You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Therapeutic Strategies Targeting IDH-Mutations: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Oncology
Contributor: Pasquale Persico

Mutations of isocitrate dehydrogenase (IDH) genes are the distinctive genetic feature of lower-grade gliomas (LGGs). Tumor-associated IDH1/2 mutations result in a loss of normal enzymatic function and the abnormal production of 2-hydroxyglutarate (2-HG), which acts as an oncometabolite causing widespread changes in histone and DNA methylation and altering cellular metabolism. The “truncal” role of IDH mutations in gliomagenesis  is examined here, giving hints on the different therapeutic strategies targeting IDH1/2-mutated gliomas.

  • isocitrate dehydrogenase (IDH) mutations
  • lower-grade gliomas
  • IDH inhibitors
  • Glioblastoma
  • clinical trials
  • targeted therapy
  • precision oncology
  • vaccines

1. Introduction

Since the first discovery of isocitrate dehydrogenase (IDH) somatic mutations in 2006, major advances have been made in understanding their contribution to cancer development, providing a strong rationale for pharmacologically targeting the mutant metabolic enzyme.
The IDH family includes three different isozymes regulating key metabolic cellular processes, such as the ‘Krebs’ cycle, glutamine metabolism, lipogenesis, and redox balance. IDH1 is located in the cytosol and peroxisomes, while IDH2 and IDH3 in the mitochondrial matrix. Physiologically, IDH1-2 is responsible for the NADP-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), producing NADPH in the process. Mutations of IDH1 and IDH2 have been identified in over 70% of lower-grade gliomas (LGGs; World Health Organization (WHO) grade II/III) and secondary glioblastoma (GBM) [1][2], and at lower frequencies in a variety of other human malignancies, including acute myeloid leukemia (AML; ≈30%), chondrosarcoma (≈50%), cholangiocarcinoma (≈15–20%), thyroid carcinoma, melanoma, angioimmunoblastic T-cell lymphoma, and in a rare subtype of breast cancer [3][4][5][6][7][8]. IDH3 is a heterodimer, not structurally related to the other two isoforms, and only rarely mutated in cancer.
Most common tumor-associated IDH1/2 mutations are located in key arginine residues (R132 for IDH1, R140, or R172 for IDH2) for the recognition of the substrate [9][10], and lead to a neomorphic gain of function enzyme with a markedly decreased affinity for isocitrate, capable instead of catalyzing the conversion of α-KG into 2-hydroxyglutarate (2-HG) in an NADPH-dependent manner. As a result, IDH-mutant (mut) cells accumulate 2-HG at supraphysiological levels (up to 100-fold higher than in IDH wild-type (wt) counterparts), while the intracellular concentration of α-KG greatly decreases [11].
It is now well documented that 2-HG has the properties of an “oncometabolite” contributing to tumorigenesis by altering epigenetic regulation, DNA repair mechanisms, multiple major metabolic pathways, and redox homeostasis [12][13].

2. IDH Mutations in Gliomas

The identification of IDH1/2 mutations in diffuse gliomas represents, doubtless, one of the major breakthroughs in the field of neuro-oncology over the last decades, which led brain tumors into a new molecular era, with several significant diagnostic, prognostic, and therapeutic implications.
Mutations in the IDH1 gene were firstly observed in 2008 by Parsons et al. in a small subset (12%) of GBMs, mainly affecting young patients, progressed from previous low-grade tumors (secondary GBM), and carrying a much better outcome [2]. IDH mutations have been subsequently recognized as the distinctive genetic feature of LGGs, occurring in more than 90% of low-grade gliomas (WHO grade II) and in 70% of anaplastic gliomas (WHO grade III) [1]. In addition to peculiar clinical characteristics such as younger age at diagnosis and an overall better prognosis, accumulating evidence allowed identifying IDH-mutated gliomas as a completely different entity at the molecular level compared to the IDH-wt counterparts [14].
Nearly all 1p/19q codeleted gliomas (oligodendroglial tumors) harbor an IDH1/2 mutation, along with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and telomerase reverse transcriptase (TERT) promoter mutation, while TP53 and ATRX alterations have been found in IDH1/2-mutated glioma without codeletion (astrocytic tumors). These great advances in molecular knowledge of brain tumors led, in 2016, to a major revision of the WHO classification with the introduction of the IDH mutational status and the presence of 1p/19q codeletion, in addition to histology, to define glioma subtypes [15]. Moreover, IDH s have been established as the most powerful positive prognostic factor for survival in gliomas, followed by age, tumor grade, and MGMT promoter methylation status. Although the underlying mechanisms have not yet been fully understood, the IDH mutational status seems to harbor also predictive significance, conferring an increased sensitivity to ionizing radiation and alkylating agents [16][17]. The WHO classification has been recently updated to better elucidate some gray areas. All IDH-mut diffuse astrocytic tumors have been considered as a single disease entity (astrocytoma, IDH-mut), graded (2, 3, or 4) based on the presence not only of microvascular proliferation or necrosis but also of other molecular markers with negative prognostic value, such as CDKN2A/B homozygous deletion. Conversely, IDH-wt low-grade astrocytoma harboring one or more of the three genetic features of classic GBM (TERT promoter mutation, epidermal growth factor receptor gene amplification, or combined gain of entire chromosome 7 and loss of entire chromosome 10), will be labeled as GBMs, carrying a very similar dismal prognosis [18].
In diffuse gliomas, over 90% of somatic IDH mutations are arginine-to-histidine heterozygous substitutions in the codon 132 (IDH1R132H mutation) of the IDH1 gene, with the remaining 10% represented by other amino acid substitutions located in the same spot. On the other hand, less than 1% of gliomas harbor IDH2 hotspot mutations, mostly occurring at arginine 172 (IDH2R172H mutation) or arginine 140 (IDH2R140 mutation) [19]. IDH mutations have been suggested to represent an early “truncal” event in the complex process of gliomagenesis, occurring in the stem cell progenitor from the subventricular zone stem cell niche before acquiring other “secondary” genetic alterations such 1p-19q codeletion, ATRX, and TP53 mutations. The progressive accumulation of 2-HG over physiological levels impairs cellular metabolism, including glutamine catabolism and Krebs Cycle, and reshapes the epigenetics of the cell. The epigenetic alterations are thought to be an essential factor of gliomagenesis. 2-HG inhibits a wide range of a-KG-dependent dioxygenases, including lysine demethylases, Ten Eleven Translocase (TET) hydroxylases, Jumonji-C domain histone demethylases (JHDMs), and prolyl hydroxylase domain (PHD), leading to a global DNA and histone hypermethylation, stem-like cell differentiation block, and altered hypoxia-inducible factor (HIF) activity [20][21][22]. Consequently, IDH-mut gliomas acquire the CpG island methylator phenotype (CIMP or G-CIMP), which may be considered a sort of genetic signature of this class of tumors, with several transcriptional changes and the silencing of numerous loci in the genome. Based on the extent of global DNA methylation, IDH-mut/G-CIMP+ tumors have been further divided into two distinct subgroups characterized by different outcomes: G-CIMP-low gliomas with a low degree of DNA methylation and unfavorable clinical outcome and G-CIMP-high gliomas characterized by higher DNA methylation and better outcome [23][24]. It remains unclear whether IDH mutation by itself is responsible for tumor development or if it requires other oncogenic events to initiate gliomagenesis. Although DNA methylation is usually believed to be reversible, a study revealed that some of the DNA methylation sites in the IDH-mut cells might persist, even when the mutant enzyme is turned off [25]. This evidence supports the hypothesis that IDH mutation plays a key role in the first steps of malignant transformation, which becomes irreversible once the cells have initiated the oncogenic process [25]. However, emerging data suggest that for a subgroup of LGGs, 2-HG produced by the mutant enzyme may become non-essential for tumor progression as they acquire tertiary driver mutations and progress to a higher grade. IDH mutations would therefore behave as “passenger mutation,” losing their oncogenic function and even being eliminated in the latest stages of glioma progression [26].

