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Losurdo, A.; Di Muzio, A.; Cianciotti, B.C.; Dipasquale, A.; Persico, P.; Barigazzi, C.; Bono, B.; Feno, S.; Pessina, F.; Santoro, A.; et al. Glioblastoma in Overcoming Microenvironment Immunosuppression. Encyclopedia. Available online: (accessed on 18 April 2024).
Losurdo A, Di Muzio A, Cianciotti BC, Dipasquale A, Persico P, Barigazzi C, et al. Glioblastoma in Overcoming Microenvironment Immunosuppression. Encyclopedia. Available at: Accessed April 18, 2024.
Losurdo, Agnese, Antonio Di Muzio, Beatrice Claudia Cianciotti, Angelo Dipasquale, Pasquale Persico, Chiara Barigazzi, Beatrice Bono, Simona Feno, Federico Pessina, Armando Santoro, et al. "Glioblastoma in Overcoming Microenvironment Immunosuppression" Encyclopedia, (accessed April 18, 2024).
Losurdo, A., Di Muzio, A., Cianciotti, B.C., Dipasquale, A., Persico, P., Barigazzi, C., Bono, B., Feno, S., Pessina, F., Santoro, A., & Simonelli, M. (2024, February 15). Glioblastoma in Overcoming Microenvironment Immunosuppression. In Encyclopedia.
Losurdo, Agnese, et al. "Glioblastoma in Overcoming Microenvironment Immunosuppression." Encyclopedia. Web. 15 February, 2024.
Glioblastoma in Overcoming Microenvironment Immunosuppression

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, bearing a survival estimate below 10% at five years, despite standard chemoradiation treatment. At recurrence, systemic treatment options are limited and the standard of care is not well defined, with inclusion in clinical trials being highly encouraged. So far, the use of immunotherapeutic strategies in GBM has not proved to significantly improve patients’ prognosis in the treatment of newly diagnosed GBM, nor in the recurrent setting.

glioblastoma T cells tumor microenvironment immune check-point blockade vaccinations adoptive cell therapy

1. Targeting the PD-1/PD-L1 Axis, Alone or in Combination with Anti-CTLA4

The striking results of immunotherapy with checkpoint blockade in different cancer types have fueled numerous clinical studies in the field of neuro-oncology. After evidence in preclinical mouse models of TIL infiltration of brain tumors and truly promising data of tumor regression mediated by inhibition of specific co-stimulatory receptors (e.g., CTLA-4 and PD-1/PDL-1) [1][2][3], clinical trials testing checkpoint blockades in GBMs were designed. Different putative targets of immunotherapeutic strategies in GBM are depicted in Figure 1a. Table 1 summarizes the clinical trials with published results exploring the use of anti-PD-1/PD-L1 therapy in GBM in different phases of clinical development. The results of the early-phase part of the CheckMate 143 trial, which tested different ICB strategies in rGBM [4], led to the opening of the first randomized phase III study exploring the efficacy of anti-PD-1 agent nivolumab in rGBM [5]. A total of 439 patients with rGBM who progressed after the traditional Stupp regimen were randomized 1:1 to receive nivolumab or the anti-VEGF mAb bevacizumab, with OS as the primary end-point [5]. This study failed to demonstrate a statistically significant difference between treatment groups in terms of both median OS (mOS) and median progression-free survival (mPFS) (mOS: 9.8 and 10 months for nivolumab and bevacizumab, respectively; mPFS: 1.5 and 3.5 months for nivolumab and bevacizumab, respectively) [5]. Post hoc hypothesis-generating analyses conducted in previously pre-specified patient subgroups showed that patients with methylated MGMT promoter and without steroid use at baseline (n = 31) treated with nivolumab reached the longest mOS of 17 months [5]. The role of ICB in nGBM was further explored in the adjuvant setting by two different phase III trials: the