TABLE 4.
List of the different immune modulatory therapeutic approaches clinical trials.
| Molecule name | Type of molecule | Target | Effects | Theoretical targeted cell types | Clinical phases | Clinical trials conclusions | Used for other diseases | References |
| Minocycline (Minocin) | Small molecule | Apaf-1? Apoptotic machinery | ↘ caspase-1, caspase-3, iNOS, MAPK | • MG | Phase III (completed 2007) | Negative effects on patients. | Acne vulgaris Infections Asthma | Chen et al., 2000; Wang et al., 2003; Gordon et al., 2007 |
| • MP | ||||||||
| Thalidomide (Contergan/Thalomid) | Small molecule | 3′-UTR of TNF-α mRNA | ↘ IL-1β, IL-6, IL-10, IL-12, TNF-α | • MG | Phase II (completed 2007) | No positive effects and can cause adverse effects. | Multiple myeloma | Clinical trial: NCT00140452 Stommel et al., 2009; Jung et al., 2019 |
| • Monocytes | ||||||||
| • MP | ||||||||
| • Other CNS cells (endothelial cells, neuronal cells, astrocytes) | ||||||||
| Pioglitazone (Actos) | Small molecule | (+) PPAR? | ↘ Inflammatory mediators modulate transcription of insulin responsive genes stimulates adipocytes differentiation | • MP | Phase II (completed 2015) | The interim analysis showed no tendency in favor of the verum group. Therefore it was decided to stop the study prematurely. | Type 2 diabetes | Clinical trial: NCT00690118 Dupuis et al., 2012; Jawaid et al., 2014 |
| • Monocytes | ||||||||
| • Adipocytes | ||||||||
| • MG | ||||||||
| Fingolimod (Gilenya) | Small molecule | (+) S1P | Decrease S1P1 Prevents lymphocytes egress from lymphoid tissues | • CD4 lymphocytes and Treg | Phase Iia (completed 2015) | Safe and well tolerated. | Multiple sclerosis Chronic inflammatory Demyelinating polyneuropathy | Potenza et al., 2016; Berry et al., 2017 |
| • MG | ||||||||
| Dimethyl Fumarate | Small molecule | (+) NRF2 (−) GAPDH | Antioxidant response ↘ Th1 ↖ Th2 ↖ Type II DC ↖ Aerobic glycolysis | • T cells (including Treg) | Phase II (completed 2019) | Assessing efficacy and safety. | Psoriasis Multiple sclerosis | Clinical trial: ACTRN12618000534280 Gross et al., 2016; Schlöder et al., 2017; Kornberg et al., 2018; Piroli et al., 2019; Holm Hansen et al., 2020; Vucic et al., 2020 |
| • DC | ||||||||
| • MP | ||||||||
| • Monocytes | ||||||||
| • MG | ||||||||
| • Other CNS cells (neurons, astrocytes) | ||||||||
| • Muscles | ||||||||
| Glatiramer Acetate (Copaxone) | Small molecule | Mimicks MBP | Modulate T cells reactivity | • T cells (including Treg) | Phase II (completed 2008) | Safe and tolerable. Glatiramer acetate at dose of 40 mg/day did not show beneficial effect in ALS. | Multiple sclerosis | Clinical trial: NCT00326625 Meininger et al., 2009 |
| Tocilizumab (Actemra) | Monoclonal antibody | (−) IL-6R | ↘ IL-6 | • MP | Phase III (completed 2018) | Safe and tolerable, reduces c reactive protein concentration in plasma and CSF of ALS patients. | Rheumatoid arthritis Systemic juvenile idiopathic arthritis Castleman’s disease Giant cell arteritis Cytokine release syndrome | Clinical trial: NCT02469896 Mizwicki et al., 2012; Fiala et al., 2013; Sheppard et al., 2017; Milligan et al., 2021 |
| • B cells | ||||||||
| • T cells | ||||||||
| • Osteoclasts | ||||||||
| • Monocytes | ||||||||
| • DC | ||||||||
| • MG | ||||||||
| • Other CNS cells (astrocytes, neuronal cells) | ||||||||
| • Muscle | ||||||||
| Celecoxib (Celebrex)/ Ciprofloxacin | Small molecule | (–) Cox-2 bacterial DNA gyrase and topoisomerase IV. | ?↘ PGE2 | • Monocytes | Phase I (combined therapy with Ciprofloxacin; active, not recruiting) | 800 mg/day was safe and tolerable but did not show beneficial effects for ALS patients. New combined trial with Ciprofloxacin is ongoing. | Celecoxib Osteoarthritis Rheumatoid arthritis Ankylosing spondylitis Acute pain Musculoskeletal pain Familial adenomatous polyposis Ciprofloxacin Infections | Clinical trial: NCT04090684 Cudkowicz et al., 2006; Gong et al., 2012; Na et al., 2013; Nagano et al., 2017 |
| • MP | ||||||||
| • Osteoblasts | ||||||||
| • Smooth muscles | ||||||||
| • Granulocytes | ||||||||
| • Bone marrow | ||||||||
| • MG | ||||||||
| • Other CNS cells | ||||||||