3. IDH as Therapeutic Target for Treatment of IDH-Mutated Gliomas

It is not surprising that IDH mutations have been launched to the top of the list of new potential therapeutic targets for IDH-mut diffuse glioma. Two distinct strategies have been proposed so far and are currently under intense clinical investigation: (i) reducing the amount of intratumoral 2-HG by directly blocking the activity of the mutant IDH enzyme; (ii) taking advantage of the cellular vulnerabilities as a consequence of 2-HG accumulation. A key point that still needs to be addressed is how to locate an IDH-targeted therapy within the treatment paradigm of the IDH-mutated LGGs, which are typically slow-growing tumors arising in the young and displaying a good prognosis. LGGs’ therapeutic management consists of maximal safe surgical resection, eventually followed by radiotherapy and chemotherapy given as adjuvant for high-risk patients or postponed at recurrence/progression for low-risk cases. A crucial concern of neuro-oncologists in treating LGGs is the onset of long-term treatment-related side effects. In particular, radiation-induced neurocognitive defects can affect multiple domains, including memory, attentional and executive functioning, information processing speed, and problem-solving capability. These cognitive disorders caused by the exposure of healthy brain tissue, endocrine disorders, insomnia, and fatigue (related to the impairment of the hypothalamic-pituitary axis) may significantly compromise these young patients’ daily-life activities and social relationships. Furthermore, chemotherapy with alkylating agents may exacerbate the risk of developing long-term toxicities and accelerate malignant transformation. Thus, the development of novel therapeutic approaches in this setting, able to control tumor growth and high-grade progression, delaying or even avoiding the use of radiation and chemotherapy, clearly represents an urgent need.
Despite the great enthusiasm for what represents the first attempt of applying “precision oncology” to LGGs’ treatment, multiple observations call for some caution. Firstly, major epigenetic changes induced by the mut-IDH enzyme may persist even after suppressing 2-HG levels [25]. Secondly, blocking the mutant IDHs might, at least in theory, lead to the transformation of usually slow-growing and good prognosis tumors into more aggressive biological subtypes. Finally, once LGGs acquire other secondary and tertiary genetic alterations during their biological evolution, IDH mutations may lose their oncogenic function and even be eliminated at the latest stages of progression.

