Table 1.
Summary of Completed Immunotherapy Clinical Trials Highlighting Strengths and Limitations of Each Trial
| Immunotherapy Approach | Phase | Sample Size |
Overall Survival (months) |
Progression-Free Survival (months) |
Strengths | Limitations |
|---|---|---|---|---|---|---|
| Vaccines | ||||||
| International randomized double-blind controlled study of rindopepimut/GM-CSF with adjuvant TMZ in patients with newly diagnosed, surgically resected, EGFRvIII-positive glioblastoma11 | 3 | 745 | 20.1 | 8 | First randomized clinical trial evaluating the efficacy of an EGFRvIII-targeted therapy for newly diagnosed glioblastoma | Uncertainties on the significance of the cutoff of EGFRvIII expression for inclusion Vaccine administration schedule designed such that it started after XRT, rather than as early as possible |
| Prospective, phase 2 clinical trial to evaluate efficacy and safety of autologous DC vaccination in patients with glioblastoma multiforme after complete surgical resection with fluorescence microscope12 | 2 | 26 | 23.4 | 12.7 | Improved inclusion and exclusion criteria to better reflect patient population and more accurate survival data Vaccine schedule designed to deliver vaccine before XRT | Selection bias in favor of patients with small superficial tumors as well as those with extensive tumor resection |
| Antitumor immunotherapy targeted against CMV in patients with newly diagnosed glioblastoma multiforme during recovery from therapeutic TMZ-induced lymphopenia13 | 1 | 11 | 18.5 | 10.8 | Provides additional support for targeting the association between CMV and glioblastoma and its use in immunotherapy | Retrospective study design There was no comparison between the efficacy of dose intensified-TMZ alone vs. dose intensified-TMZ plus pp65-DC |
| Phase 1 study of safety, tolerability, and immunologic effects of SVN53-67/M57-KLH in patients with survivin-positive malignant gliomas14 | 1 | 9 | 86.6 | 17.6 | First-in-human study showed the safety, tolerability, and immunogenicity of SurVaxM in patients with recurrent malignant glioma after failure of standard therapy | Small sample size |
| Phase 1 trial of IMA950 (a novel multipeptide vaccine) plus GM-CSF in patients with newly diagnosed glioblastoma15 | 1 | 45 | 15.3 | NR | Investigates the most biologically effective and clinically feasible administration schedule | Enrolled patients were not randomized Trial not prospectively powered to compare the 2 cohorts |
| Phase 1 study of vaccination with lethally irradiated glioma cells mixed with GM-K562 cells in patients undergoing craniotomy for recurrent tumor16 | 1 | 11 | 12.4 | NR | First study showing safety and feasibility of combining autologous irradiated glioblastoma cells with GM-K562 cells as vaccination in patients who had undergone craniotomy for recurrent tumor | Attrition of enrolled patients because of disease progression or clinical decline |
| Phase 1 study on the use of racotumomab antiidiotype antibody in patients with pediatric malignancies that express N-glycolylated gangliosides and are resistant to conventional treatment17 | 1 | 15 | 3 months after study entry | NR | First phase 1 study showing that racotumomab is safe and immunogenic in a population of pediatric patients with advanced and refractory pediatric tumors | Limited antitumor activity in heavily pretreated patients with refractory malignancies |
| Phase II study of CDX-110 with radiation and TMZ in patients with newly diagnosed glioblastoma multiforme18 | 2 | 65 | 21.8 | 5.5 | Multicenter phase 2 study of CDX-110 with XRT and TMZ confirming the results of improved survival from previous phase 2 trials of rindopepimut | Selected patients have favorable prognostic factors including gross total resection and completion of chemoradiation without progression, which can affect the outcome Small open-label single-arm study design |
| Pilot study to evaluate the effects of vaccinations with HLA-A2-restricted glioma antigen-peptides in combination with poly-ICLC for adults with World Health Organization grade II low-grade gliomas19 | 1 | 23 | NR | 17 | First clinical study of peptide-based vaccination using novel glioma associated antigen-derived epitopes and adjuvant poly-ICLC in high-risk World Health Organization grade 2 low-grade gliomas showing tolerability and efficacy of this approach | Unequal distribution of patients among the 3 cohorts, with cohort 2 only having 1 patient |
| Phase 1 trial on the feasibility and tolerance of treating recurrent glioblastoma multiforme with DC vaccination and TMZ20 | 1 | 14 | 23 | NR | First phase 1 trial to explore the feasibility of manufacturing autologous monocyte-derived DC-based vaccines in patients with glioblastoma multiforme in which previous exposure to TMZ was an entry criterion | Attrition of enrolled patients because of insufficient yield of DC vaccines (21%), radionecrosis, and rapid progression Limited conclusions can be drawn regarding efficacy of this combination therapy |
| Phase 1/2a trial of autologous tumor vaccine and TMZ administration in patients with primary glioblastoma21 | 1/2 | 24 | 22.2 | 8.2 | Phase 1/2a trial showing the safety of fractionated radiation therapy, TMZ, and tumor vaccine with favorable survival outcome | Characteristics of the patients included in the study were not typical of patients with glioblastoma in general (younger age, and high extent of resection) Selection bias because of including 5 patients who had positive prognostic factors (IDH1R123-H positive) This study does not prove efficacy for the combination of fractionated radiation therapy, TMZ, and tumor vaccine |
