Table 1.
Summary of human clinical studies involving immunomodulatory therapies.
| Reference | Study type/clinical phase | Study cohort/Patients | Intervention | Treatment outcome/therapeutic response |
|---|---|---|---|---|
| Cytokine therapy | ||||
| G-CSF, GM-CSF | ||||
| Clark et al. (2005) | Meta-analysis of 13 clinical trials | Total of 1,518 patients in the 13 trials | Six studies used G-CSF, six used GM-CSF, one used G-CSF, and GM-CSF treatment | G-CSF and/or GM-CSF use reduced the duration of neutropenia andthe length of stay during febrileneutropenia episodes; however, it wasinconclusive whether administrationimproved infection-relatedmortality |
| Mhaskar et al. (2014) | Meta-analysis of 14 RCTs | 1,553 patients with chemotherapy-induced febrile neutropenia in 14 trials | Treatment with antibiotics plus G-CSF or GM-CSF vs. antibiotics alone | Shorter duration of neutropenia, faster recovery of fever, shorter empiric antibiotic use, administration of the CSFs did not improve overall mortality and infection (including fungal)-related mortality |
| Wan et al. (2015) | Phase IV | 206 allo-HSCT patients | Prophylactic treatment with G-CSF, GM-CSF, or G-CSF + GM-CSF | IFD-related mortality was lower in GM-CSF, G-CSF + GM-CSF group |
| M-CSF | ||||
| Nemunaitis et al. (1993) | Phase I/II trials | Long term follow up of 46 stem cell transplantation patients | The experimental group was given recombinant human M-CSF daily with conventional antifungal treatment. | There was better survival in the patients who received M-CSF, compared against historical controls (27% vs. 5%) |
| Interferon-gamma | ||||
| Pappas et al. (2004) | Phase II, double-blind, placebo-controlled trial | 70 HIV positive patients with acute Cryptococcus meningitis (23 controls, 25 receiving 100 μg of IFN-γ, 22 receiving 200 μg of IFN-γ) | Patients received 100 or 200 μg of IFN-γ or placebo three times a week for 10 weeks, in addition to standard therapy consisting of intravenous amphotericin B, with or without flucytosine, for 14 days, followed by fluconazole. | Patients who received IFN-γ showed a trend toward rapid sterilization of cerebrospinal fluid (CSF). Lower dosage of 100 μg IFN-γ achieved similar results as the 200 μg IFN-γ recipients |
| Jarvis et al. (2012) | Open label RCT | 88 HIV-infected patients infected with Cryptococcus meningitis (31 controls, 29 receiving 2 doses, and 20 receiving 6 doses) | Patients were randomized to receive standard antifungal therapy for 2 weeks (amphotericin B plus flucytosine), or standard antifungal therapy plus two doses of 100 μg IFN-γ, or standard antifungal therapy plus six doses of 100 μg IFNγ | The IFNγ therapies caused significantly faster CSF Cryptococcus clearance, with no significant increase in adverse events. Two doses of IFN-γ yielded similar outcomes as six doses |
| Delsing et al. (2014) | Open label clinical case series | 11 patients with invasive Candida and/or Aspergillus infections, consisting of 3 placebo controls, 3 with IFN-γ, 5 more treated with IFN-γ included as therapy of last resort | The experimental group was administered IFN-γ, 50 μg/m2 body surface, three times a week, in addition to standard antifungal therapy | Five of eight patients treated with IFN-γ recovered from the IFD. Two of the patients admitted into the study as last resort passed away due to infectious complications. One of eight was lost to follow up. All three patients in the control group recovered |
| Cytokine agonist therapy | ||||
| Erbagci et al. (2005) | Case report | One patient with recalcitrant hyalohyphomycosis caused by Acremonium strictum | Imiquimod topical 5% cream applied to area of fungal lesions and oral itraconazole antifungal treatment | Full regression of the fungal lesions after 2 months of therapy, and complete regression of all clinical and hematological abnormalities |
| de Sousa et al. (2014) | Case series | Four patients with Chromoblastomycosis, caused by Fonsecaea pedrosoi | Imiquimod topical 5% cream applied to area of fungal lesion, with or without antifungal treatment | After application of imiquimod cream, two patients had complete clearance of infection. The other two patientssaw improvement after usingimiquimod |