4. Immunotherapeutic Approaches for IDH Mutant Gliomas

4.1. Preclinical Studies

Given the remarkable clinical successes in other tumor types, great efforts have been undertaken in latest years to explore the role of immunotherapy in the field of neuro-oncology and even in the context of LGGs. It has been observed that spontaneous IDH1R132H-specific CD4+ T-helper-1 (TH1) and humoral immune responses might occur in LGG patients. Moreover, there are now several preclinical evidences demonstrating that the oncometabolite 2-HG greatly contributes to shaping the immunosuppressive glioma microenvironment and plays a crucial role in immune escape mechanisms [27]. Berghoff et al., analyzing a cohort of 43 WHO grade II/III gliomas (39 IDH-mut, 4 IDH-wt) and 14 IDH-mut GBMs, demonstrated that IDH-mut tumors have fewer CD3+ and PD1+ tumor-infiltrating lymphocytes (TILs) and decreased expression of programmed cell death ligand (PD-L1) compared to their wt counterparts (series of 117 IDH-wt GBMs) [28]. Using data of 677 diffuse gliomas grades II-IV from The Cancer Genome Atlas (TCGA) database, authors found that PD-L1 gene expression was statistically significantly higher in IDH-wt WHO grade II/III gliomas compared with IDH-mut WHO grade II/III gliomas [28]. Moreover, PD-L1 gene promoter methylation levels were higher in IDH-mut than IDH-wt samples [28].
Gene expression data from the same TCGA database revealed a reduced expression of cytotoxic T lymphocyte-associated genes and IFN-γ-inducible chemokines, including CXCL10 in IDH-mut tumors compared with IDH-wt tumors [29]. The introduction of mutant IDH1 or treatment with 2-HG in immortalized normal human astrocytes and syngeneic mouse glioma models led to a reduction of CXCL10 levels, which was associated with decreased production of STAT1 and also suppressed the accumulation of T-cells into tumors [29]. All these effects are reversible by treatment with IDH-C35, a specific inhibitor of IDH1-mut.
Bunse et al. demonstrated that 2-HG directly impairs T-cells’ activation, proliferation, and cytokine secretion by altering the calcium-dependent transcriptional activity of nuclear factors and suppressing ATP-dependent TCR signaling and polyamine biosynthesis [30]. Moreover, in different syngeneic IDH1-mut tumor models, 2-HG inhibited the development of antitumor T-cell immunity induced by IDH-1 vaccination, adoptive T-cell transfer, and checkpoint blockade while pharmacological inhibition of the neomorphic enzymatic function of mut-IDH1 by administration of BAY-1436032 alleviates intratumoral immune suppression [30] (Table 1).
Table 1. Preclinical studies of IDH-targeted agents in glioma mouse models.
Reference Agents Results Additional Findings
Rohle, D. et al., 2013 [31] AG-5198 50–60% growth inhibition (p = 0.015, two-tailed t-test)
No toxicity along 3 weeks of daily treatment		 Reduced staining with Ki-67 antibody in treated mice
Tateishi, K. et al., 2015 [32] IDH1i Near-complete elimination of 2-HG within brain tumors after 5 days of treatment
No effect on tumor size and survival: mOS 46 days in both treated mice and controls (95% CI; 45–48; p = 0.79)		 No effect on expression of IDH1, Ki-67, GFAP, or nestin within the tumors
Popovici-Muller, J. et al., 2018 [33] Ivosidenib (AG-120) Low brain penetration in rats with intact blood–brain–barrier: 4.1% (AUC 0−8 h (brain)/AUC 0−8 h (plasma))
Robust time-dependent, reversible tumor 2-HG reduction (IC50 range 5–13 nM)		  
Pusch, S. et al., 2017 [34] BAY 1436032 Significantly reduced 2-HG concentration (p = 0.00000057) and prolonged survival (p = 0.025) compared to untreated controls SOX2 expression reduced by half in tumors of treated mice
Konteatis, Z. et al., 2020 [35] Vorasidenib (AG-881) >97% inhibition of 2-HG production in mice glioma tissue  
Bunse, L. et al., 2018 [30] BAY 1436032 Oral administration of BAY-1436032 in combination with PD-1 inhibition increased overall survival in mice Enhanced intratumoral CD4 T-cell proliferation
Schumacher, T. et al., 2014 [36] IDH1 (R132H) peptide vaccine Effective control growth in syngeneic IDH1 (R132H)-expressing tumors Robust interferon IFN-γ T-cell response
Mutation-specific anti-IDH1 antibodies detectable in serum of immunized mice
Pellegatta, S. et al., 2015 [37] IDH1 (R132H) peptide vaccine Significant survival gain compared to controls with 25% of cured mice Higher amounts of peripheral CD8+ T-cells, higher production of IFN-γ, anti-IDH1-mut antibodies in immunized mice
Kadiyala, P. et al., 2021 [38] AGI-5198 +/− IR 2-HG levels in mIDH1 brain tumor tissue reduced by approximately 2.4-fold (p ≤ 0.0001) after treatment with AGI-5198
40% long-term survivors among mice treated with AGI-5198 or AGI-5198 + IR
Anti-PD-L1 + AGI-5198 + IR and TMZ improved 90-day survival rate by 40% (95% CI: 0–95%, 1-sided p = 0.08)		 AGI-5198 administration led to a 3-fold (p ≤ 0.001) increase in the PD-L1 expression on the CD45–/Nestin+ tumor cells compared with untreated controls
Increased infiltration of CD8+ T-cells (p < 0.01) in tumors treated with anti-PD-L1 + AGI-5198 + IR and TMZ
2-HG 2-hydroxyglutarate; AUC area under the curve; CD4 cluster of differentiation 4; CD8 cluster of differentiation 8; GFAP glial fibrillary acidic protein; IC50 half maximal inhibitory concentration; IDH isocitrate dehydrogenase; IFN-γ interferon γ; IR ionizing radiation; mOS median overall survival; PD-1 programmed cell death protein 1; PD-L1 programmed death-ligand 1; SOX2 SRY-Box Transcription Factor 2; TMZ temozolomide.
Zhang et al. have shown that glioma cells harboring IDH1 mutation acquire resistance to natural killer (NK) cell-mediated lysis due to the epigenetic silencing of NKG2D ligands ULBP1 and ULBP3 by 2-HG-induced hypermethylation [39], making IDH-mut tumors less vulnerable to NK-cell-mediated lysis as compared to IDH-wt. Furthermore, decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH-mut glioma cells, suggesting a potential method to sensitize IDH-mut gliomas to NK cell-mediated immune surveillance in the clinic [39].
A couple of years later, the same group demonstrated that 2-HG impaired both the classical and the alternative pathways of complement activation, provoking a reduced complement-mediated glioma cell injury and a decreased complement-mediated opsonization and phagocytosis [40]. Moreover, 2-HG inhibits antitumor T-cell response, directly suppressing T-cell migration, proliferation, and cytokine secretion [40].
IDH1R132H is a tumor-specific neoantigen with high penetrance and uniform expression in all tumor cells, representing an ideal target for mutation-specific vaccination strategies. An immunogenic epitope in the IDH1R132H protein suitable for building a mut-specific vaccine has been firstly identified by Schumacher and colleagues [36]. In a murine sarcoma model lacking mouse MHC and transgenic for human MHC class I and II, vaccination with IDH1R132H p123–142 resulted in robust interferon (IFN)-γ mutation-specific T-cell responses that were effective in control growth of syngeneic IDH1(R132H)-expressing tumors [36] (Table 1). IDH1-mut vaccines demonstrated efficacy also in an intracranial glioma model genetically modified to harbor the R132H mutation, producing a significant survival gain compared to controls and 25% of cured mice [37] (Table 1). In addition, higher amounts of peripheral CD8+ T-cells, higher production of IFN-γ, and evidence of anti-IDH1-mut antibodies were observed in immunized mice [37].
More recently, Kadiyala et al. developed a genetically engineered mouse model of glioma expressing IDH1R132H and loss of ATRX and TP53 to better understand the role played by 2-HG in influencing the glioma immune microenvironment [38] (Table 1). 2-HG inhibition by treatment with a specific IDH1R132H inhibitor alone or in combination with radiation and temozolomide (TMZ) substantially prolonged survival of IDH1-mut glioma-bearing mice, increased PD-L1 expression levels to similar levels as observed in IDH-wt gliomas, contributing in also generating an anti-glioma immunity [38]. Moreover, the coadministration of PD-L1 blockade with IDH1R132H inhibition and the standard of care (RT + TMZ) markedly enhanced the outcome of IDH1-mut glioma-bearing mice, counteracting T-cell exhaustion and eliciting an immunological memory with the generation of memory CD8+ T-cells [38]. These data supported the design of clinical trials investigating the efficacy of IDH1R132H inhibitors in combination with standard of care (SOC) and anti-PD-L1 immune checkpoint blockade to treat glioma patients expressing with IDH mutations.

