.gov/pubmed/29226797
[180]
Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, et al. Her2-specific chimeric antigen receptor-modified virus-specificT cells for progressive glioblastoma: A phase 1 dose-escalation trial. JAMA Oncol, 2017; 3(8): 1094-1101. 10.1001/jamaoncol.2017.018428426845https://www.ncbi.nlm.nih.gov/pubmed/28426845
[181]
Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor t-cell therapy. N Engl J Med, 2016; 375(26): 2561-2569. 10.1056/NEJMoa161049728029927https://www.ncbi.nlm.nih.gov/pubmed/28029927
[182]
Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang WC, et al. Bioactivity and safety of il13ralpha2-redirected chimeric antigen receptor cd8+T cells in patients with recurrent glioblastoma. Clin Cancer Res, 2015; 21(18): 4062-4072. 10.1158/1078-0432.CCR-15-042826059190https://www.ncbi.nlm.nih.gov/pubmed/26059190
[183]
Zah E, Lin MY, Silva-Benedict A, Jensen MC, Chen YY. T cells expressing cd19/cd20 bispecific chimeric antigen receptors prevent antigen escape by malignant b cells. Cancer Immunol Res, 2016; 4(6): 498-508. 10.1158/2326-6066.CIR-15-023127059623https://www.ncbi.nlm.nih.gov/pubmed/27059623
[184]
Walseng E, Koksal H, Sektioglu IM, Fane A, Skorstad G, Kvalheim G, et al. A tcr-based chimeric antigen receptor. Sci Rep, 2017; 7(1): 10713. 10.1038/s41598-017-11126-y28878363https://www.ncbi.nlm.nih.gov/pubmed/28878363
[185]
Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing erbb2. Mol Ther, 2010; 18(4): 843-851. 10.1038/mt.2010.2420179677https://www.ncbi.nlm.nih.gov/pubmed/20179677
[186]
Richman SA, Nunez-Cruz S, Moghimi B, Li LZ, Gershenson ZT, Mourelatos Z, et al. High-affinity gd2-specific carT cells induce fatal encephalitis in a preclinical neuroblastoma model. Cancer Immunol Res, 2018; 6(1): 36-46. 10.1158/2326-6066.CIR-17-021129180536https://www.ncbi.nlm.nih.gov/pubmed/29180536
[187]
Ankri C, Shamalov K, Horovitz-Fried M, Mauer S, Cohen CJ. HumanT cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J Immunol, 2013; 191(8): 4121-4129. 24026081https://www.ncbi.nlm.nih.gov/pubmed/24026081
[188]
Prosser ME, Brown CE, Shami AF, Forman SJ, Jensen MC. Tumor pd-l1 co-stimulates primary human cd8(+) cytotoxicT cells modified to express a pd1:Cd28 chimeric receptor. Mol Immunol, 2012; 51(3-4): 263-272. 10.1016/j.molimm.2012.03.02322503210https://www.ncbi.nlm.nih.gov/pubmed/22503210
[189]
Shin JH, Park HB, Oh YM, Lim DP, Lee JE, Seo HH, et al. Positive conversion of negative signaling of ctla4 potentiates antitumor efficacy of adoptive t-cell therapy in murine tumor models. Blood, 2012; 119(24): 5678-5687. 10.1182/blood-2011-09-38051922538857https://www.ncbi.nlm.nih.gov/pubmed/22538857
[190]
Kobold S, Grassmann S, Chaloupka M, Lampert C, Wenk S, Kraus F, et al. Impact of a new fusion receptor on pd-1-mediated immunosuppression in adoptiveT cell therapy. J Natl Cancer Inst, 2015; 107(8):djv146. 10.1093/jnci/djv13625991002https://www.ncbi.nlm.nih.gov/pubmed/25991002
[191]
Liu X, Ranganathan R, Jiang S, Fang C, Sun J, Kim S, et al. A chimeric switch-receptor targeting pd1 augments the efficacy of second-generation carT cells in advanced solid tumors. Cancer Res, 2016; 76(6): 1578-1590. 10.1158/0008-5472.CAN-15-252426979791https://www.ncbi.nlm.nih.gov/pubmed/26979791
[192]
Gustafson MP, Lin Y, New KC, Bulur PA, O'Neill BP, Gastineau DA, et al. Systemic immune suppression in glioblastoma: The interplay between cd14+hla-drlo/neg monocytes, tumor factors, and dexamethasone. Neuro-oncology, 2010; 12(7): 631-644. 10.1093/neuonc/noq00120179016https://www.ncbi.nlm.nih.gov/pubmed/20179016
[193]
Mirzaei R, Sarkar S, Yong VWT. Cell exhaustion in glioblastoma: Intricacies of immune checkpoints. Trends Immunol, 2017; 38(2): 104-115. 10.1016/j.it.2016.11.00527964820https://www.ncbi.nlm.nih.gov/pubmed/27964820
Share
Back to top