CheckMate 498 trial randomized newly diagnosed GBM (nGBM) patients with unmethylated MGMT promoter to receive either nivolumab plus RT or standard TMZ plus RT, while the CheckMate 548 trial randomized methylated MGMT promoter patients to receive nivulomab plus TMZ and RT or placebo plus TMZ and RT [6][7]. Final results of CheckMate 498 showed an overlapping OS in the two groups (mOS 13.4 and 14.9 months for the experimental and control arm, respectively), with a similar incidence of grade 3/4 TRAEs (21.9% and 25.1% in the experimental and control arm, respectively) [6]. These findings may lead to a twofold speculative conclusion: on the one hand, knowing the poor efficacy of TMZ in unmethylated MGMT promoter patients [8], nivolumab may seem detrimental in this population; on the other hand, the researchers might conclude that TMZ continues to provide an albeit limited benefit in this population. Similarly, the CheckMate 548 trial did not meet its primary end-points, with no statistically significant differences in terms of both OS and PFS when nivolumab was added to standard TMZ and RT (mOS: 28.9 vs. 32.1 months and mPFS: 10.6 vs. 10.3 months in the experimental and placebo arms, respectively), even in the subgroup of patients without baseline corticosteroids [7]. Taking together the data that emerged from these phase III trials evaluating a global population of 1715 patients, of whom 496 were in the relapsed setting and the remaining at first diagnosis, it seems reasonable to conclude that the use of anti-PD-1 agents is not effective as a treatment for GBM in different phases of the disease course. However, as highlighted by phase 0 and translational trials, the timing of ICB may be crucial in influencing the quality, strength, and durability of the immune response. In the seminal paper by Cloughesy and colleagues, testing pembrolizumab in the neo\adjuvant setting in rGBM, patients randomized to receive immunotherapy in the neoadjuvant setting had a significantly prolonged survival compared to those in the adjuvant arm [9]. The significance of these outcomes were strengthened by translational data showing the upregulation of T cell and IFN-γ-related gene signatures and the enhanced clonal expansion of T cells (with focal induction of PD-L1) in the TME, underlying the potential capacity of ICB to stimulate/boost anti-tumor T cell responses and generate specific immunologic memory when given to an intact (not pre-treated) TME [9]. Despite the poor survival results coming from randomized clinical trials conducted so far, the chapter on immunotherapy with ICB in GBM may not yet be concluded. Several early-phase trials involving combinations of ICB, anti-angiogenic agents, or integration with other innovative immunotherapeutic strategies such as cellular or peptide vaccines are under intensive clinical investigation, with the aim of reverting immunoresistance, re-sensitizing GBM tumor cells, and finally avoiding immunotolerance (Table 2).
Figure 1. Schematic representation of different T cell-based immunotherapeutic strategies and targets in GBM. (a) ICB; (b) DC-vaccines; (c) CAR-T cells.
Table 1. Clinical trials (with published results) exploring the use of anti-PD-1/PD-L1 therapy in GBM.
Title Identifier Study Design Treatment Population Main Results Main TRAEs
A Randomized Phase 3 Open Label Study of Nivolumab vs. Temozolomide in Combination with Radiation Therapy in Newly Diagnosed Adult Subjects with Unmethylated MGMT Glioblastoma (CheckMate 498) [6] NCT02617589 Phase 3 A: nivolumab + radiotherapy
B: temozolomide + radiotherapy
Newly diagnosed methylated GBM A: 13.0 months
B: 14.2 months
A: 21.9% G3-4 TRAEs
B: 25.1% G3-4 TRAEs
Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter (CheckMate548) [7] NCT02667587 Phase 3 A: nivolumab + temozolomide + radiotherapy
B: placebo + temozolomide + radiotherapy
Newly diagnosed methylated GBM A: mPFS 10.6 months; mOS 31.3 months
B: mPFS 10.3 months; mOS 33 months
A: 52.4% G3-4 TRAEs
B: 33.6% G3-4 TRAEs
Effect of Nivolumab vs. Bevacizumab in Patients with Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial [5] NCT02017717 Phase 3 A: nivolumab
B: bevacizumab
Recurrent GBM A: mOS: 9.8 months
B: mOS 10 months
A: 18.1% G3-4 TRAEs
B: 15.2% G3-4 TRAEs
Circulating Immune Cells and Outcome Analysis from the Phase II Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent Glioblastoma [10] NCT02336165 Phase 2 A: RT + durvalumab
B: durvalumab
B2: durvalumab + bevacizumab
B3: bevacizumab
C: durvalumab + bevacizumab
Newly diagnosed unmethylated GBM
Recurrent GBM
A: mOS 15.1 months
B: mOS 6.7 months
B2: mOS 8.7 months
B3: mOS 9.3 months
C: mOS 4.5 months
Fatigue G>2: 18%
Hyperlypase G>2: 8.8%
Hyperamilase G>2: 5.6%
Hypertension G>2: 5.6%
Tremelimumab and Durvalumab in Combination or Alone in Treating Patients with Recurrent Malignant Glioma NCT02794883 Phase 2 A: tremelimumab
B: durvalumab
C: tremelimumab + durvalumab
Recurrent GBM A: mOS 7.2 months
B: mOS 11.7 months
C: mOS 7.7 months
Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma [11] NCT02337491 Phase 2 A: pembrolizumab + bevacizumab
B: pembrolizumab + placebo
Recurrent GBM A: mOS 8.8 months
B: mOS 10.3 months
A: 20% Hypertension G3
B: 10% Headache G3
Nivolumab with DC Vaccines for Recurrent Brain Tumors NCT02529072 Phase 1 A: pre-surgery nivolumab
B: pre-surgery nivolumab + DC vaccine
Grade III and Grade IV brain tumors A: mOS 8 months
B: mOS 15.3 months
Study of Cabiralizumab in Combination with Nivolumab in Patients With Selected Advanced Cancers NCT02526017 Phase 1 cabiralizumab + nivolumab GBM
Other advanced solid tumors
mOS 8 months NR
Intracerebral administration of CTLA-4 and PD-1 immune checkpoint-blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial [12] NCT03233152 Phase 1 nivolumab (iv) + ipilimumab (intratumoral) Recurrent GBM mOS 37 weeks
mPFS 11.7 weeks
Combined immunotherapy with controlled interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: An open-label, multi-institutional phase I trial [13] NCT04006119 Phase 1 Cemiplimab-rwlc + Ad-RTS-hIL-12 (intratumoral) + Veledimex (oral) Recurrent GBM mOS 8.9 months NR
GBM: glioblastoma; G: grade; TRAEs: treatment-related adverse events; mOS: median overall survival; mPFS: median progression-free survival; RT: radiotherapy; NR: not reported.
Table 2. Ongoing clinical trials exploring combinations of ICB, anti-angiogenic agents, or integration with other innovative immunotherapeutic strategies.
Title Identifier Study Design Treatment Population Recruitment Status
Neoadjuvant PD-1 Antibody Alone or Combined with Autologous Glioblastoma Stem-like Cell Antigen-Primed DC Vaccines (GSC-DCV) for Patients With Recurrent Glioblastoma: A Phase II, Randomized Controlled, Double Blind Clinical Trial NCT04888611 Phase 2 A: camrelizumab + GSC-DCV
B: camrelizumab + placebo
Recurrent GBM Recruiting
Testing the Use of the Immunotherapy Drugs Ipilimumab and Nivolumab Plus Radiation Therapy Compared to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Unmethylated Glioblastoma NCT04396860 Phase 2/3 A: TMZ+RT
B: TMZ+RT + ipilimumab + nivolumab
Newly diagnosed unmethylated GBM
Active, not recruiting
Efficacy and Safety Study of Neoadjuvant Efineptakin Alfa (NT-I7) and Pembrolizumab in Recurrent Glioblastoma [14] NCT05465954 Phase 2 Efineptakin Alfa + pembrolizumab Recurrent GBM Recruiting
A phase II open-label, randomized study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol [15] ISRCTN84434175 Phase 2 A: temozolomide + ipilimumab