4.2. Clinical Trials

Based on all these preclinical data, the German National Cancer Center has conducted a multicenter, first-in-humans Phase I trial, evaluating the feasibility, safety, and immunogenicity of a vaccine targeting the IDH1R132H mutant protein among newly diagnosed patients with IDH1-mut glioma (NOA16, NCT02454634) [41][42] (Table 2).
Table 2. Clinical trials with IDH-targeted therapies in gliomas with available data.
Reference NCT Number Study Design Treatment Population Main Results Adverse Events (in ≥10% of Patients)
Mellinghoff, I.K. et al., 2020 [43] NCT02073994 Phase I Ivosidenib (AG-120) single agent Advanced IDH1-mut solid tumors
35 non-enhancing recurrent gliomas
31 enhancing recurrent gliomas		 500 mg once daily selected for expansion part
DCR 88% vs. 45%; median PFS 13.6 vs. 1.4 months in non-enhancing vs. enhancing cohort		 No DLT
Headache; fatigue; nausea; vomiting; seizure; diarrhea; aphasia; hyperglycemia; neutropenia; depression; hypophosphatemia; paresthesia
Mellinghoff, I.K. et al., 2021 [44] NCT02481154 Phase I Vorasidenib (AG-188) single agent Advanced IDH1 and/or IDH2-mut solid tumors
22 non-enhancing recurrent gliomas
30 enhancing recurrent gliomas		 Recommended dose <100 mg in gliomas
Non-enhancing glioma: ORR 18% (1 PR; 3 minor responses; 17 SD)
Enhancing glioma: ORR 0% (17 SD)
Median PFS: 36.8 vs. 3.6 months in non-enhancing vs. enhancing groups		 DLT (grade ≥2 ALT/AST increase) in 5 pts at ≥100 mg dose levels
Headache; AST/ALT increase; fatigue; nausea; seizure; hyperglicemia; vomiting; constipation; dizziness; neutropenia; cough; diarrhea; aphasia; hypoglycemia
Mellinghoff, I.K. et al., 2019 [45] NCT03343197 Phase I Perioperative Ivosidenib (AG-120) (n = 13) or vorasidenib (AG-188) (n = 14) single agent Recurrent non-enhancing IDH1R132H-mut LGGs undergoing craniotomy 2-HG concentration 92% (ivosidenib) and 92.5% (vorasidenib) lower in resected tumor tissue of treated patients Diarrhea; constipation; hypocalcemia; nausea; anemia; hyperglicemia; pruritus; headache; fatigue
Wick, A. et al., 2021 [46] NCT02746081 Phase I BAY-1436032 single agent Advanced IDH1R132X-mut solid tumors
26 LGG astrocytoma
13 LGG oligodendroglioma
16 GBM		 1500 mg twice daily selected for expansion cohorts
LGG: ORR 11% (1 CR; 3 PR; 15 SD)
GBM: ORR 0%, SD 29%.
PFS-rate at three months: 0.31 vs. 0.22 in LGG vs. GBM		 No DLT
Fatigue; disgeusia
Natsume, A. et al., 2019 [47] NCT03030066 Phase I DS-100b single agent Recurrent/progressive IDH1R132X-mut glioma 125–1400 mg twice daily
Non-enhancing glioma (n = 9):
2 minor responses; 7 SD
Enhancing glioma (n = 29): 1 CR; 3 PR; 10 SD		 DLT (grade 3 WBC decrease) at 1000 mg
twice daily
Skin hyperpigmentation; diarrhea; pruritus; nausea; rash; headache
Platten, M. et al., 2021 [41] NCT02454634 Phase I IDH1-vac single agent Newly diagnosed IDHR132H-mut grade 3 or 4 astrocytomas 93.3% IDH1-vac induced immune response
3-years PFS: 63%
3-years OS: 84%		 No RLTs
Mild site reactions
2-HG 2-Hydroxyglutarate; ALT alanine transaminase; AST aspartate transaminase; CR complete response; DCR disease control rate; DLT dose-limiting toxicity; GBM glioblastoma; IDH Isocitrate dehydrogenase; LGG low-grade glioma; ORR objective response rate; OS overall survival; PFS progression-free survival; PR partial response; RLT regime-limiting toxicity; SD stable disease; WBC white blood cells.
The vaccine consisted of 300 mg of a 20-mer R132H peptide emulsified in montanide and was administered subcutaneously at 2-week intervals for the first four doses, followed by four additional doses given every four weeks (weeks 1, 3, 5, 7, 11, 15, 19, and 23). The primary safety endpoint was the Regime-Limiting Toxicity (RLT), defined as protocol-specified, treatment-related, severe AEs [41].
Immunogenicity was evaluated by assessing an IDH1R132H-specific T and/or B-cell response, measured by IFN-γ ELISpot and ELISA, respectively, at any established time points (six in total) during the trial. Brain MRI scans were performed every three months to assess disease response according to the RANO criteria [41].
From May 2015 to November 2018, a total of 33 patients with histologically-confirmed IDH1R132H-mutated, newly-diagnosed grade 3 or 4 astrocytomas, according to the WHO 2016 classification, were enrolled across seven German centers, and 32 of them received at least one dose of vaccine [41]. Patients were divided into three subgroups, according to their previous treatments: RT alone (treatment group 1, including six patients), CT with TMZ for three cycles (treatment group 2, including three patients), or standard chemoradiation with TMZ (treatment group 3, including 23 patients) [41]. Vaccination for patients in group 1 started 4–6 weeks after the end of radiotherapy, for patients in group 2 on the fourth cycle of TMZ monotherapy, and for patients in group 3 on the first cycle of adjuvant TMZ, respectively [41]. About two-thirds (66%) of the patients had grade 3 astrocytoma, while 34% had a grade 4 tumor [41]. A gross total resection was performed in about half of the cases (53%), while 38% and 9% of patients underwent a subtotal resection or just a biopsy, respectively [41].
