Table 2 ∣.
Antigen-specific immunotherapy approaches in phase I or II clinical trials
| Study type | Vehicle or reagent | Major findings | Clinical trial ID |
|---|---|---|---|
| Cell-based approaches | |||
| Neuroinflammation | |||
| Tolerogenic fibroblasts | Tolerogenic fibroblasts | No significant safety concerns or side effects up to 16 weeks after infusion | NCT05080270 |
| Tolerogenic DCs (TOLERVIT-MS) | Vitamin D3-moDCs + IFNβ | Interim report: no safety concerns | NCT02903537 |
| “Negative” DC vaccine (MS-tolDC) | Vitamin D3-moDCs | Interim report: no safety concerns | NCT02618902 |
| Regulatory DCs (TolDec-EM-NMO) | Dexamethasone–GM-CSF–IL-4-moDCs with seven peptides from MBP, MOG, PLP, AQP4 | Safe; induction of TR1 cells and decreased CD8+ T cells, NK cells, CD14+CD56+ cells | NCT02283671 |
| Peptide-coupled PBMCs (ETIMS) | Autologous PBMCs coupled with seven peptides | No adverse effects, reduced antigen-specific T cell response, no effects on immunoglobulins or recall antibody effect | NCT01414634 |
| Mesenchymal stem cells (MSCIMS) | Mesenchymal stem cells | Safe; neuroprotective; met some secondary visual end points | NCT00395200 |
| T cell vaccine | Irradiated MBP-reactive T cells against nine epitopes | Reduction in EDSS, walking time and relapses | NCT01448252 |
| T cell vaccine | Irradiated MBP-reactive T cells | Depletion of autoreactive T cells; smaller lesion volume | 269 |
| Rheumatoid arthritis | |||
| Autologous tolerogenic DCs (AutoDECRA) | Dexamethasone–vitamin D-moDCs with synovia | Safe, but no systemic effects detected | NCT01352858 |
| Autologous tolerogenic DCs (TolDCfoRA) | Dexamethasone-moDCs | Well tolerated | NCT03337165 |
| DC vaccine to suppress the immune response to citrullinated antigen (BAY11-7082; Rheumavax) | NF-κB-inhibitor-moDCs | Safe; fewer effector T cells and decreased pro-inflammatory cytokines | ACTRN12610000373077 |
| Autologous DCs (CreaVax-RA) | moDCs pulsed with PAD4, citrullinated vimentin and fillagrin. HNRPA2/B1 | Safe; reduction in autoantibody and IFNγ-producing T cells | CRiSKCT0000035 |
| Inflammatory bowel disease | |||
| Intralesional tolerogenic DCs (TolDecCDintra) | Dexamethasone-moDCs | Terminated (low recruitment) | NCT02622763 |
| Antigen-specific Treg cell therapy | Treg cells with ovalbumin | No adverse effects; symptom reduction | 2006-004712-44 |
| Autologous tolerogenic DCs | Dexamethasone–vitamin D-moDCs | Mixed clinical response | 2007-003469-42 |
| Type 1 diabetes | |||
| Immunotherapy vaccine (PIpepTolDC) | Autologous tolerogenic DCs loaded with proinsulin peptides | Ongoing | NCT04590872 |
| Autologous tolerogenic DCs | Autologous moDCs primed with peptides | Ongoing | NCT05207995 |
| AVT001 | Autologous moDCs | Ongoing | NCT03895996 |
| Tolerogenic DCs (D-Sense) | Vitamin D3-moDCs with proinsulin | Not published | NTR5542 |
| Polyclonal Treg cells + IL-2 (TILT) | Polyclonal Treg cells | No adverse effects but poor Treg cell survival | NCT02772679 |
| Tolerogenic DCs | Dexamethasone-vitamin D3-moDCs pulsed with islet antigen | Long-lasting CD4+ T cell tolerance and temporary bystander tolerance | 2013-005476-18 |
| Autologous immunoregulatory DCs | Anti-CD40/CD80/CD8-moDCs with six ODNs | Not published | NCT02354911 |