| Phase 1/2 trial of heat shock protein peptide complex 96 vaccine for patients with recurrent high-grade glioma22 | 1/2 | 41 | 9.9 | 4.5 | Establishes safety and comparable efficacy of administering heat shock protein peptide complex 96 vaccine for patients with recurrent high-grade glioma | Open-label study design The inclusion criteria of gross total resection and high functional status limits the applicability of the study to all patients with glioblastoma 20% of enrolled patients had insufficient tumor resected to produce vaccine Although progression-free survival is reported, it is not one of the primary end points of the study because of limitations in assessing this metric |
| Pilot study to evaluate the effects of vaccinations with HLA-A2- restricted glioma antigen-peptides with poly-ICLC for children with newly diagnosed malignant brain stem gliomas, nonbrainstem high-grade gliomas, recurrent low-grade gliomas, or recurrent high-grade gliomas23 | 1 | 60 | 13.3 | NA | First clinical evaluation of peptide-based vaccination using novel glioma associated antigen-derived epitopes in an emulsion-based vehicle, administered in conjunction with immunoadjuvant therapy for recurrent childhood low-grade gliomas showing reasonable safety and immunologic efficacy of this approach, as well as preliminary evidence of clinical activity | Open-label study design |
| Phase 1/2 trial of vaccine therapy with tumor stem cell derived messenger RNA-transfected DCs in patients receiving standard therapy for glioblastoma24 | 1 | 20 | 25.3 | 23.1 | First study targeting a characterized population of cancer stem cells in gliomas, which also shows feasibility, safety of an active immunotherapy targeting glioma stem cells | Insufficient glioma stem cells to produce vaccines in the treatment group Evaluation of tumor response such as tumor volume is limited because of small sample size |
| Checkpoint inhibitor | ||||||
| Randomized phase 3 study evaluating the efficacy and safety of nivolumab vs. bevacizumab in patients with recurrent glioblastoma: CheckMate 14325 | 3 | 369 | 9.8 | 1.5 | First large randomized clinical trial of programmed cell death protein pathway inhibition in the setting of glioblastoma | Open-label study design |
| Prospective clinical trial designed to evaluate the efficacy and safety of ipilimumab in patients with melanoma metastatic to the brain26 | 2 | 72 | 7 vs. 4 | NR | First open-label study that established ipilimumab shows activity in melanoma patients with brain metastases, particularly when they have stable, asymptomatic metastases that do not need corticosteroid treatment | Prospective open-label study design Small sample size, preventing formal analysis |
| Phase 2 clinical trial looking at the effects of pembrolizumab alone or when combined with bevacizumab in patients with recurrent glioblastoma27 | 2 | 80 | 8.8 for combination therapy. | 4.1 for combination therapy | First study looking at pembrolizumab in combination with bevacizumab | Open-label study design Patients were randomized, but it is difficult to compare the 2 cohorts directly |
| Adoptive T cell therapy | ||||||
| Randomized pilot trial in patients with newly diagnosed glioblastoma implicating polyfunctional T cell responses as a biomarker for effective antitumor immunotherapy28 | 1 | 22 | NR | NR | First study to produce and safely administer CMV pp65-specific T cells with DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline) to patients with newly diagnosed glioblastoma | Single-institution single-blind study design |
| Multicenter randomized open-label phase 3 clinical trial to assess the efficacy and safety of ‘INNOCELL Immuncell-LC’ with TMZ in newly diagnosed glioblastoma in Korea29 | 3 | 180 | 22.5 | 8.1 | First prospective multicenter randomized controlled study of cytokine-induced killer cells immunotherapy for newly diagnosed glioblastoma | Open-label study design |
| Pilot feasibility and safety study of cellular immunotherapy for recurrent/refractory malignant glioma using genetically modified autologous CD8+ T cell clones30 | 1 | 3 | 11 after relapse | NR | First-in-human pilot safety and feasibility trial evaluating chimeric antigen receptor–engineered, autologous primary human CD8+ cytotoxic T lymphocytes targeting IL13Rα2 for the treatment of recurrent glioblastoma | Small patient population |
| Phase 1 trial to assess safety of autologous human CMV-specific T cell therapy for glioblastoma multiforme31 | 1 | 19 | 13.3 | 8.2 | First clinical trial for adoptive immunotherapy using CMV-specific T cells in patients with recurrent GBM | Attrition from the initial study participants. The number of patients receiving the therapy was 11 No definitive conclusions can be drawn regarding survival |
| Administration of HER2 chimeric antigen receptor expressing CMV-specific cytotoxic T cells in patients with glioblastoma multiforme32 | 1 | 16 | 24.5 | 3.5 after T cell infusion | First phase 1 dose-escalation study, establishing the safety of autologous HER2-CAR VSTs in 17 patients with progressive glioblastoma | No definitive conclusions can be drawn regarding survival The small sample size, which had attrition from screening patients for HER2 positivity to T cell infusion Study population involved pediatric patients. Inclusion of children (<18 years old), who have a better prognosis than adults, might have also affected the outcome |
GM-CSF, granulocyte-macrophage colony-stimulating factor; TMZ, temozolomide; XRT, radiation therapy; DC, dendritic cell; CMV, cytomegalovirus; NR, not reported.