The trial met its primary safety endpoint as IDH1R132H-vaccine was well tolerated, with no RLTs observed, and most of the AEs consisting of mild site reactions; 29 out of the 32 patients completed all planned study vaccinations [41].
Most patients (93.3%) developed an IDH vaccine-induced immune response; T-cell responses were observed in 26 out of 30 patients analyzed, while B-cell responses in 28 out of 30, respectively [41]. A mutation-specificity score (MSS) was built as an explorative measure of the magnitude and duration of IDH1R132H-induced T-cell responses: it was observed that higher MSSs were associated with high levels of TH1 and TH17 T-helper cell subtypes cytokines, such as IL-17, TNF, and IFN-gamma [41].
With a median follow-up of 46.9 months, PFS and OS at three years were 63% and 84%, respectively, with no significant differences between grade III and grade IV patients [41].
The authors described a relatively high rate of pseudoprogression in the trial population (37.5%, 12 out of 32 patients) compared to that reported in a molecularly-matched 60-patient population selected as a control cohort (16.5%, 10 out of 60 patients) [41]. Pseudoprogression was observed only in patients with a detectable immune response in the peripheral blood and correlated with IDH vaccine-specific T-cell levels [41]. Only one patient with PsPD underwent post-vaccination surgery, and the presence of IDH1 R132H-reactive intratumoral CD4+ TCR14+ cells was confirmed in the surgical specimen, suggesting that vaccination induces a clonal expansion of specific T-helper cells able to reach the brain tissue [41].
Mature clinical data of immune checkpoint blockade in IDH-mut gliomas are still lacking. However, a Phase II clinical trial (NCT02968940) in which the anti-PD-L1 avelumab has been associated with hypofractionated RT as treatment of patients with IDH-mut GBMs recently completed the enrollment, and results are now awaited (Table 3). In addition, there are many other clinical trials investigating PD-1/PD-L1 blockade alone or in combination with other agents, such as specific mut-IDH inhibitors or PARP inhibitors (NCT03991832, NCT03557359, NCT03718767, NCT03925246), still ongoing. Results of these studies, when available, will help clinicians to clarify the role of checkpoint inhibition in the context of IDH-mut LGGs (Table 3).
Table 3. Ongoing clinical trials in IDH-mutant gliomas.
NCT Number Study Phase Population Experimental Treatment Status
NCT04164901 Phase 3 Residual or recurrent IDH1/2-mut grade 2 gliomas Vorasidenib versus placebo Recruiting
NCT03684811 Phase 1b/2 Advanced IDH1-mut gliomas and other solid tumors (HCC; bile duct carcinoma; cholangiocarcinoma; other epatobiliary carcinomas; chondrosarcoma) FT 202 single agent or in combination with chemotherapy (azacitidine; gemcitabine and cisplatin) or immunotherapy (nivolumab) Active, not recruiting
NCT02968940 Phase 2 IDH-mut GBM Avelumab and hypofractionated RT Completed
NCT03991832 Phase 2 Advanced IDH-mut gliomas and other solid tumors (cholangiocarcinoma and others) Durvalumab and Olaparib Recruiting
NCT03557359 Phase 2 Recurrent/progressive IDH-mut gliomas Nivolumab Active, not recruiting
NCT03718767 Phase 2 IDH-mut gliomas Nivolumab Recruiting
NCT03925246 Phase 2 Recurrent IDH-mut high grade gliomas Nivolumab Active, not recruiting
NCT03212274 Phase 2 Advanced IDH1/2-mut gliomas and other solid tumors (cholangiocarcinoma and others) Olaparib Recruiting
NCT03561870 Phase 2 Recurrent IDH-mut gliomas Olaparib Active, not recruiting
NCT03749187 Phase 1 IDH1/2-mut gliomas PARP inhibitor (BGB-290) and TMZ Recruiting
NCT03914742 Phase 1/2 IDH1/2-mut gliomas PARP inhibitor (BGB-290) and TMZ Recruiting
NCT02702492 Phase 1 Solid tumors or NHL KPT-9274 (dual inhibitor of PAK4 and NAMPT) ± Nivolumab Terminated
NCT03666559 Phase 2 Recurrent IDH1/2-mut gliomas Azacitidine Recruiting
NCT03922555 Phase 1 Recurrent/progressive non-enhancing IDH-mut gliomas ASTX727 (cedazuridine + cytidine antimetabolite decitabine) Recruiting
GBM glioblastoma; HCC hepatocellular carcinoma; IDH isocitrate dehydrogenase; NAMPT nicotinamide phosphoribosyltransferase; PAK4 p21-activated kinase 4; PARP poly (ADP-ribose) polymerase.

