Dendritic cell vaccines for high-grade gliomas

Figures & data

Table 1 Clinical trials of DC immunotherapy for GBM and other HGGs

Study	Phase	Number of patients	Antigen	Adjuvant	Route	Toxicities	Clinical efficacy
Kikuchi et al^Citation40	I	5 GBM-r 2 AA-r 1 AO-r	Cultured glioma cells from surgical specimen		Intradermal	None	2 patients had a partial response.
Yu et al^Citation41	I	7 GBM-n 2 AA-n	Autologous glioma surface peptides		Subcutaneous	Fever (n=1) Nausea (n=1) Lymphadenopathy (n=1)	Median overall survival 455 d for treatment group vs 257 d for control group.
Yamanaka et al^Citation42	I/II	7 GBM-r 3 AG-r	Tumor lysate from surgical specimen		Intradermal and intracavitary	Headache (n=1)	2 patients had a minor response (GBM). 4 patients had overall survival >2 y (2 GBM, 2 AG).
Caruso et al^Citation43	I	2 GBM-r 3 EPM-r 1 AA-r 1 PXA-r	Tumor RNA from surgical specimen		Intradermal and intravenous	None	1 patient had a partial response (AA). All GBM patients had progressive disease.
Kikuchi et al^Citation44	I	6 GBM-r 7 AA-r 2 AOA-r	Cultured glioma cells from surgical specimen	IL-12	Intradermal	Fever (n=4) Seizure (n=1) Liver dysfunction (n=6) Leukocytopenia (n=7)	7 patients had either stable imaging or a partial response at 8-weeks. 2 patients survived >1 y.
Rutkowski et al^Citation45	I	10 GBM-r 1 PXA-r 1 ALL-r	Tumor lysate from surgical specimen		Intradermal	Grade IV neurotoxicity from peritumoral edema (n=1) Hematotoxicity (n=2) Chemical meningitis (n=1)	4 patients had at least a partial response. 2 patients (1 GBM and 1 PXA) who underwent GTR remained disease free >30 m after treatment.
Yu et al^Citation46	I	9 GBM-r 1 GBM-n 3 AA-r 1 AA-n	Tumor lysate from surgical specimen		Subcutaneous	Seizures (n=2) Headache (n=3) Fatigue (n=1)	Median overall survival of 133 w in study group vs 30 w for matched controls.
Liau et al^Citation47	I	5 GBM-r 7 GBM-n	Acid-eluted tumor-associated peptides (enriched in MHC-I)		Intradermal	Seizure (n=1) Fatigue (n=5) Headache (n=2) Lymphadenopathy (n=2) Nausea/vomiting (n=3) Myalgia (n=1)	Improved median time to progression from surgery (19.9 m vs 8.2 m) and overall survival from surgery (35.8 m vs 18.3 m) in treatment group compared to historical data.
Yamanaka et al^Citation48	I/II	18 GBM-r 2 AA-r 2 AOA-r 2 AG-r	Tumor lysate from surgical specimen		Intradermal and intracavitary (n=11)	Headache (n=1)	1 partial response, 3 minor response, and 6 stable disease (GBM). Median overall survival increased (480 d vs 400 d in GBM).
Okada et al^Citation49	I	1 GBM-r 5 GBM-n 1 AA-r	Tumor lysate from surgical specimen	TFG-IL-4-Neo-TK-transfected fibroblasts	Intradermal	Headache (n=1)	Patients with recurrent disease had a partial response. Median time to progression was 6 m. No clinical benefit was observed in the newly diagnosed patients.
De Vleeschouwer et al^Citation50	I/II	56 GBM-r	Tumor lysate from surgical specimen	Tumor lysate	Intradermal	Grade IV neurotoxicity from peritumoral edema (n=1) Hematotoxicity (n=2) Transient focal neurological deficits (n=6) Headache (n=9) Chemical meningitis (n=1) Nausea/vomiting (n=2) Seizures (n=4) Fatigue (n=7) Myalgia (n=3)	Median overall survival 9.6 m. Trend toward survival benefit in all patients who had weekly vaccinations. Subgroup analysis demonstrated significant benefit in adult patients who had weekly vaccinations.
Walker et al^Citation51	I	2 GBM-r 7 GBM-n 3 AA-r 1 AA-n	Irradiated tumor cells		Intradermal	None reported	2 patients with GBM had partial responses after postvaccination chemotherapy. 2 patients with AA had a partial response and 1 had a complete response after postvaccination chemotherapy.
Wheeler et al^Citation52	II	23 GBM-r 11 GBM-n	Tumor lysate from surgical specimen		Subcutaneous	1 patient developed cutaneous GBM, which was attributed to delayed type hypersensitivity testing.	17 of the 34 GBM patients were deemed vaccine responders based on their IFN-γ levels. Overall survival was significantly longer in vaccine responders (642 +/− 61 d) as compared to non-responders (430 +/− 50 d).
Sampson et al^Citation53	I	12 GBM-n	Peptide specific for EGFRvIII conjugated to KLH		Intradermal	None reported. No toxicities exceeded grade 2 per the National Cancer Institute’s Common Toxicity Criteria	Median overall survival after diagnosis was 22.8 m in vaccinated patients. Trend toward survival benefit.