B: temozolomide
Newly diagnosed GBM Active, not recruiting
A Phase I/II Multicenter Trial Evaluating the Association of Hypofractionated Stereotactic Radiation Therapy and the Anti-Programmed Death-ligand 1 (PD-L1) Durvalumab (Medi4736) for Patients With Recurrent Glioblastoma (STERIMGLI) [16] NCT02866747 Phase 1/2 A: hFSRT
B: durvalumab + hFSRT
Recurrent GBM Active, not recruiting
Phase Ib/II Trial of Anti-PD-1 Immunotherapy and Stereotactic Radiation in Patients with Recurrent Glioblastoma NCT04977375 Phase 1/2 pembrolizumab + stereotactic RT Recurrent GBM Recruiting
Pembrolizumab and Vorinostat Combined With Temozolomide for Newly Diagnosed Glioblastoma NCT03426891 Phase 1 TMZ+RT + pembrolizumab + vorinostat Newly diagnosed GBM Active, not recruiting
A Phase II Study of Checkpoint Blockade Immunotherapy in Patients with Somatically Hypermutated Recurrent WHO Grade 4 Glioma NCT04145115 Phase 2 nivolumab + ipilimumab Recurrent Somatically Hypermutated GBM Recruiting
Phase II Study of Pembrolizumab Plus SurVaxM for Glioblastoma at First Recurrence [17] NCT04013672 Phase 2 A: SurVaxM + pembrolizumab (no prior anti-PD1 therapy)
B: SurVaxM + pembrolizumab (prior anti-PD1 therapy)
Recurrent GBM Active, not recruiting
Phase II Study of Pembrolizumab (MK-3475) in Combination with Standard Therapy for Newly Diagnosed Glioblastoma NCT03197506 Phase 2 A: neoadj and adj pembrolizumab (TMZ+RT)
B: adj pembrolizumab (TMZ+RT)
Newly diagnosed GBM Recruiting
Pembrolizumab for Newly Diagnosed Glioblastoma (PERGOLA) NCT03899857 Phase 2 TMZ+RT + pembrolizumab Newly diagnosed GBM Active, not recruiting
Avelumab in Patients With Newly Diagnosed Glioblastoma Multiforme (SEJ) [18] NCT03047473 Phase 2 TMZ+RT + avelumab Newly diagnosed GBM Completed
Phase I/II Study to Evaluate the Safety and Clinical Efficacy of Atezolizumab (Anti-PD-L1) in Combination With Cabozantinib in Patients with Recurrent Glioblastoma (rGBM) NCT05039281 Phase 1/2 cabozantinib + atezolizumab Recurrent GBM Recruiting
Combination of Checkpoint Inhibition and IDO1 Inhibition Together With Standard Radiotherapy or Chemoradiotherapy in Newly Diagnosed Glioblastoma. A Phase 1 Clinical and Translational Trial NCT04047706 Phase 1 A (methylated): BMS-986205 + nivolumab (TMZ+RT)
B (unmethylated): BMS-986205 + nivolumab (RT)
Newly diagnosed GBM Active, not recruiting
ASP8374 + Cemiplimab in Recurrent Glioma NCT04826393 Phase 1 ASP8374 + cemiplimab Recurrent GBM Active, not recruiting
Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma NCT04201873 Phase 1 A: DC Tumor Cell Lysate Vaccine + pembrolizumab
B: DC Tumor Cell Lysate Vaccine + placebo
Recurrent GBM Recruiting
Pharmacodynamic Study of Pembrolizumab in Patients With Recurrent Glioblastoma NCT02337686 Phase 2 Pembrolizumab Recurrent GBM Active, not recruiting
An Open-Label, Multi-Center Trial of INO-5401 and INO-9012 Delivered by Electroporation (EP) in Combination With REGN2810 in Subjects With Newly-Diagnosed Glioblastoma (GBM) NCT03491683 Phase 1\2 A (unmethylated): INO-5401 + INO-9012 + cemiplimab (TMZ+RT)
B (methylated): INO-5401 + INO-9012 + cemiplimab + nivolumab (RT)
Newly Diagnosed GBM Active, not recruiting
A Phase 1 Study to Evaluate IL13Rα2-Targeted Chimeric Antigen Receptor (CAR) T Cells Combined with Checkpoint Inhibition for Patients With Resectable Recurrent Glioblastoma NCT04003649 Phase 1 A: IL13Rα2-CAR-T + ipilimumab + nivolumab
B: IL13Rα2-CAR-T + nivolumab
C: IL13Rα2-CAR-T
Recurrent GBM Recruiting
Phase I Study of PD-L1 Inhibition With Avelumab and Laser Interstitial Thermal Therapy (LITT) in Patients with Recurrent Glioblastoma [19] NCT03341806 Phase 1 A: avelumab
B: avelumab + MRI-guided LITT
Recurrent GBM Completed
GBM: glioblastoma; RT: radiotherapy; TMZ: temozolomide.