This entry is adapted from the peer-reviewed paper 10.3390/cancers14051125

References

  1. Yan, H.; Parsons, D.W.; Jin, G.; McLendon, R.; Rasheed, B.A.; Yuan, W.; Kos, I.; Batinic-Haberle, I.; Jones, S.; Riggins, G.J.; et al. IDH1 and IDH2 Mutations in Gliomas. N. Engl. J. Med. 2009, 360, 765–773.
  2. Parsons, D.W.; Jones, S.; Zhang, X.; Lin, J.C.-H.; Leary, R.J.; Angenendt, P.; Mankoo, P.; Carter, H.; Siu, I.-M.; Gallia, G.L.; et al. An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science 2008, 321, 1807–1812.
  3. Patel, J.P.; Gönen, M.; Figueroa, M.E.; Fernandez, H.; Sun, Z.; Racevskis, J.; van Vlierberghe, P.; Dolgalev, I.; Thomas, S.; Aminova, O.; et al. Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia. N. Engl. J. Med. 2012, 366, 1079–1089.
  4. Amary, M.F.; Bacsi, K.; Maggiani, F.; Damato, S.; Halai, D.; Berisha, F.; Pollock, R.; O’Donnell, P.; Grigoriadis, A.; Diss, T.; et al. IDH1 and IDH2 Mutations Are Frequent Events in Central Chondrosarcoma and Central and Periosteal Chondromas but Not in Other Mesenchymal Tumours: IDH1 and IDH2 Mutations Frequency in Mesenchymal Tumours. J. Pathol. 2011, 224, 334–343.
  5. Ganguly, B.B.; Kadam, N.N. Mutations of Myelodysplastic Syndromes (MDS): An Update. Mutat. Res. Rev. Mutat. Res. 2016, 769, 47–62.
  6. Farshidfar, F.; Zheng, S.; Gingras, M.-C.; Newton, Y.; Shih, J.; Robertson, A.G.; Hinoue, T.; Hoadley, K.A.; Gibb, E.A.; Roszik, J.; et al. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. Cell Rep. 2017, 18, 2780–2794.
  7. Stein, E.M.; DiNardo, C.D.; Pollyea, D.A.; Fathi, A.T.; Roboz, G.J.; Altman, J.K.; Stone, R.M.; DeAngelo, D.J.; Levine, R.L.; Flinn, I.W.; et al. Enasidenib in Mutant IDH2 Relapsed or Refractory Acute Myeloid Leukemia. Blood 2017, 130, 722–731.
  8. DiNardo, C.D.; Stein, E.M.; de Botton, S.; Roboz, G.J.; Altman, J.K.; Mims, A.S.; Swords, R.; Collins, R.H.; Mannis, G.N.; Pollyea, D.A.; et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N. Engl. J. Med. 2018, 378, 2386–2398.
  9. Dang, L.; White, D.W.; Gross, S.; Bennett, B.D.; Bittinger, M.A.; Driggers, E.M.; Fantin, V.R.; Jang, H.G.; Jin, S.; Keenan, M.C.; et al. Cancer-Associated IDH1 Mutations Produce 2-Hydroxyglutarate. Nature 2009, 462, 739–744.
  10. Bhavya, B.; Anand, C.R.; Madhusoodanan, U.K.; Rajalakshmi, P.; Krishnakumar, K.; Easwer, H.V.; Deepti, A.N.; Gopala, S. To Be Wild or Mutant: Role of Isocitrate Dehydrogenase 1 (IDH1) and 2-Hydroxy Glutarate (2-HG) in Gliomagenesis and Treatment Outcome in Glioma. Cell Mol. Neurobiol. 2020, 40, 53–63.
  11. Yen, K.E.; Bittinger, M.A.; Su, S.M.; Fantin, V.R. Cancer-Associated IDH Mutations: Biomarker and Therapeutic Opportunities. Oncogene 2010, 29, 6409–6417.
  12. McBrayer, S.K.; Mayers, J.R.; DiNatale, G.J.; Shi, D.D.; Khanal, J.; Chakraborty, A.A.; Sarosiek, K.A.; Briggs, K.J.; Robbins, A.K.; Sewastianik, T.; et al. Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 2018, 175, 101–116.e25.
  13. Liu, P.-S.; Wang, H.; Li, X.; Chao, T.; Teav, T.; Christen, S.; di Conza, G.; Cheng, W.-C.; Chou, C.-H.; Vavakova, M.; et al. α-Ketoglutarate Orchestrates Macrophage Activation through Metabolic and Epigenetic Reprogramming. Nat. Immunol. 2017, 18, 985–994.
  14. Eckel-Passow, J.E.; Lachance, D.H.; Molinaro, A.M.; Walsh, K.M.; Decker, P.A.; Sicotte, H.; Pekmezci, M.; Rice, T.; Kosel, M.L.; Smirnov, I.V.; et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N. Engl. J. Med. 2015, 372, 2499–2508.
  15. Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary. Acta Neuropathol. 2016, 131, 803–820.
  16. Tran, A.N.; Lai, A.; Li, S.; Pope, W.B.; Teixeira, S.; Harris, R.J.; Woodworth, D.C.; Nghiemphu, P.L.; Cloughesy, T.F.; Ellingson, B.M. Increased Sensitivity to Radiochemotherapy in IDH1 Mutant Glioblastoma as Demonstrated by Serial Quantitative MR Volumetry. Neuro-Oncology 2014, 16, 414–420.