Ardon et al^Citation54	I	22 GBM-r 5 AA-r 2 PXA-r 1 AOA-r 1 AGG-r 1 DIPG-r 5 MB/PNET-r 4 EPM-r 3 ATRT-r	Tumor lysate from surgical specimen	Imiquimod, +/− tumor lysate	Intradermal	Fatigue (n=8) Headache (n=5) Fever (n=3) Pruritus (n=3) Vomiting (n=2) Flu-like illness (n=1)	Median overall survival for GBM patients was 12.2 m. 4 Patients with GBM were long-term survivors >24 m. Median overall survival in all HGG patients was 13.5 m.
Ardon et al^Citation55	I	8 GBM-n	Tumor lysate from surgical specimen	Tumor lysate	Intradermal	Grade IV status epilepticus (n=1) Grade IV ischemic stroke (n=1) Grade III hematotoxicity (n=1) Seizures (n=1) Dysphasia (n=3) Lymphopenia (n=1) Fatigue (n=4) Transient confusion (n=2) Malaise (n=1) Myalgia (n=1)	Median overall survival was 24 m. Median progression free survival was 18 m. 3 patients were alive at time of last follow-up, with one being free from recurrence at 34 m.
Chang et al^Citation56	I/II	8 GBM-r 8 GBM-n 1 AA-r 1 MOG-r 1 MOG-n	Heat shocked and irradiated tumor cells		Subcutaneous	Grade I–IV lymphopenia (n=9) Elevation in AST/ALT (n=8)	Median overall survival 520 d vs 380 d. 18.8% of vaccinated GBM patients had survival >5 y.
Fadul et al^Citation57	I	10 GBM-n	Irradiated tumor lysate		Intranodal	Neck pain (n=1)	Median progression- free survival and overall survival 9.5 m and 28 m, respectively. 4 patients alive without evidence of progression at time of last follow-up (>26 m).
Okada et al^Citation58	I/II	13 GBM-r 5 AA-r 3 AO-r 1 AOA-r All patients were HLA-A2+	GAA epitopes from synthetic peptides (IL-13Rα2, EphA2, gp100, YKL-40)	Poly-ICLC (intramuscular)	Intranodal	Lymphopenia (n=1) Fatigue (n=16) Myalgia (n=7) Fever (n=5) Chills/rigors (n=4) Headache (n=7)	Median time to tumor progression was 4 m and 13 m for GBM and AA, respectively. 2 GBM patients had objective tumor regression (1 partial response and 1 complete response). 5 patients were alive at time of last follow-up.
Prins et al^Citation59	I	8 GBM-r 15 GBM-n	Tumor lysate from surgical specimen	Imiquimod or Poly-ICLC	Intradermal	Transient increase in T2/FLAIR hyperintensity (n=3) Palpable lymphadenopathy (n=1) Fatigue (n=4) Nausea/vomiting (n=4) Diarrhea (n=1) Constipation (n=1) Fever (n=2) Myalgia/arthralgia (n=2) Shingles (n=1) Allergic rhinitis (n=1) Pruritus (n=2) GERD/abdominal pain (n=2) Headaches (n=1) Rash (n=2) Lip blisters (n=1)	Median overall survival 31.4 m. Median time to tumor progression 15.9 m. Median overall survival significantly longer in patients treated at initial diagnosis of GBM compared to recurrent patients.
Akiyama et al^Citation60	I	7 GBM-r 1 AA-r 1 AO-r All patients were either HLA-A2+ or HLA-A24+	Synthetic peptides (WT-1, HER2, MAGE-A3, MAGE-A1, and gp100)	None	Intradermal	Mile hepatic dysfunction (n=1)	1 patient had stable disease for 2 y. 8 patients had progressive disease.
Ardon et al^Citation61	I/II	77 GBM-n	Tumor lysate from surgical specimen	Boost vaccines	Intradermal	Grade V infection (n=1) Grade IV status epilepticus (n=4) Grade IV ischemic stroke (n=1) Grade III/IV hematotoxicity (n=19) Grade III/IV dementia (n=1) Seizures (n=5) Atopy to TMZ (n=1) Abscess (n=1) DVT (n=1) Hydrocephalus (n=1) Ischemic bowel (n=1) Lung/peripheral edema (n=1) Osteoporotic fracture (n=1)	Median overall survival 18.3 m in ITT analysis. Median progression- free survival 10.4 m in the ITT group vs 20.4 m in the PP group. MGMT promoter methylation associated with significantly better survival.
Cho et al^Citation62	II	18 GBM-n 16 GBM-n (control) Randomized	Tumor lysate from surgical specimen		Subcutaneous	Transient hepatotoxicity (n=1) Mild lymphopenia (n=1) Scalp infection (n=1) Post-op hemiplegia (n=1) Elevated ICP (n=1) Nausea/vomiting (n=2)	Median overall survival of treatment group 31.9 m vs 15.0 m for control group. Median progression- free survival of treatment group 8.5 m vs 8.0 m for control group.
Jie et al^Citation63	II	13 GBM-n 12 GBM-n (control) Non- randomized	Heat shocked tumor cells		Subcutaneous	Fever (n=2)	Median overall survival 17.0 m in treatment group vs 10.5 m for control group. Median progression- free survival 11.92 m for treatment group vs 7.75 m for control.
