Cellular-Based Immunotherapies for Patients with Glioblastoma Multiforme

Table 1

Synopsis of DC-based immunotherapy trials for GBM patients.

Patients	Phase	Route	Antigen format	Immune response	Clinical response	References
22 patients (13 recurrent GBM, 5 AA, 3 AO, 1 AOA)	Phase I/II	Intranodal + intramuscular injections of poly-ICLC	Synthetic peptides for GAAs	Induced positive immune responses against at least one of the GAAs in PBMCs in 58% of patients (after 4 vaccinations). Significant upregulation: interferon-alpha and CXCL10.	4 recurrent GBM are progression free for at least 12 months; 1 CR (recurrent GBM). Median TTP: 4 months.	[61]
23 patients (15 newly diagnosed GBM, 8 recurrent GBM)	Phase I	Intradermal + intramuscular injections of poly-ICLC	Autologous tumor lysate + imiquimod or poly-ICLC	No dose-limiting toxicity. Tumor samples with a mesenchymal gene expression signature had a higher number of CD3^+ and CD8^+ tumor-infiltrating lymphocytes	Newly diagnosed: median OS: 35.9 months, with a mean follow-up time of more than 4 years, and 1-, 2-, and 3-year survival rates of 93%, 77%, and 58%, respectively. Recurrent: median OS was 17.9 months from the time of initial glioblastoma diagnosis. OS was significantly longer for those who received DC vaccination at initial diagnosis compared with those who enrolled in this trial at the time of recurrence.	[62]
8 patients (newly diagnosed GBM)	Phase I/II	Intradermal	Autologous tumor lysate	DTH (2/5) increased CD8^+/CD25^+ in PBL (6/7) ATR PBMC (5/8) IFN-gamma ELISPOT)	Median OS: 24 months	[63]
45 children (23 recurrent GBM, 5 AA, 1 AOA, 16 other HGG)	Phase I	Intradermal	Autologous tumor lysate + imiquimod	No data available	Median PFS for relapsed GBM: 4.3 months; median OS for relapsed GBM: 12.2 months	[64]
12 patients (newly diagnosed GBM)	Phase I	Intradermal	EGFRvIII antigen + KLH	DTH EGFRvIII (5/9); DTH KLH (9/9); ATR PBMC (10/12) (EGFRvIII-induced proliferation)	Median OS: 22.8 months	[65]
56 patients (recurrent GBM)	Phase I/II	Intradermal	Autologous tumor lysate	DTH (9/21 at time of diagnosis, 9/17 after 2 vaccinations)	3-month PFS; OS: 9.6 months; 24-month OS: 14.8%; total resection is a predictor for better PFS; younger age and total resection are predictors for better OS.	[66]
34 patients (23 recurrent GBM, 11 newly diagnosed GBM)	Phase II	Subcutaneous	Autologous tumor lysate	Postvaccine antigen-directed IFNg response in PBMCs (17/34); DTH-test resulted in cutaneous GBM in 1 patient (DTH was subsequently discontinued)	Newly diagnosed: 8/17 (47%) vaccine responders versus. 3/15 (20%) nonresponders; Recurrent: TTS, 621±81 and 402±49 d; TTP, 28±94 and 142±22 d (8 responders and 13 nonresponders); TTP, 343±116 and 136±19 d (8 responders and 15 nonresponders)	[67]
24 patients (18 recurrent GBM, 6 grade III glioma)	Phase I/II	Intradermal or intradermal + intratumoral (Ommaya reservoir)	Autologous tumor-lysate	DTH to tumor lysate (8/24); ATR PBMC (7/24) (IFN-gamma ELISPOT)	1 PR, 3 MR, 6 SD (GBM); 4 SD (Grade III glioma); median OS: 16 months versus 13.3 months; longer survival if DC maturation or IC injection. One grade IV neurotoxicity event (stupor) observed.	[68]
12 patients (7 newly diagnosed GBM, 5 recurrent GBM)	Phase I	Intradermal	Acid-eluted tumor associated peptides	CTL response (6/12); tumor infiltration CD8^+ CD45RO^+ cells (4/8)	Median TTP: 19.9 months—OS 18 to >58 months—median OS: 35.8 months. 1PR; Median OS: 23.4 versus 18.3 months. No dose-limiting toxicity observed	[69]
14 patients (1 newly diagnosed GBM, 9 recurrent GBM, 4 AA)	Phase I	Subcutaneous	Autologous tumor lysate	Increased IFNγ RNA in PBMC (6/10) ATR T cells (4/9) (HER-2, gp100, MAGE-1 tetramers); CD8^+, CD45RO^+ cells infiltration (3/6)	Median survival: 33.3 versus 7.5 months (8/9 recurrent GBM).	[70]
15 patients (6 recurrent GBM, 7 AA, 2 OAA)	Phase I	Intradermal	DC fusion with autologous glioma cells	DTH to tumor lysate (15/15); increased cytotoxic activity (2/15); increased intracellular IFN-gamma in CD8^+ T cells (1/15)	1 SD (GBM); 3 PR, 1 MR (AA); 1 PR, 1 SD (AOA)	[71]
7 patients (2 recurrent GBM, 1 AA, 4 other HGG)	Phase I	Intradermal	Autologous tumor RNA	No anti-tumor responses (0/3) (IFN-gamma ELISA)	1 PR (1XA); 4 SD (1AA, 3 other HGG)	[72]
25 patients (newly diagnosed GBM: 13 plus chemotherapy, 12 without chemotherapy)	Phase I/II	Intradermal	Autologous tumor lysates or peptide elutions	Vaccine alone: ATR PBMC (4/11) Vaccine + chemotherapy: ATR PBMC (4/13) (lytic activity and IFN-gamma PCR)	Vaccine or chemotherapy alone: 24-month survival: 8% Vaccine + chemotherapy: 3 PR; 24-month survival: 42%	[73]
10 patients (7 recurrent GBM after radiotherapy, 3 recurrent grade III glioma)	Phase I/II	Intradermal and/or intratumor (Ommaya)	Autologous tumor lysate	Increase in NK cells in PBMCs (5/10); DTH to tumor lysate (3/10); increased T-cell mediated antitumor activity (2/10)	2 MR, 2SD (GBM), 2SD (Grade III glioma); OS > 50 months.	[74]
9 patients (7 newly diagnosed GBM, 2 AA after radiotherapy)	Phase I	Subcutaneous	Tumor-specific MHC-I-associated peptides	Systemic CTL cytotoxicity against tumor (4/9) (lytic activity); tumor infiltration: CD4^+, CD8^+, CD45RO^+ cells (2/4)	Prolonged median survival compared to control group: 15.2 versus 8.6 months (GBM)	[75]

Abbreviations: AA: anaplastic astrocytoma; AO: anaplastic oligodendroglioma; AOA: anaplastic oligoastrocytoma; ATR: anti-tumor responses; CR: complete response; DTH: delayed-type hypersensitivity; GAA: glioblastoma associated antigen; GBM: glioblastoma multiform; HGG: high-grade glioma; KLH: keyhole limpet haemocyanin; MR: Minor response; OS: overall survival; PBMC: peripheral blood mononuclear cells; PFS: progression-free status; PR: partial response; PXA: pleomorphic xanthoastrocytoma; SD: stable disease; TMZ: Temozolomide; TTP: Time to tumor progression; TTS: Time to tumor survival; XA: xanthoastrocytoma.