| NP001 | pH-adjusted IV formulation of purified sodium chlorite | Chlorite is converted into taurine chloramine ↘ NF-kB expression | Modulation of monocytes activation and ↘ IL-1β | • MP | Phase IIb (completed) | Safe but do not significantly slow progression of the disease. Study lacks precision to exclude important effect. | / | Miller et al., 2014, 2015, 2018 |
| • Monocytes | ||||||||
| • MG | ||||||||
| • Other CNS cells | ||||||||
| Ravulizumab (Ultomiris) | Monoclonal antibody | (−) Complement 5 | ↘ Inflammation | • MP | Phase III (stopped in 2021) | Pivotal study. Role of complement-mediated damage in ALS patient is evident, lack of efficacy. | Paroxysmal nocturnal hemoglobinuria Atypical hemolytic uremic syndrome | Clinical trial: NCT04248465 Lee et al., 2017; Wang et al., 2017 |
| • Monocytes | ||||||||
| • Granulocytes | ||||||||
| • T cells | ||||||||
| • MG | ||||||||
| • DC | ||||||||
| • B cells | ||||||||
| • Astrocytes | ||||||||
| • Muscle | ||||||||
| Anakinra (Kineret) | Monoclonal antibody | (−) IL-1R | ↘ IL-1α, IL-1β | • T cells | Phase II (recruiting since 2011) | Safe, tolerable. No reduction on disease progression, increased serum inflammatory markers. | Rheumatoid arthritis Cryopyrin-associated periodic syndrome Macrophage activation syndrome Schnitzler’s syndrome Hemophagocytic lymphohistiocytosis | Clinical trial: NCT01277315 Cohen, 2004; Maier et al., 2015 |
| Low dose-IL-2 (Aldesleukin) | Small molecule | (−) IL-2R, IL-15Rβ | Promotes Treg differentiation + pleiotrope actions on the immune system | • T cells | Phase II (active, not recruiting) | Safe, increased Tregs, no differences on plasma NFL. | Malignant melanoma Renal cell cancer Autoimmune disease | Clinical trial: NCT03039673 Camu et al., 2020 |
| • Cells in the CNS | ||||||||
| Rapamycin (Rapamune) | Small molecule | (−) mTOR | Promotes Treg differentiation ↖ Autophagy | • T cells | Phase II (active, not recruiting) | Already well known pharmacokinetics, safety and tolerability. | Organ transplant rejection Lymphangioleiomyomatosis | Clinical trial: NCT03359538 Staats et al., 2013; Madill et al., 2017; Mandrioli et al., 2018 |
| • Neuronal cells | ||||||||
| • Astrocytes | ||||||||
| RNS60 | Experimental nanostructured drug containing various oxygen nanobubbles | (+) p-Akt pro survival pathway (−) NF-κB | ↘ Mitochondrial alteration and oxidative stress ↖ Anti-inflammatory phenotype ↖ IL-4 | • MN | Phase II (active, not recruiting) | Long-term administration was safe and well-tolerated. | / | Clinical trial: NCT03456882 Vallarola et al., 2018; Paganoni et al., 2019 |
| • NMJ | ||||||||
| • T cells | ||||||||
| • Muscle | ||||||||
| • MP | ||||||||
| • MG | ||||||||
| • Astrocytes | ||||||||
| • Schwann cells | ||||||||
| • Monocytes | ||||||||
| Masitinib (Masivet) | Small molecule | (−) TKR c-kit, CSF1R, tyrosine protein kinase Lyn, proto-oncogene tyrosine protein kinase Fyn | ↘ Proliferation of MG and MP Other effects unknown? | • Mast cells | Phase III (active, recruiting) | Safe and tolerable. Slows ALSFRS-R decline of 27% after 48 we of treatment, VFC of 22% and ALSAQ-40 of 29%. | European approval of Masitinib for treatment of ALS (Alsitek) was refused in 2018 | Trias et al., 2016, 2017, 2018; Mora et al., 2020 |
| • MP | ||||||||
| • MG | ||||||||
| • Neutrophils | ||||||||
| • Schwann cells | ||||||||
| • NK | ||||||||
| • Muscle | ||||||||
| • Monocytes | ||||||||
| • DC | ||||||||
| • T cells | ||||||||
| • Other CNS cells (high level of the target in the cerebellum, astrocytes, neuronal cells) | ||||||||
| Ibudilast | Small molecule | (−) PDE 3, 4, 10, 11 (−) TLR-4, NO (−) MIF | ↘ IL-1β, TNF-α, IL-6, ROS ↖ IL-10, NTF (BDNF, NGF, NT-4) | • MP | Phase II/III (active, recruiting) | Safe and tolerable. Sentinel ALS muscle strength was significantly reduced 2 we post cessation of the treatment. | Asthma Allergic conjunctivitis Hay fever Stroke | Gibson et al., 2006; Cho et al., 2010; Cox et al., 2013; Brooks et al., 2015, 2016, 2017; Ha et al., 2019; Oskarsson et al., 2020; Babu et al., 2021 |
| • Other CNS cells (astrocytes, neuronal cells) | ||||||||