2. Other Co-Stimulatory and Co-Inhibitory Pathways

PD-1/TIGIT-axis emerged as putative immunotherapy targets in GBM in the analysis of TCGA datasets from 153 GBM patients. GBM patients with upregulated PD-1 and TIGIT genes and their cognate ligand genes displayed reduced OS and PFS compared to patients who did not upregulate the same genes [20]. In a GBM mouse model, treatment with anti-TIGIT/anti-PD-1 resulted in increased survival of the mice, reduced tumor volume, and increased immune infiltration in tumor lesions compared to single ICBs or isotype treatments [20]. A phase I clinical trial has been set up to study an anti-TIGIT antibody (AB154) in combination with anti-PD-1 therapy in rGBM (NCT04656535). In similar preclinical GBM models, dual blockade of TIM-3 and PD-1 or dual blockade of TIM-3 and BTLA [21] resulted in increased OS in treated mice compared to controls or single ICB treatment. Interestingly, both of these combination therapies proved more effective in increasing the proportion of cytokine-producing CD8+ T cells and in reducing the frequency of immunosuppressive Tregs within the tumor compared to single ICB treatment [21][22]. A phase I trial of anti-TIM3 in combination with anti-PD-1 treatment is now addressing the efficacy of this combination strategy in patients with rGBM (NCT03961971). Another marker of early T cell exhaustion, LAG3 (CD223), whose inhibition has been shown in preclinical models to be able to skew CD4+ cells away from the Treg phenotype [23], has been tested in a phase I trial for rGBM, alone or in combination with anti-PD-1 therapy (NCT02658981). Preliminary results of the first 44 patients enrolled indicated a mOS of 8 months for the anti-LAG3 monotherapy (with no dose-limiting toxicities (DLTs) for the highest safe dose of 800 mg) and 7 months for the combination therapy with anti-PD-1 [24]. Preclinical evidence demonstrated that another strategy for reshaping the TME, promoting effector T cell function, and inhibiting Tregs might be the activation of the glucocorticoid-induced TNFR-related gene (GITR) [25]. Nevertheless, GITR activating monotherapy has not proved effective in solid tumors [26], and combination strategies, together with another ICB (e.g., anti-PD-1) [27], chemotherapy [28], or RT [29], have been tested in pre-clinical and clinical trials to improve GITR agonism. An initial signal of the potential efficacy of these combination strategies came from a phase II trial for rGBM, where patients were treated with an anti-PD-1 plus a GITR agonist (INCAGN01876) together with fractionated stereotactic RT (FSRT) at disease recurrence (Cohort A) or, if amenable to surgery, patients were allocated to receive an anti-PD-1 plus INCAGN01876, with (Cohort B1) or without (Cohort B2) pre-surgical FSRT (NCT04225039). The combination of an anti-PD-1 plus INCAGN01876 and FSRT without surgical resection did not demonstrate efficacy in patients with rGBM, but interestingly, patients in Cohort B1 had significantly longer mPFS and mOS compared to patients in Cohort B2 (PFS 11.7 vs. 2.0 months, respectively; p = 0.0002, and mOS 20.1 vs. 9.4 months, respectively; p = 0.001), with a concomitant increase in inflammatory cytokine responses and proliferative T cells [30].

3. Vaccines

Vaccines are among the therapies that capitalize on the established efficacy of the immune system in fighting cancer; they work by activating the adaptive immune system, particularly T cells, against antigens that might be set up and injected from outside to be carried on the membrane of APCs, or activated APCs can be administered directly [31]. The optimal source of antigens to be used for APC loading is still controversial, as the “perfect” antigen should bear tumor specificity in order to avoid autoimmune attacks on healthy cells but also be broadly present at the tumor site, allowing targeting of as many cancer cell clones as possible. In view of this, the researchers can distinguish so-called tumor-associated antigens (TAAs), ubiquitous non-mutated proteins that are upregulated in tumors compared to normal tissues (e.g., EGFR, IL-13Rα2, and gp100), and tumor-specific antigens (TSAs), produced and expressed only by tumor cells (e.g., EGFRvIII). For example, taking into account GBM therapy, a phase III trial evaluating Rindopepimut, a peptide vaccine targeting the EGFR mutation EGFRvIII, did not show any survival benefit in patients with nGBM [32]. In contrast, favorable results were reported for a peptide vaccine against the surviving molecule, a TAA, namely SurVaxM, tested in a phase II trial in resected nGBM, showing a mPFS of 11.4 months and a mOS of 25.9 months [33].
