Immunomonitoring of Mold Invasive Infections (IMMUNOFIL)

Mold invasive infections are associated with an important mortality despite optimization of the antifungal treatment. In a few case reports, immune checkpoints inhibitors, initially developed for neoplastic diseases, have shown a potential beneficial effect in such devastating infections by restoring an efficient immune response. The investigators propose a longitudinal monitoring of the adaptative immune response, notably immune checkpoint expression on T cells, during mold invasive infections to help identify the patients who could benefit from the adjunction of immunotherapy and the optimal timing of such strategy.

Study Overview

• Status: Not yet recruiting
• Conditions: Invasive Fungal Disease

Detailed Description

Invasive fungal diseases (IFD) still cause substantial morbidity and mortality. New therapeutic approaches are therefore urgently needed, notably for patients not responding to conventional antifungal treatment. One strategy to prevent treatment failure is to improve the immune functions of immunocompromised hosts. Indeed, antifungals therapeutic efficacy is limited without the help of host immune reactivity (Stevens et al., 2000). As several studies have suggested that IFD are associated with an impaired Th1 host immune response, various cytokines have been evaluated in experimental and human fungal infections. In particular, adjunction of recombinant IFNγ has been proposed as a treatment option in patients with poor prognosis IFD with partial success. More recently, it has been shown that, when T cells are exposed to persistent antigens and/or inflammatory signals due to inefficient control of persisting infections, or in the context of tumors, a deterioration of their functions is observed, a state called "exhaustion". Molecular pathways involved in exhaustion have been partially deciphered, highlighting the importance of molecules called immune checkpoint such as PD-1 or CTLA-4. Furthermore, it was shown that blockade of these molecules can reverse this dysfunctional state. Immune checkpoint inhibitors (such as anti-PD1 antibodies) have become major weapons in oncology. In infectious diseases, and more particularly IFDs, data are much more limited. In animal models of several IFD, such as aspergillosis, cryptococcosis and histoplasmosis, repetitive administration of anti-PD-1 monoclonal antibodies significantly improved fungal clearance and survival of lethally infected animals. In humans, three case-reports, including one published by our team, have reported the efficacy of anti-PD-1 therapy combined with IFN-γ in the treatment of refractory IFDs. Therefore, by reversing T cell exhaustion, immune checkpoint blockade represents a therapeutic perspective for IFD treatment.

The use of immune checkpoint inhibitors may, however, entail severe, notably autoimmune off-target adverse effects and should be carefully balanced and monitored. The development of tools allowing identification of patients who could benefit from immunotherapy is of particular importance as well as assessment of the optimal timing of these innovative treatments. As such, a better understanding of the host immune response is one of the major approaches to developing new or improved antifungal strategies to control IFDs. Longitudinal data regarding the evolution of exhaustion markers expression in T cells of patients treated for an IFD are lacking.

The goal is to better characterize the adaptative immune response directed against molds, notably immune checkpoint expression, in order to identify the patients who could benefit from the adjunction of immunotherapy and the optimal timing of such strategy.

For this purpose, the investigators will include adult patients with mold IFD either at diagnosis or refractory to conventional therapy. They will measure activation and exhaustion markers on circulating T cells and monocytes by flow cytometry at three timepoints (enrollment, day 14 and week 6). Moreover, for patients with invasive aspergillosis or mucormycosis, they will evaluate the capacity of specific T cells to produce Th1, Th2 and Th 17 cytokines and to proliferate after specific antigenic stimulation, in the absence and in the presence of an anti-PD1 antibody in vitro (4 colors FLUOROSPOT) at two timepoint (enrollment and week 6). These data will provide a longitudinal assessment of the anti-fungal immune response. They will be correlated with the underlying diseases of the patients, the type of mold infection (aspergillosis, mucormycosis, fusariosis or scedosporiosis), the treatment received and the outcome. These results should help to better identify patients who could benefit from adjunctive anti PD-1 treatment and the optimal timing for such treatment.

• Study Type: Observational
• Enrollment (Estimated): 20

Contacts and Locations

• Study Contact: Name: Alexandra SERRIS, MD, PhD; Phone Number: +33 6 68 80 24 92; Email: alexandra.serris@aphp.fr
• Study Contact Backup: Name: Gael PLASTOW, Master; Phone Number: +33 1 44 38 18 57; Email: gael.plastow@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • Hôpital Necker Enfants Malades
    • Contact: Alexandra SERRIS, MD; Phone Number: +33 6 68 80 24 92; Email: alexandra.serris@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Tertiary care centers

Description

Inclusion Criteria:

• Age > 18 years
• Mold invasive fungal infection: Aspergillus, Mucorales, Fusarium, Scedosporium
• Proven or probable according to 2019 EORTC/MGS criteria modified by the adjunction of diabetes mellitus in the host criteria and Mucorales PCR in the microbiological criteria
• Within 14 days of IFD diagnosis or at a refractory state defined by the 2009 MGS/EORT failure criteria (clinical, radiological, or microbiological failure) of a first-line antifungal treatment leading to a change of therapy by the attending physician of the patient

Exclusion Criteria:

• Lymphocyte count < 0.5 G/L
• Bacterial infection in the last 14 days
• Previous treatment with anti-PD1 antibodies

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Cohort of patients with mold invasive fungal infection; Patients >18 y, with a diagnosis of proven or probable mold invasive fungal infection (Aspergillus, Mucorales, Fusarium or Scedosporium), according to modified 2019 EORTC/MGS criteria, at diagnosis or at a refractory state after a first-line antifungal treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune checkpoint expression on T cells	percentage of circulating T cells expressing immune checkpoint molecules as well as the intracellular transcription factor TCF1 and mean fluorescence intensity (MFI) of this expression in each cell sub-population	Day 0, day 14, week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aspergillus/Mucorales FLUOROSPOT	Qualitative and quantitative measure of specific T cells IFN-γ/IL-2/IL-5/IL-17 production by FLUOROSPOT after antigenic stimulation in absence and presence of an anti-PD1 antibody in patients with invasive aspergillosis or mucormycosis	Day 0, week 6
T cell proliferation	T cell proliferation test after antigenic stimulation	Day 0, week 6
Immune checkpoint expression on monocytes	Percentage of circulating monocytes expressing immune checkpoint molecules	Day 0, day 14, week 6

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Chair: Fanny LANTERNIER, MD, PhD, APHP

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: February 22, 2024
• First Submitted That Met QC Criteria: February 22, 2024
• First Posted (Actual): February 29, 2024

Study Record Updates

• Last Update Posted (Actual): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: anti-PD1; Mold invasive fungal infection; Aspergillus, Mucorales, Fusarium, Scedosporium; adaptative immunity against filamentous fungi; immune checkpoint molecules
• Additional Relevant MeSH Terms: Bacterial Infections and Mycoses; Infections; Mycoses; Invasive Fungal Infections
• Other Study ID Numbers: APHP221174; 2023-A01398-37 (Registry Identifier: ID-RCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No