| CD4+CD127lowCD25+ polyclonal Treg cells | Polyclonal Treg cells + IL-2 | Treg cell survival but also expansion of cytotoxic T cells | NCT01210664 |
| Autologous DCs | Antisense CD40, CD80, CD86 ODNs-moDCs | Safe; induction of B220+CD11c+ B cells | NCT00445913 |
| Treg cells | Autologous ex vivo-expanded Treg cells | No adverse effects; elevated C-peptide levels and lower insulin dependence after 1 year | ISRCTN06128462 |
| Systemic lupus erythematosus | |||
| Autologous polyclonal Treg cells | Treg cells | Increased Treg cells in inflamed tissue | NCT02428309 |
| Graft rejection after kidney transplantation | |||
| DCreg | Donor-derived tolerogenic DCs | Ongoing | NCT03164265 |
| Donor alloantigen reactive Treg cells (ARTEMIS) | Donor alloantigen reactive Treg cells | No adverse effects | NCT02474199 |
| Autologous tolerogenic DCs (ONEatDC) | GM-CSF-moDCs | No adverse effects, fewer infections | NCT02252055 |
| Regulatory macrophages (ONEmreg12) | Donor-derived regulatory macrophages induced with GM-CSF + IFNγ | No adverse effects, fewer infections | NCT02085629 |
| Donor alloantigen-reactive Treg cells (The ONE Study) (DART) | Donor-alloantigen-reactive Treg cells with donor antigen | No adverse effects, fewer infections | NCT02244801 |
| Natural Treg cells (ONEnTreg13) | CD4+CD25+FOXP3+ Treg cells | No adverse effects, fewer infections | NCT02371434 |
| Treg cells (ONETreg1) | CD4+CD25+FOXP3+ Treg cells | No adverse effects, fewer infections | NCT02129881 |
| Treg cells (The ONE Study) | Treg cells induced with belatacept ex vivo with donor antigen | No adverse effects, fewer infections | NCT02091232 |
| Graft-versus-host disease | |||
| Ex vivo expanded donor Treg cells | Donor Treg cells cultured with recipient DCs | Not published | NCT01795573 |
| T cell-depleted graft with simultaneous infusion T cells | Conventional T cells and Treg cells in predefined ratio | Safe, no adverse effects | NCT01660607 |
| Treg cells | Induced Treg cells | No adverse effects | NCT01634217 |
| Treg cells | Induced Treg cells | Safe, low risk of acute GVHD | NCT00602693 |
| Free antigen approaches | |||
| Multiple sclerosis | |||
| ATX-MS-1467 | Synthetic peptides of four epitopes of MBP | Study 1 showed temporary lesion reduction; study 2 showed lesion reduction up to 48 weeks with higher doses | NCT01973491 |
| Myelin peptides | Transdermal peptide mix | Reduction of gadolinium-enhancing lesions | 270 |
| Myelin peptides | Transdermal peptide mix | Induction of TR1 cells but not FOXP3+ Treg cells | 271 |
| MBP8298 (MAESTRO-03) | MBP8298 | No difference to placebo | NCT00468611 |
| BHT-3009 | MOG-DNA | Fewer lesions and reduction of a spectrum of antibodies | NCT00382629 |
| Glatiramer acetate | Random peptides resembling MBP | Reduced number of lesions | 272 |
| Type 1 diabetes | |||
| TOL-3021 in new onset disease (DAWN) | DNA-plasmid encoding proinsulin | Ongoing | NCT03794973 |
| TOL-3021 in established disease (DAY) | DNA-plasmid encoding proinsulin | Ongoing | NCT03794960 |
| Proinsulin peptide (MonoPepT1De) | Proinsulin | No adverse effects, reduced insulin use increase, FOXP3 and IL-10 induction | NCT01536431 |
| BHT-3021 | DNA-plasmid encoding proinsulin | No adverse effects, C-peptide level increased but no effect on insulin requirement | NCT00453375 |