| • MG | Another study conclude that 100 mg/day in ALS, no significant reductions in motor cortical glial activation over 12–24 we, CNS neuroaxonal loss (NFL measure) over 36–40 we. Future pharmacokinetic and dose finding studies required. | |||||||
| • Monocytes | ||||||||
| • Neutrophils | ||||||||
| • DC | ||||||||
| • Granulocytes | ||||||||
| • Mast cells | ||||||||
| • Muscle | ||||||||
| • Bone marrow | ||||||||
| Zilucoplan | Small molecule | (−) Complement 5 | ↘ Inflammation | • MP | Phase II (active, recruiting) | Implication of complement in ALS patients. | / | Clinical trial: NCT04297683 Lee et al., 2017; Wang et al., 2017 |
| • Monocytes | ||||||||
| • Granulocytes | ||||||||
| • T cells | ||||||||
| • MG | ||||||||
| • DC | ||||||||
| • B cells | ||||||||
| • Astrocytes | ||||||||
| • Muscle | ||||||||
| Fasudil | Small molecule | (−) Rho kinase | ↘ Pro-inflammatory cytokines ↖ Axonal regeneration, NMJ, actin cytoskeleton plasticity ↖ Akt pro-survival pathway | • MG | Phase IIa (active, recruiting) | Previous reports in the first compassionate use of Fasudil show in n = 3 patients slow VFC significant increase in one of the patients and safety and tolerability. | Stroke Subarachnoid hemorrhage Pulmonary hypertension | Clinical trial: NCT03792490 Tönges et al., 2014; Lingor et al., 2019; Koch et al., 2020 |
| • Muscle | ||||||||
| • Other CNS cells (neuronal cells, endothelial cells, astrocytes) | ||||||||
| • MP | ||||||||
| • DC | ||||||||
| • NK | ||||||||
| • T cells | ||||||||
| • Mast cells | ||||||||
| Verdiperstat | Small molecule | (−) MPO enzyme | ↘ Oxidative stress, inflammation | • Monocytes | Phase III (enrolling by invitation) | / | / | Clinical trial: NCT04436510 Patnaik et al., 2020 |
| • DC | ||||||||
| • Neutrophils | ||||||||
| • MG | ||||||||
| • MP | ||||||||
| • Bone marrow |
Main targets are listed for each molecule. This may be non-exhaustive as some molecules have very large spectrum of action still not well described. The main effects are presented similarly. The listing is based on actual literature and may evolve with time. Targeted cell types are presented. In blue bold are the cell types predicted to be targeted by the molecule in accordance with the literature. In black are other cell types expressing the target and that may also be impacted by the treatment. The expression of each cellular target was investigated via proteinatlas.org in order to index cell types susceptible to be targeted by the drug. Main focus was driven on immune related cell types. Trials are sorted depending on their clinical trial ongoing status. 3′ UTR, 3′ untranslated transcribed region; ALS, amyotrophic lateral sclerosis; ALSAQ-40, Amyotrophic Lateral Sclerosis Assessment Questionnaire; ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale; Apaf-1, apoptotic protease activating factor 1; BDNF, brain-derived neurotrophic factor; C5, complement 5; CNS, central nervous system; CSF, central nervous system; COX-2, cyclooxygenase-2; CSF1R, colony stimulating factor 1 receptor; DC, dendritic cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL-1α, interleukin-1 alpha; IL-1β, interleukin-1 beta; IL-1R, interleukin-1 receptor; IL-2R, interleukin-2 receptor; IL-4, interleukin-4; IL-6, interleukin-6; IL-6R, interleukin-6 receptor; IL-10, interleukin-10; IL-12, interleukin-12; IL-15R, interleukin-15 receptor beta; iNOS, inducible nitric oxide synthase; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; MG, microglia; MIF, macrophages migration inhibitory factor; MP, macrophage; MPO, myeloperoxidase; mTOR, mechanistic target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NFL, neurofilament light chain; NGF, nerve growth factor; NK, natural killer; NMJ, neuro-muscular junction; NO, nitric oxide; NRF2, nuclear factor erythroïd-2-related factor 2; NT-4, neurotrophin 4; NTF, neurotrophic factors; PDE, phosphodiesterase; PGE2, prostaglandin E2; PPARγ, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate receptor; S1P1, sphingosine-1-phosphate receptor 1; TLR-4, Toll-like receptor 4; TNFa, tumor necrosis alpha; TKR, tyrosine-kinase receptor; VFC, vital force capacity.