| Cellular therapy | ||||
| Granulocyte transfusion (GTX) | ||||
| West et al. (2017) | Review of GTX from case series, prophylactic GTX in eight RCTs, therapeutic GTX in five RCTs | Adult and pediatric patients with underlying malignancy and IFD and/or bacterial infection | The experimental groups were given prophylactic GTX or therapeutic GTX | Low-grade evidence that prophylactic GTX may reduce the incidence of fungaemia, but non-selective prophylaxis for all neutropenic patients does not prevent mortality due to IFD |
| Estcourt et al. (2015, 2016) | Meta-analysis of 11 RCTs and 10 RCTs, respectively | 653 participants in total (Estcourt et al., 2015); 587 participants in total (Estcourt et al., 2016) | Estcourt et al. (2015) – The experimental groups were given prophylactic GTX vs. controls without GTX.Estcourt et al. (2016) – The experimental group were given therapeutic GTX vs. controls without GTX | Both Estcourt et al. (2015, 2016) found that prophylactic and therapeutic GTX, respectively, had low grade evidence for decreasing the risk of bacterial or fungal infections, or decreasing mortality rate. There was insufficient evidence to detect significant differences in mortality due to infection between GTX-treated patients and controls, and the GTX efficacy may be dose-dependent. The statistical power of the 10 trials is insufficient to determine whether GTXs affected all-cause mortality |
| Raad et al. (2013) | Case series, retrospective review | Patients with hematological malignancies, prolonged neutropenia, and proven or probable invasive aspergillosis (IA) | Retrospective review of outcomes with or without therapeutic GTX | Therapeutic GTX treated patients with IA had a higher risk of not responding to antifungal treatment and had higher mortality compared to controls |
| Seidel et al. (2008) | Phase III randomized controlled trial | 74 patients with neutropenia were randomized to receive standard antimicrobial/antifungal therapy plus GTX (n = 38) vs. the no-GTX control arm (n = 34) | Therapeutic GTX was administered to patients, in addition to standard antimicrobial/antifungal therapy | No statistical significance between the two groups |
| Price et al. (2015), The RING study | Phase III, open label, multicenter randomized controlled trial | Patients with neutropenia from 14 centers were randomized to receive standard antimicrobial therapy plus GTX (n = 56), or the control arm without GTX (n = 58) | Patients received daily GTX until neutrophil count recovery, resolution or improvement of infection, toxicity or 42 days, whichever was earlier. G-CSF was used to increase the granulocyte count in donors | No statistical significance was found between the GTX arm and the control arm, challenges encountered included low enrolment and variation in granulocyte dosage. Subjects who received >0.6 billion granulocytes/kg tended to have better outcomes than those receiving a lower dose of granulocytes |
| Adoptive T-cell therapy | ||||
| Perruccio et al. (2005) | Phase I/II clinical trial | Transplant patients with evidence of IA (n = 10), controls (n = 13) | T-cells from donors were stimulated with Aspergillus antigen, selected for non-recipient reactive clones, and expanded. Patients were randomized to receive treatment with liposomal amphotericin B alone, with or without, single infusion of donor pathogen-specific T-cells | Nine out of 10 patients had resolution of Aspergillus infection after receiving a single dose of Aspergillus-specific T-cell clones, compared to a response rate of only 53% (7 out of 13) in the control group |
| Tzannou et al. (2017) | Phase II clinical trial | 38 patients with 45 viral infections, consisting of 31 with a single virus infection and seven with two virus infections | Virus-specific T-cell lines for five viruses, Epstein–Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6) were manufactured from donors. All patients had at least a single infusion of partially | The patients had cumulative complete or partial response rate of 92%. Of special mention is by week 6, 13 of 14 patients with BKV-associated hemorrhagic cystitis had complete resolution of gross hematuria |