Here, the researchers will focus on so-called DC-vaccines, specifically describing the results of the most recent phase II and III randomized clinical studies. As previously shown, DCs might be distinguished into conventional/myeloid DC 1-2 (cDC1, cDC2) and plasmacytoid DC (pDC); the cDC1 subtype appears to have a higher affinity for activating CD8+ T cells, while cDC2 is for CD4+ T cells [34]. In manufacturing DC-based vaccines, it is unknown which subsets or combinations are most efficient; nevertheless, the most common technology involves the production of monocyte-derived DC ex vivo by in vitro stimulation of monocytes isolated from peripheral blood mononuclear cells (PBMCs). The specific methodology to isolate and culture/differentiate monocytes into cDCs is still controversial, with different cell culture media, serum sources, and required concentrations of GM-CSF and IL-4 used in different studies [35]. Also, the sources of antigens used to activate autologous ex vivo-generated DC may be different in nature, such as whole-tumor lysate, antigenic peptides, viral transfection, or messenger RNA (mRNA) electroporation. A schematic representation of the DC vaccine strategies is depicted in Figure 1b. The development of trials with DC vaccines in GBM has been hampered by issues common to other solid tumors, such as the selection of the best antigen to stimulate an effective and sustained immune response, the timing of administration (e.g., neo-adjuvant setting or advanced disease), the expansive cost of manufacturing, and the long turnaround time. While specific problems in developing DC vaccines for GBM include the low sample size given the disease’s low incidence, severely limiting the ability to conduct large trials with control arms, and the short disease median OS, especially for relapsed GBM, greatly reducing the time window available to produce and demonstrate the efficacy of therapies aiming to activate the immune system [36]. A list of trials testing DC vaccination in GBM with reported results is displayed in Table 3. The phase III trial assessing tumor lysate-loaded DC vaccine (DCVax-L) in patients with nGBM, although formally meeting its primary endpoint, with a mOS of 19.3 versus 16.5 months (HR = 0.80; 98% CI, 0.00–0.94; p = 0.002) for patients receiving DCVax-L and placebo plus TMZ, respectively, was very controversially conducted [37]. Important limitations, both in the nature and methodology of this study, need to be highlighted. Firstly, in the original trial design, the primary end-point was PFS determined by MRI, but due to difficulties in distinguishing progressive disease from pseudo-progression related to immune-related necrosis or inflammation, OS was used for the definitive statistical analyses as the primary end-point. Moreover, this study was presented as randomized, double-blind, with a crossover design, but due to the high number of patients accessing the crossover phase, the placebo group was depleted, and the survival analyses were conducted using a post hoc external control population for whom individual patient level data were not available, and thus a propensity score analysis was not feasible. Thus, taking all this into account, the trial should not be considered to answer the question on DCVax-L activity in GBM, and its post hoc conclusive analyses are to be accounted for only as hypothesis-generating [38].
Table 3. Clinical trials (with published results) testing DC vaccination in GBM.
Title Identifier Study Design Vaccine Production Population Main Results Treatment Related Adverse Events (TRAEs)
A Phase III Clinical Trial Evaluating DCVax®-L, Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen For The Treatment Of Glioblastoma Multiforme (GBM) [37] NCT00045968 Phase 3 Tumor lysate Newly diagnosed GBM
Recurrent GBM
nGBM mOS: 19.3 months
rGBM mOS: 13.2 months
G 3\4 TRAEs: 2 cases of intracranial edema (G3), 1 case of nausea (G3), and 1 case of lymph node infection (G3)
Phase II Trial of Autologous Dendritic Cells Loaded With Autologous Tumor Associated Antigens (AV-GBM-1) as an Adjunctive Therapy Following Primary Surgery Plus Concurrent Chemoradiation in Patients With Newly Diagnosed Glioblastoma [39] NCT03400917 Phase 2 Lysate of irradiated autologous tumor-initiating cells Newly diagnosed GBM mOS: 16 months
2-years OS: 27%
mPFS: 10.4 months
G 3\4 TRAEs: none
A Randomized, Double-blind, Controlled Phase IIb Study of the Safety and Efficacy of ICT-107 in Newly Diagnosed Patients With Glioblastoma Multiforme (GBM) Following Resection and Chemoradiation [40] NCT01280552 Phase 2 Synthetic peptide epitopes targeting GBM associated antigens MAGE-1, HER-2,