Lasky et al^Citation64	I	4 GBM-r 1 GBM-n 1 AA-r 1 AOA-n All pediatric patients	Tumor lysate from surgical specimen		Intradermal	Grade IV elevation of alkaline phosphatase (n=1) Headache (n=7)	2 patients with newly diagnosed tumors alive at time of last follow- up (>40 m). All patients with recurrent tumors died within 10 m of surgery.
Phuphanich et al^Citation65	I	3 GBM-r 17 GBM-n 1 Brainstemglioma All patients were HLA-A1+ or HLA-A2+	TAA epitopes synthetic peptides (HER2, TRP-2, gp100, MAGE-1, IL-13Rα2, and AIM-2)		Intradermal	Diarrhea (n=1) Fatigue (n=3) Flushing (n=1) Pruritus (n=2) Rash (n=2) Vomiting (n=1)	Median overall survival 38.4 m. 6 patients had no evidence of recurrence from 49 m to 66 m. Median progression- free survival was 16.9 m.
Prins et al^Citation66	I	Tumor lysate study 8 GBM-r 15 GBM-n 5 AA GAA study 2 GBM-r 2 GBM-n 2 AA Patients in GAA study were HLA-A2+	2 parallel studies – one used tumor lysate from the surgical specimen and the other used GAAs (survivin, her-2/neu, gp100, and TRP-2).		Intradermal	Fatigue (n=8) Nausea/vomiting (n=8) Diarrhea (n=3) Fever (n=4) Lymphadenopathy (n=2) Myalgia (n=1) Pruritus (n=2) Rash (n=7) Anorexia (n=1) GERD/abdominal pain (n=3) Arthralgia (n=3) Shingles (n=1) Rhinitis (n=1) Constipation (n=1) Blisters (n=1) Seizures (n=6) Twitching/tremor (n=2) Spasms (n=1) Photophobia (n=1) Vertigo/dizziness (n=2) Sensation changes/paresthesias (n=8) Flu-like illness (n=2) Motor neuropathy (n=1) Diplopia (n=1) Otitis (n=1) Nephrolithiasis (n=1) Nail bed changes (n=1)	60% of screened patients were ineligible for the GAA study based on HLA type. Median overall survival for tumor lysate study was 34.4 m. Median overall survival in GAA study was 14.5 m.
Vik-Mo et al^Citation67	I/II	7 GBM-n	Transfection of mRNA from glioma stem cells.	+/− booster vaccines	Intradermal	Grade III fatigue (n=1) Seizures (n=1) Grade I–II fatigue (n=6) Anorexia (n=5) Pain (n=4) Nausea/vomiting (n=2) Constipation (n=2)	Median overall survival 759 d vs 585 d for matched controls. 3 patients survived >1,000 d.
Hunn et al^Citation68	I	14 GBM-r	Autologous tumor lysate previously exposed to TMZ		Intradermal	Grade III syncopal event (n=1) Thrombocytopenia (n=3) Post-op neurological deficit (n=1) Seizure (n=3) Headache (n=2) Nausea/vomiting (n=2)	2 patients had prolonged progression- free survival. Median overall survival from initial diagnosis was 23 m. Immune response (based on IFN-γ levels) was associated with better overall survival.
Mitchell et al^Citation69	I/II	12 GBM-n	Transfected synthetic pp65 mRNA from CMV	Td toxoid or mature DCs used as site preconditioning	Intradermal	None reported	Proportion of DCs in VDLNs much greater in patients given Td. Median overall and progression-free survival for Td group inestimable as 3/6 patients were alive without evidence of progression at last follow-up (>44.1 m). Median progression- free and overall survival 10.8 m and 18.5 m for DC group. IDH reported.
Sakai et al^Citation70	I	6 GBM-r 2 AA-r 1 AOA-r 1 OG-r	WT-1 antigen and/or tumor lysate from surgical specimen (depending on immunostaining for WT-1)		Intradermal	Fever (n=6) Fatigue (n=6)	Median overall survival in all patients: 26 m (19 m post-initial vaccine). Median overall survival in GBM patients: 18 m (7 m post-initial vaccine). 1 patient with GBM was alive at last follow-up (>46 m).
Batich et al^Citation71	I	11 GBM-n	Transfected synthetic pp65 mRNA from CMV admixed with GM-CSF	Dose intensified TMZ	Intradermal	Grade III immunologic reaction related to GM- CSF sensitization (n=1)	Median overall survival of 41.1 m vs 19.2 m for historical controls. Median progression- free survival of 25.3 m vs 8.0 m for historical controls. 4 patients alive without evidence of progression at time of last follow-up (>59 m).
Inogés et al^Citation72	II	31 GBM-n	Tumor lysate from surgical specimen		Intradermal	Fatal bacterial pneumonia (n=2) Grade III neutropenia (n=2) Grade III thrombocytopenia (n=2) Post-op neurological deficit (n=2) Investigators claimed all adverse events were unrelated to vaccine.	Median overall survival of 23.4 m. Median progression- free survival of 12.7 m. No correlation was found between immune response and survival. MGMT promoter methylation was associated with improved survival.

