Table 1.

Completed and ongoing clinical trials of immunotherapy for glioblastoma. CTLA4, Cytotoxic T-Lymphocyte Antigen 4. PD-1, Programmed cell death protein 1. OS, overall survival. PFS, progression-free survival. GBM, glioblastoma. NICs, Nanoscale immunoconjugates. mAbs monoclonal antibodies. TMZ, temozolomide. RT, radiation therapy. MGMT, (O[6]-methylguanine-DNA methyltransferase). EGFR, epidermal growth factor receptor. PEP-CMV, peptide vaccine derived from cytomegalovirus. DCs, dendritic cells. ATL, Autologous tumor lysate. TSC, Tumor Stem Cells. GAA, glioma-associated antigen. NK, natural killer. Treg, regulatory T lymphocyte. QoL, quality of life. pp65, phosphoprotein 65. CAR-T, chimeric antigen receptor T-cell. HER2, Human Epidermal Growth Factor Receptor 2.

Treatment	Target (s)	Type of Study	Year	Primary Endpoint	n°	Results	Identifier
NICs on Poly(β-L-malic acid) with covalently attached anti-CTLA 4 and anti PD-1 antibody	CTLA-4 PD-1	Murine	2019	OS of mice bearing intracranial GBM treated with free mAbs or NICs alone or in combination.		Significant improvement of OS in mice trated with checkpoint inhibitor mAb attached to NIC
Nivolumab plus Ipilimumab	PD1 and CTLA-4	Phase III	2013	Effectiveness and Safety of Nivolumab Compared to Bevacizumab and of Nivolumab With or Without Ipilimumab in GBM Patients	529	Median OS was 9.8 months with nivolumab versus 10.0 months with bevacizumab	NCT02017717
Nivolumab	PD1	Phase III	2015	OS in Nivolumab compared to TMZ with RT for newly-diagnosed GBM	560	Median OS was 13.40 months with nivolumab versus 14.88 months in TMZ	NCT02617589 (concluded)
Nivolumab	PD1	Phase III	2016	OS in TMZ Plus RT combined with Nivolumab or placebo in newly diagnosed MGMT-Methylated GBM	716	Median PFS was 10.64 months with RT, TMZ plus Nivolumab versus 10.32 months in RT, TMZ Plus Placebo	NCT02667587 (ongoing)
VICTORI Rindopepimut	Vaccine anti-EGFR III	Phase I	2009	Rindopepimut toxicity in GBM patients with gross total resection and standard external beam RT	15	Minimal toxicity without symptoms of autoimmunity, without statistically significant improvement of outcome.
ACTIVATE Rindopepimut	Vaccine anti-EGFR III	Phase II	2010	PFS and OS of vaccinated patients with newly diagnosed EGFRvIII-expressing GBM with minimal residual disease	35	OS and PFS of vaccinated patients were greater than that observed in a control group	NCT00643097
ACT II Rindopepimut	Vaccine anti-EGFR III and TMZ	Phase II	2011	If TMZ-induced lymphopenia with standard or intensified dose would enhance immune responses to the anti-EGFRIII-vaccine	22	Humoral and cellular vaccine-induced immune responses are more enhanced by a intensified TMZ dose than the standard TMZ dose
ACT III Rindopepimut	Vaccine anti-EGFR III and TMZ	Phase II	2011	Efficacy and safety of Rindopepimut in EGFRvIII-positive GBM with gross total resection and no evidence of progression after RT and TMZ	65	Vaccine well-tolerated. Improved PFS and OS	NCT00458601
PERFORMANCE	PEP-CMV vaccination	Phase I	2016	Efficacy and safety of PEP-CMV vaccine	27	Vaccine generates an immune response No adverse events	NCT02864368 (terminated)
DCs vaccine	ATL-pulsed DCs vaccine	Phase I	2011	Vaccine safety and efficacy in inducing immunologic response in GBM after RT and TMZ.	10	Vaccinated patients with major immune response had improved survival, with no serious adverse events
DCs vaccine	ATL-pulsed DCs vaccine versus GAA peptide-pulsed DCs vaccine	Phase I	2013	Comparison of safety, feasibility and immune responses of ATL-pulsed DC vaccine, with GAA peptide-pulsed DCs vaccine	34	More activated NK cells in GAA patients. Correlation between decreased Treg ratios (post/pre vaccination) and OS in both trials.
DCs vaccine	TSC derived mRNA- Transfected DCs vaccine	Phase I Phase II	2009	Safety, immunological response, time to disease progression and survival time in vaccinated GBM patients	20	No adverse autoimmune events or other side effects. PFS was 2.9 times longer in vaccinated patients	NCT00846456 (completed)
DCs vaccine ICT-107	Autologous DCs pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2	Phase II	2017	ICT-107 tested efficacy, safety, QoL and immune response	124	No adverse autoimmune events. PFS significantly improved in ICT-107-treated patients with maintenance of QoL. HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.	NCT01280552 (completed)
DCs vaccine	DC cells pulsed with CMV-pp65 RNA vaccine	Phase I	2017	Pp65-specific cellular responses and the effects on long-term PFS and OS	11	Long-term PFS (25.3 months) and OS (41.1 months) in vaccinated patients
CAR-T therapy	Autologous anti-EGFRvIII CAR T cells	Phase I	2014	Safety and feasibility of CAR T-EGFRvIII	11	No incidence of cytokine-release syndrome or neurotoxicity. OS not affected by therapy	NCT02209376 (terminated)
CAR-T therapy	HER2-specific CAR-modified virus-specific T cells	Phase I	2019	Dose-Escalation Trial	16	Infusions well tolerated, with no dose-limiting toxic effects	NCT01109095 (completed)
Oncolytic viruses therapy	Recombinant oncolytic Polio/Rhinovirus PVSRIPO	Phase I	2021	Dose-finding and safety Study in recurrent GBM	61	Intratumoral reinfusion of PVSRIPO via CED is safe, and encouraging efficacy results have been observed	NCT01491893 (completed)
Oncolytic viruses DNX-2401 + Pembrolizumab	Genetically modified oncolytic adenovirus+ Anti-PD1	Phase II	2021	Objective response rate and OS	49	Not disclosed	NCT02798406 (completed)
Oncolytic viruses Toca 511	Vocimagene amiretrorepvec vector for a yeast cytosine deaminase gene which converts the prodrug Toca FC into the antimetabolite 5-fluorouracil	Phase I	2016	Safety, efficacy, and molecular profiling of Toca 511 OS	45	Excellent tolerability OS for recurrent high grade glioma was 13.6 months, statistically improved relative to an external control