AIM-2, TRP-2, gp100, and IL13Rα2
Newly diagnosed GBM mOS: 17 months (vs. 15 months, NS)
mPFS: 11.2 months (vs. 9 months, p = 0.011)
G 3\4 TRAEs: no difference from the control group (G3 nervous system disorders, fatigue, WBC decrease, and infections)
A Phase II Feasibility Study of Adjuvant Intra-Nodal Autologous Dendritic Cell Vaccination for Newly Diagnosed Glioblastoma Multiforme NCT00323115 Phase 2 Tumor lysate Newly diagnosed GBM mOS: 28 (15-44) months
mPFS: 9.5 (5-41) months
Phase I Trial of Vaccination With Autologous Dendritic Cells Pulsed With Lysate Derived From an Allogeneic Glioblastoma Stem-like Cell Line for Patients With Newly Diagnosed or Recurrent Glioblastoma [41] NCT02010606 Phase 1 Lysate from an allogeneic stem-like cell line Newly diagnosed GBM
Recurrent GBM
mOS: 20.36 months
mPFS: 8.75 months
mOS: 11.97 months
mPFS: 3.23 months
G 3\4 TRAEs: none
A phase I trial of surgical resection with Gliadel Wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with malignant glioma [42] N.A. Phase 1 Tumor lysate Newly diagnosed GBM
Recurrent GBM
mOS: 27.7 months
mPFS: 4.8 months
mOS: 10.9 months
mPFS: 1.9 months
G 3\4 TRAEs: none
Anti-Tumor Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed Glioblastoma Multiforme During Recovery From Therapeutic Temozolomide-induced Lymphopenia NCT00639639 Phase 1 CMV pp65 Newly diagnosed GBM ATTAC-GM mOS: 37.7 months
ATTAC-Td mOS: 38.3 months
Evaluation of Overcoming Limited Migration and Enhancing Cytomegalovirus-specific Dendritic Cell Vaccines With Adjuvant TEtanus Pre-conditioning in Patients With Newly-diagnosed Glioblastoma NCT02366728 Phase 2 CMV pp65 Newly diagnosed GBM Arm1 (unpulsed DC): mOS 16 months
Arm2 (Td pre-conditioning): mOS 20 months
Arm3 (Basiliximab + Td pre-conditioning): mOS 19 months
Arm 1: 1\27 pts (lung infection)
Arm 2: 4\28 pts (urinary infection, nervous system, and psychiatric disorders)
Arm 3: 2\9 pts (colon perforation, nervous system disorders)
nGBM: newly diagnosed glioblastoma; rGBM: recurrent glioblastoma; G: grade; TRAEs: treatment-related adverse events; mOS: median overall survival; mPFS: median progression-free survival; N.A.: not applicable; SAEs: severe adverse events.
As GBM cells might contain sequences and express the viral gene products of CMV [43], investigators at Duke University designed a set of clinical trials assessing a vaccination with CMV pp65-specific autologous DCs. The ATTAC trial (testing the pre-conditioning of the vaccine site with tetanus/diphtheria (Td) toxoid) [NCT00639639], the ATTAC-GM (expanded cohort receiving GM-CSF containing autologous CMV DC vaccines with dose-intensified TMZ) [NCT00639639], and the ELEVATE trial [NCT02366728] [44]. The vaccination was administered with TZM in nGBM after surgical resection and chemoradiation and proved very encouraging 5-year OS rates of 33.3% (mOS 38.3 months; 95% CI, 17.5–∞) and 36.4% (mOS 37.7 months; 95% CI, 18.2–109.1) for ATTAC-Td and ATTAC-GM, respectively, without significant TRAEs [44]. In the confirmatory double-blind randomized phase II trial (ELEVATE), the 3-year OS for the Td arm was 34% (95% CI, 19–63%) compared to 6% (95% CI, 1–42%) in the unpulsed DCs arm [45]. Translational analyses in the ATTAC study showed a steady increase in the Treg population after the first dose of maintenance TMZ, followed by an increase in peripheral CD8+ T cells and the CD8+:Treg ratio after pp65 vaccination [46]. Therefore, in the ELEVATE trial, the investigators added a second experimental arm using the anti-Treg monoclonal antibody Basiliximab (anti-IL-2rα) in order to test whether inhibition of the initial increase in the Treg pool may serve as a boost for the T-mediated response induced by the pp65 DC vaccine. Preliminary data did not show a survival advantage in the Basiliximab arm compared with patients treated with DC vaccine plus Td pre-conditioning, with a mOS of 19 (16.7–25.6) and 20 (10.26–NA) months, respectively [NCT02366728].
While promising, therapies in GBM based on DC vaccines are far from clinical practice, and the researchers still await the results of larger, more advanced-phase trials to demonstrate a substantial clinical benefit. Translational analyses will be crucial to understanding how to develop a vaccine able to induce strong and long-lasting T-cell-mediated immune activation against GBM cells. Many early-phase clinical trials are attempting to increase the immunogenic potential of the DC vaccines in GBM; specifically, the most promising ongoing strategies are testing the combination of DC vaccines with ICB or local therapies such as RT or medicated wafers [42][47].