Abbreviations: -n, new diagnosis; -r, recurrent tumor; AA, anaplastic astrocytoma; AG, anaplastic mixed glioma; AGG, anaplastic ganglioglioma; ALL, acute lymphocytic leukemia; AO, anaplastic oligodendroglioma; AOA, anaplastic oligoastrocytoma; ATRT, atypical teratoid-rhabdoid tumor; CMV, cytomegalovirus; d, days; DC, dendritic cell; DIPG, diffuse intrinsic pontine glioma; DVT, deep venous thrombosis; EPM, ependymoma; GAA, glioma associated antigen; GBM, glioblastoma; GERD, gastroesophageal reflux disease; GM-CSF, granulocyte-macrophage colony-stimulating factor; GTR, gross total resection; HLA, human leukocyte antigen; HGG, high-grade glioma; ICP, intracranial pressure; IDH, isocitrate dehydrogenase; IFN, interferon; IL, interleukin; ITT, intention to treat; KLH, keyhole limpet hemocyanin; m, months; MB, medulloblastoma; MHC, major histocompatibility complex; MOG, malignant oligodendroglioma; mRNA, messenger ribonucleic acid; Poly-ICLC, polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose; PNET, primitive neuro-ectodermal tumor; PP, per protocol; PXA, pleomorphic xanthoastrocytoma; Td, tetanus diphtheria; TMZ, temozolomide; VDLN, vaccine draining lymph node; WT, Wilms tumor; y, years.

Figure 1 Dendritic cell vaccine studies by antigen type.

Figure 2 Dendritic cell vaccine studies by phase of trial.

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