| DPT-1 | Insulin, GAD65 | No effect on prevention of familial disease development | |
| Rheumatoid arthritis | |||
| Chicken type II collagen | Chicken type II collagen | Improvement of symptoms, albeit less than methotrexate-treated control group | ChiCTR-TRC-00000093 |
| Altered peptide ligand approaches | |||
| Multiple sclerosis | |||
| RTL1000 | TCR ligand | No adverse effects at <100 mg; no worsening of disease | NCT00411723 |
| NBI-5788 | Altered peptide ligand | Suspended after detection of increased brain lesions in some patients | NCT00079495 |
| CGP77116 | Altered peptide ligand | Aborted owing to exacerbation of disease in three patients | NCT00001781 |
| NBI-5788 | Altered peptide ligand | Hypersensitivity reactions, reduced lesion load | 200 |
| Type 1 diabetes | |||
| NBI-6024 | Altered peptide ligand | No effect compared with placebo | NCT00873561 |
| Antigen and adjuvant approaches | |||
| Multiple sclerosis | |||
| NeuroVax | TCR peptides in IFA | Ongoing | NCT02057159 |
| Type 1 diabetes | |||
| Diamyd (DIAGNODE-3) | rhGAD65–Alum+vitamin D HLA-DR3-DQ2+ haplotype | Ongoing | NCT05018585 |
| Diamyd booster | Booster Diamyd+vitamin D3 | Ongoing | NCT05351879 |
| MER3101: MAS-1 adjuvanted (MER3101) | β-chain + MER3101 administered into lymph nodes | Ongoing | NCT03624062 |
| Diamyd (DIAGNODE-2) | rhGAD65–alum+vitamin D3 administered into lymph nodes | No significant improvement in overall groups but increased glycaemic control in HLA-DR3-DQ+ subjects | NCT03345004 |
| Diamyd (DIAGNODE-1) | rhGAD65–alum+vitamin D | No adverse effects; TH2 cell induction; TH1 cell reduction; C-peptide baseline increased | NCT02352974 |
| Islet β-chain | IFA–β-chain emulsion | Insulin-specific antibody and T cell induction; induction of long-lasting antigen-specific Treg cells, no HBA1C or insulin use changes | NCT00057499 |
| Diamyd in newly diagnosed disease (DIAPREVENT) | rhGAD65–alum | No change in C-peptide levels | NCT00751842 |
| Diamyd in newly diagnosed disease (DIAPREVENT) | GAD–alum | No adverse effects; no difference in insulin secretion | NCT00529399 |
| Nanoparticle-based approaches | |||
| Multiple sclerosis | |||
| Xemys | CD206-targeted liposomes with three MBP peptides | Cytokine normalization | #930 [FASEMS-01/01] |
| Rheumatoid arthritis | |||
| DEN-181 | Liposomes with collagen peptide + NF-κB inhibitor | Reduced effector T cells, increased Treg cells | 176 |
| AG4263 | Iron particles coated with peptide–MHC class II-bound antigen | No long-lasting effects | 273 |
| Coeliac disease | |||
| TIMP-GLIA | PLGA nanoparticles with gliadin TAK-101 | Reduction of IFNγ-producing cells on challenges | NCT03738475 |
AQP4, aquaporin 4; DC, dendritic cell; EDSS, expanded disability status scale; GAD, glutamic acid decarboxylase; GVHD, graft-versus-host disease; GM-CSF, granulocyte-monocyte colony-stimulating factor; IFA, incomplete Freunds adjuvant; IFNβ, interferon-β; IFNγ, interferon-γ; MBP, myelin basic protein; moDC, monocyte-derived dendritic cell; MOG, myelin oligodendrocyte glycoprotein; NF-κB, nuclear factor-κB; ODNs, oligodeoxynucleotides; PAD4, peptidylarginine deiminase 4; PLGA, poly(lactic-co-glycolic acid); PLP, proteolipid protein; TCR, T cell receptor; Treg cell, regulatory T cell.