4. Adoptive Cell Therapy and Chimeric Antigen Receptor T Cell Therapy

Adoptive cell therapy (ACT), also known as cellular immunotherapy, is a form of treatment that uses immune cells to target and potentially eliminate cancer cells. ACT approaches range from isolating a patient’s immune cells (e.g., T lymphocytes, DCs, or NK cells), expanding their number in vitro, and then reinfusing them, to genetically engineered (via gene therapy) autologous immune cells such as chimeric antigen receptor T (CAR-T) cells. In the former case, tumor-infiltrating immune cells are obtained from the enzymatically digested tumor specimens and activated ex vivo; then specific clones, presenting with high avidity for tumor antigens, are selected and expanded before reinfusion. In the latter, patients’ T cells are equipped with engineered synthetic receptors, known as CARs, to recognize and eliminate tumor cells expressing a specific target antigen; importantly, this binding is independent from the MHC receptor, thus possibly overcoming the limitation of the previously described form of ACT. Here, the researchers will focus on treatment strategies based on CAR-T cells, the most investigated and clinically meaningful ACT application of autologous T cells; a schematic representation of the generation of CAR-T cells is depicted in Figure 1c. CARs are composed of four main components: an extracellular target antigen-binding domain, a hinge region, a transmembrane domain, and one or more intracellular signaling domains. Indeed, different subsequent generations of CARs, based on the quality and quantity of co-stimulatory intracellular receptors with tyrosin-kinase activity, in series with the CD3ζ have been designed and proposed for clinical testing. After the success of CAR-T cell-based approaches in hematological malignancies and the approval for clinical use in several countries of CAR-T therapy for the treatment of relapsed or refractory lymphomas, leukemia, or multiple myeloma [48][49][50][51], this specific ACT application has been under investigation in many different solid tumors. Nevertheless, specific issues characterizing solid tumors in contrast to hematological malignancies, such as inefficient trafficking and infiltration at the tumor site, immunosuppressive TME, and antigen heterogeneity, have been limiting the clinical applicability of this treatment strategy [52][53]. Overexpression of mutant EGFR variant III (EGFRvIII), present in about 30% of nGBM [54], has been recognized as a tumor-specific, oncogenic epitope able to mediate increased cellular growth, invasion and angiogenesis, and resistance to chemoradiation in GBM cells [55]. Thus, EGFRvIII has been selected as a putative target and is actually the most explored in clinical trials for CAR-T cells against GBM cells. Nevertheless, taking into account the three completed phase I clinical trials testing EGFRvIII CAR-T cells in GBM (NCT02209376, NCT02664363, and NCT01454596), no clear radiological responses were observed. It is worth noting that in the study by O’Rourke and colleagues, 1 patient had residual stable disease for over 18 months after a single dose of CAR-T EGFRvIII cells; translational analyses on tissue specimens after surgery (available for 7 of the enrolled patients) showed antigen decrease at the site of active GBM in 5 out of 7 patients and increased expression of inhibitory molecules and Tregs, highlighting how important it would be for future studies to understand how to overcome immune changes in the TME [56]. Another tumor-specific antigen, Interleukin 13 receptor α2 (IL13Rα2), linked to GBM poor prognosis, has been used to engineer IL13Ra2-specific CAR-T cells to be infused via a catheter/reservoir system into the resection cavity in a pilot safety and feasibility trial that demonstrated fair tolerability and transient anti-glioma responses in 2 out of 3 patients treated [57]. Thus, a phase I trial has been designed with modified co-stimulation and the linker of the IL13Ra2-specific CAR-T to improve antitumor efficacy [58]. Multiple infusions of CAR-T cells were administered both directly into the tumor cavity and into the ventricular system; no grade 3 or higher TRAEs were observed, and a stable regression of tumor localizations (both intracranial and spinal) lasted for 7.5 months after the first CAR-T infusion [58]. Given that overexpression of human epidermal growth factor receptor 2 (HER2) is well known to drive carcinogenesis in several different solid tumors (such as breast cancer, gastric cancer, CRC, and NSCLC) and that it is also found in around 80% of GBMs [59], HER2 CAR-T cell therapy has been extensively explored, with mixed clinical results and concerns about toxicities due to off-target effects [60]. In a phase I trial of HER2-positive GBM testing HER2-CAR CMV pp65-bispecific cytotoxic T lymphocytes, no DLTs were observed, 1 patient experienced PR for more than 9 months, and 7 patients had SD lasting 8 weeks to 29 months, with a mOS of 11.1 months (95% CI, 4.1–27.2 months), leaving an open window for further exploring this therapeutic target [61].


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