  17. Wang, P.; Wu, J.; Ma, S.; Zhang, L.; Yao, J.; Hoadley, K.A.; Wilkerson, M.D.; Perou, C.M.; Guan, K.-L.; Ye, D.; et al. Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents. Cell Rep. 2015, 13, 2353–2361.
  18. Louis, D.N.; Perry, A.; Wesseling, P.; Brat, D.J.; Cree, I.A.; Figarella-Branger, D.; Hawkins, C.; Ng, H.K.; Pfister, S.M.; Reifenberger, G.; et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary. Neuro-Oncology 2021, 23, 1231–1251.
  19. Han, S.; Liu, Y.; Cai, S.J.; Qian, M.; Ding, J.; Larion, M.; Gilbert, M.R.; Yang, C. IDH Mutation in Glioma: Molecular Mechanisms and Potential Therapeutic Targets. Br. J. Cancer 2020, 122, 1580–1589.
  20. Xu, W.; Yang, H.; Liu, Y.; Yang, Y.; Wang, P.; Kim, S.-H.; Ito, S.; Yang, C.; Wang, P.; Xiao, M.-T.; et al. Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases. Cancer Cell 2011, 19, 17–30.
  21. Kohli, R.M.; Zhang, Y. TET Enzymes, TDG and the Dynamics of DNA Demethylation. Nature 2013, 502, 472–479.
  22. Lu, C.; Ward, P.S.; Kapoor, G.S.; Rohle, D.; Turcan, S.; Abdel-Wahab, O.; Edwards, C.R.; Khanin, R.; Figueroa, M.E.; Melnick, A.; et al. IDH Mutation Impairs Histone Demethylation and Results in a Block to Cell Differentiation. Nature 2012, 483, 474–478.
  23. Noushmehr, H.; Weisenberger, D.J.; Diefes, K.; Phillips, H.S.; Pujara, K.; Berman, B.P.; Pan, F.; Pelloski, C.E.; Sulman, E.P.; Bhat, K.P.; et al. Identification of a CpG Island Methylator Phenotype That Defines a Distinct Subgroup of Glioma. Cancer Cell 2010, 17, 510–522.
  24. Malta, T.M.; de Souza, C.F.; Sabedot, T.S.; Silva, T.C.; Mosella, M.S.; Kalkanis, S.N.; Snyder, J.; Castro, A.V.B.; Noushmehr, H. Glioma CpG Island Methylator Phenotype (G-CIMP): Biological and Clinical Implications. Neuro-Oncology 2018, 20, 608–620.
  25. Turcan, S.; Makarov, V.; Taranda, J.; Wang, Y.; Fabius, A.W.M.; Wu, W.; Zheng, Y.; El-Amine, N.; Haddock, S.; Nanjangud, G.; et al. Mutant-IDH1-Dependent Chromatin State Reprogramming, Reversibility, and Persistence. Nat. Genet. 2018, 50, 62–72.
  26. Johannessen, T.-C.A.; Mukherjee, J.; Viswanath, P.; Ohba, S.; Ronen, S.M.; Bjerkvig, R.; Pieper, R.O. Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis. Mol. Cancer Res. 2016, 14, 976–983.
  27. Schumacher, T.; Bunse, L.; Wick, W.; Platten, M. Mutant IDH1: An Immunotherapeutic Target in Tumors. OncoImmunology 2014, 3, e974392.
  28. Berghoff, A.S.; Kiesel, B.; Widhalm, G.; Wilhelm, D.; Rajky, O.; Kurscheid, S.; Kresl, P.; Wöhrer, A.; Marosi, C.; Hegi, M.E.; et al. Correlation of Immune Phenotype with IDH Mutation in Diffuse Glioma. Neuro-Oncology 2017, 19, 1460–1468.
  29. Kohanbash, G.; Carrera, D.A.; Shrivastav, S.; Ahn, B.J.; Jahan, N.; Mazor, T.; Chheda, Z.S.; Downey, K.M.; Watchmaker, P.B.; Beppler, C.; et al. Isocitrate Dehydrogenase Mutations Suppress STAT1 and CD8+ T Cell Accumulation in Gliomas. J. Clin. Investig. 2017, 127, 1425–1437.
  30. Bunse, L.; Pusch, S.; Bunse, T.; Sahm, F.; Sanghvi, K.; Friedrich, M.; Alansary, D.; Sonner, J.K.; Green, E.; Deumelandt, K.; et al. Suppression of Antitumor T Cell Immunity by the Oncometabolite (R)-2-Hydroxyglutarate. Nat. Med. 2018, 24, 1192–1203.
  31. Rohle, D.; Popovici-Muller, J.; Palaskas, N.; Turcan, S.; Grommes, C.; Campos, C.; Tsoi, J.; Clark, O.; Oldrini, B.; Komisopoulou, E.; et al. An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells. Science 2013, 340, 626–630.
  32. Tateishi, K.; Wakimoto, H.; Iafrate, A.J.; Tanaka, S.; Loebel, F.; Lelic, N.; Wiederschain, D.; Bedel, O.; Deng, G.; Zhang, B.; et al. Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion. Cancer Cell 2015, 28, 773–784.
  33. Popovici-Muller, J.; Lemieux, R.M.; Artin, E.; Saunders, J.O.; Salituro, F.G.; Travins, J.; Cianchetta, G.; Cai, Z.; Zhou, D.; Cui, D.; et al. Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers. ACS Med. Chem. Lett. 2018, 9, 300–305.