| HLA-matched virus-specific T-cells, 11 had a second infusion after 4 weeks, and four patients had three infusions | ||||
| Monoclonal antibodies | ||||
| Larsen et al. (2005) | Phase I clinical trial | 20 HIV-positive patients who had a history of culture positive Crypotcoccus meningitis, with resolution of symptoms at least 12 weeks prior to the study | Patients were divided into six groups of escalating doses of 18B7 therapeutic monoclonal antibody against C. neoformans. The changes in serum cryptococcal antigen titres were monitored | 18B7 antibodies was generally well tolerated at lower doses. At higher concentrations above 1 mg/kg, subjects developed infusion-associated back and muscle pain. They established that 18B7 can be safely given to subjects in doses below 1 mg/kg |
| Pachl et al. (2006) | Multinational phase III clinical trial | 139 patients who had culture-positive Candida infection | The experimental group received intravenous Mycograb every 12 h for 5 days plus lipid-amphotericin B, while controls received lipid-amphotericin B alone | The complete overall response by day 10 was 84% for the Mycograb group and 48% for controls, and other indicators were also better for the Mycograb group, such as, better clinical response rate, Candida-attributable mortality, and rate of culture-confirmed clearance of the infection |
| Immunomodulation by other substances | ||||
| Vitamins | ||||
| Nguyen et al. (2015) | Phase I, open label clinical trial | Cystic fibrosis patients who had low levels of vitamin D and allergic bronchopulmonary aspergillosis | The experimental group was given 6 months of daily vitamin D3 (cholecalciferol) supplementation | Aspergillus induced IL-13 and IgE levels to be significantly decreased after 24 weeks (P=0.04) |
| Repurposing of existing drugs | ||||
| Spellberg et al. (2012), DEFEAT Mucor study | Phase II, randomized, double-blinded, placebo-controlled trial | 20 patients with proven or probable mucormycosis, 11 with deferasirox treatment, and nine placebo | Patients were randomized to receive treatment with liposomal amphotericin B plus/minus deferasirox (20 mg/kg/day for 14 days) | Patients given deferasirox had a higher mortality compared to the controls. The patients in the deferasirox arm of the trial were more likely to have active malignant cancer, neutropenia and corticosteroid therapy, and less likely to receive concurrent antifungals, which makes interpretation of results inconclusive |
| Rhein et al. (2016), ASTRO-CM study | Open label, dose-finding study | 172 HIV-infected adult patients with Cryptococcus meningitis | The experimental group received adjunctive sertraline at doses of 100–400 mg/day, in addition to standard antifungal therapy | The rate of fungal clearance was better in the sertraline group, led to lower recurrence, and possibly decreased incidence of paradoxical immune reconstitution inflammatorysyndrome |
| Promising future therapies | ||||
| Immunomodulation through probiotics and the microbiome | ||||
| Demirel et al. (2013) | Randomized, comparative trial | Very low birth weight, preterm infants with gestational age ≤1,500 g | The infants were either given oral Saccharomyces boulardii prophylaxis (five billion colony forming unit per day) added to breast milk or formula once a day, starting with the first feed until discharged, or oral nystatin suspension every 8 h | In the S. boulardii group, there was lower rates of sepsis, Candida colonization and less feeding intolerance. S. boulardii was not found to grow in any of the positive blood cultures. Both groups observed no serious effects from the S. boulardii and nystatin |
| Feizizadeh et al. (2014) | Meta-analysis review of 22 randomized controlled trials | Pediatric patients with diarrhea | The experimental group was given S. boulardii | S. boulardii supplementation resulted in better outcomes, such as shorter duration of diarrhea, and reduced stool frequency. It did not cause any serious adverse events |