  34. Pusch, S.; Krausert, S.; Fischer, V.; Balss, J.; Ott, M.; Schrimpf, D.; Capper, D.; Sahm, F.; Eisel, J.; Beck, A.-C.; et al. Pan-Mutant IDH1 Inhibitor BAY 1436032 for Effective Treatment of IDH1 Mutant Astrocytoma in Vivo. Acta Neuropathol. 2017, 133, 629–644.
  35. Konteatis, Z.; Artin, E.; Nicolay, B.; Straley, K.; Padyana, A.K.; Jin, L.; Chen, Y.; Narayaraswamy, R.; Tong, S.; Wang, F.; et al. Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma. ACS Med. Chem. Lett. 2020, 11, 101–107.
  36. Schumacher, T.; Bunse, L.; Pusch, S.; Sahm, F.; Wiestler, B.; Quandt, J.; Menn, O.; Osswald, M.; Oezen, I.; Ott, M.; et al. A Vaccine Targeting Mutant IDH1 Induces Antitumour Immunity. Nature 2014, 512, 324–327.
  37. Pellegatta, S.; Valletta, L.; Corbetta, C.; Patanè, M.; Zucca, I.; Riccardi Sirtori, F.; Bruzzone, M.G.; Fogliatto, G.; Isacchi, A.; Pollo, B.; et al. Effective Immuno-Targeting of the IDH1 Mutation R132H in a Murine Model of Intracranial Glioma. Acta Neuropathol. Commun. 2015, 3, 4.
  38. Kadiyala, P.; Carney, S.V.; Gauss, J.C.; Garcia-Fabiani, M.B.; Haase, S.; Alghamri, M.S.; Núñez, F.J.; Liu, Y.; Yu, M.; Taher, A.; et al. Inhibition of 2-Hydroxyglutarate Elicits Metabolic Reprogramming and Mutant IDH1 Glioma Immunity in Mice. J. Clin. Investig. 2021, 131, e139542.
  39. Zhang, X.; Rao, A.; Sette, P.; Deibert, C.; Pomerantz, A.; Kim, W.J.; Kohanbash, G.; Chang, Y.; Park, Y.; Engh, J.; et al. IDH Mutant Gliomas Escape Natural Killer Cell Immune Surveillance by Downregulation of NKG2D Ligand Expression. Neuro-Oncology 2016, 18, 1402–1412.
  40. Zhang, L.; Sorensen, M.D.; Kristensen, B.W.; Reifenberger, G.; McIntyre, T.M.; Lin, F. D-2-Hydroxyglutarate Is an Intercellular Mediator in IDH-Mutant Gliomas Inhibiting Complement and T Cells. Clin. Cancer Res. 2018, 24, 5381–5391.
  41. Platten, M.; Bunse, L.; Wick, A.; Bunse, T.; le Cornet, L.; Harting, I.; Sahm, F.; Sanghvi, K.; Tan, C.L.; Poschke, I.; et al. A Vaccine Targeting Mutant IDH1 in Newly Diagnosed Glioma. Nature 2021, 592, 463–468.
  42. Reardon, D.A.; Weller, M. Vaccination for IDH-Mutant Tumors: A Novel Therapeutic Approach Applied to Glioma. Med 2021, 2, 450–452.
  43. Mellinghoff, I.K.; Ellingson, B.M.; Touat, M.; Maher, E.; de La Fuente, M.I.; Holdhoff, M.; Cote, G.M.; Burris, H.; Janku, F.; Young, R.J.; et al. Ivosidenib in Isocitrate Dehydrogenase 1—Mutated Advanced Glioma. J. Clin. Oncol. 2020, 38, 3398–3406.
  44. Mellinghoff, I.K.; Penas-Prado, M.; Peters, K.B.; Burris, H.A.; Maher, E.A.; Janku, F.; Cote, G.M.; de la Fuente, M.I.; Clarke, J.L.; Ellingson, B.M.; et al. Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial. Clin. Cancer Res. 2021, 27, 4491–4499.
  45. Mellinghoff, I.K.; Cloughesy, T.; Wen, P.; Taylor, J.; Maher, E.; Arrillaga-Romany, I.; Peters, K.; Choi, C.; Ellingson, B.; Lin, A.; et al. ACTR-66. A phase 1, open-label, perioperative study of Ivosidenib (AG-120) and Vorasidenib (AG-881) in recurrent IDH1 mutant, low-grade glioma: Updated results. Neuro-Oncology 2019, 21, vi28–vi29.
  46. Wick, A.; Bähr, O.; Schuler, M.; Rohrberg, K.; Chawla, S.P.; Janku, F.; Schiff, D.; Heinemann, V.; Narita, Y.; Lenz, H.-J.; et al. Phase I Assessment of Safety and Therapeutic Activity of BAY1436032 in Patients with IDH1-Mutant Solid Tumors. Clin. Cancer Res. 2021, 27, 2723–2733.
  47. Natsume, A.; Wakabayashi, T.; Miyakita, Y.; Narita, Y.; Mineharu, Y.; Arakawa, Y.; Yamasaki, F.; Sugiyama, K.; Hata, N.; Muragaki, Y.; et al. Phase I Study of a Brain Penetrant Mutant IDH1 Inhibitor DS-1001b in Patients with Recurrent or Progressive IDH1 Mutant Gliomas. J. Clin. Oncol. 2019, 37, 2004.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Academic Video Service
Feedback