NT-I7 for Progressive Multifocal Leukoencephalopathy

Overseen By Anita M Fletcher, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Must not be taking: Immune-suppressive medications

Disqualifiers: Autoimmune CNS, Immune-mediated vital organ, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 23

12 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Progressive multifocal leukoencephalopathy (PML) is a brain infection. It is caused by a virus. PML can happen in people with a weakened immune system. PML is associated with cognitive and visual impairment as well as motor and speech disturbances. There is no treatment for PML. Researchers want to see if a new drug can help. Objective: To see if the drug NT-I7 can help increase lymphocyte numbers, which may help control PML infection. Eligibility: Adults ages 18 and older with PML who are enrolled in Protocol #13-N-0017. Design: Participants will be screened under Protocol #13-N-0017. Participants will have a 7-day inpatient stay, outpatient visits, and follow-up phone calls. Participants will have a medical history and physical exam. They will give urine samples. Blood will be drawn from an arm vein or through an intravenous (IV) catheter. Participants will get up to 3 doses of NT-I7. It will be given by injection into the muscle. Participants will have lumbar punctures ( spinal taps ). A thin needle will be inserted into the spinal canal in the lower back. Cerebrospinal fluid will be removed. X-ray may be used to guide the procedure. Participants will have magnetic resonance imaging (MRI) of the brain. The MRI scanner is a metal cylinder surrounded by a magnetic field. During MRIs, participants will lie on a table that slides in and out of the scanner. Soft padding or a coil will be placed around their head. They will get gadolinium, a contrast agent, through an IV catheter. Participation will last for 12 to 19 months. ...

Will I have to stop taking my current medications?

The trial requires that you stop ongoing treatment with immune-suppressive medications, except for short-term use of topical steroids or systemic steroids for less than two weeks.

What data supports the effectiveness of the drug NT-I7 for treating progressive multifocal leukoencephalopathy?

Research shows that recombinant human interleukin-7 (a component of NT-I7) has been used successfully in patients with progressive multifocal leukoencephalopathy, leading to improved immune responses and clinical outcomes. In one case, it helped clear the virus causing the disease and improved the patient's condition. ^{1 2 3 4 5}

Is NT-I7 (Efineptakin alfa) safe for humans?

Research in nonhuman primates showed that a treatment similar to NT-I7, called MVA-hIL-7-Fc, was safe and did not cause any acute adverse reactions. This suggests that NT-I7 may be generally safe in humans, but more specific human data would be needed for confirmation. ^{1 3 4 6 7}

How is the drug NT-I7 different from other treatments for progressive multifocal leukoencephalopathy?

NT-I7 is unique because it uses interleukin-7, a protein that boosts the immune system by increasing T cells, which are crucial for fighting infections like the JC virus that causes progressive multifocal leukoencephalopathy. There are no standard treatments for this condition, making NT-I7 a novel option. ^{1 2 4 5 7}

Research Team

Irene CM Cortese, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Eligibility Criteria

Adults over 18 with Progressive Multifocal Leukoencephalopathy (PML) and low lymphocyte counts, enrolled in Protocol #13-N-0017. Participants must be able to travel for study visits, provide consent, follow procedures, and use reliable birth control if applicable. Excludes those on immune-suppressive meds (except short-term steroids), with autoimmune CNS diseases or conditions that could affect the trial.

Inclusion Criteria

My CD4 or CD8 cell count is 200 or less and can't be quickly fixed.

I am 18 years old or older.

You have been diagnosed with a specific brain infection called PML using specific criteria from 2013.

Exclusion Criteria

Unwilling to have coded samples and/or data saved or used in other studies

You are currently receiving experimental treatments for PML that could affect the study results.

History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial or interfere with study participation; or not in the best interest of the subject to participate, in the opinion of the treating investigator

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive up to 3 doses of NT-I7 by injection into the muscle, with inpatient observation for the first 7 days following any experimental drug dosing.

7 days

7-day inpatient stay

Second Inpatient Stay

Participants return for a second 7-day inpatient stay by Day 21.

7 days

7-day inpatient stay

Outpatient Visits

Scheduled outpatient visits at NIH at month 2, 3, 6, 9, and 12 following any drug dosing.

12 months

5 outpatient visits

Follow-up

Follow-up phone calls will be conducted at month 4, 5, 7, and 8 to monitor safety and effectiveness.

4 months

4 follow-up phone calls

Treatment Details

Interventions

• NT-I7

Trial Overview The trial is testing NT-I7, a new drug designed to boost lymphocyte numbers which may help fight PML infection. It involves an initial 7-day hospital stay followed by outpatient visits and phone calls for up to 19 months. Procedures include injections of NT-I7 into the muscle, lumbar punctures, blood draws, urine samples, and MRI scans with contrast agents.

Participant Groups

Group I: NT-I7 Experimental Treatment 1 Intervention

480 microgram/kg IM (initial dose)

NT-I7 is already approved in United States for the following indications:

Approved in United States as NT-I7 for:

• Orphan drug designation for glioblastoma multiforme
• Orphan drug designation for advanced pancreatic cancer

Who Is Running the Clinical Trial?

National Institute of Neurological Disorders and Stroke (NINDS)

Lead Sponsor

Trials

1,403

Recruited

655,000+

NeoImmuneTech

Industry Sponsor

Trials

16

Recruited

780+

Findings from Research

A 61-year-old man with progressive multifocal leukoencephalopathy and idiopathic CD4+ T-cell lymphocytopenia showed significant clinical improvement after receiving recombinant human interleukin 7, including regression of brain abnormalities and clearance of JC virus DNA from plasma.

Despite initial success, the patient's CD4+ T-cell count returned to baseline after one year, highlighting the need for further research to understand the long-term effects and potential of interleukin 7 in treating similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of progressive multifocal leukoencephalopathy with interleukin 7. Alstadhaug, KB., Croughs, T., Henriksen, S., et al.[2015]

A patient with severe lymphopenia following bone marrow transplantation developed progressive multifocal leukoencephalopathy, a serious brain infection caused by the John Cunningham virus (JCV).

Treatment with recombinant human interleukin-7 successfully restored T-cell responses against JCV, cleared the virus from the cerebrospinal fluid, and led to significant clinical improvement, highlighting its potential as an effective therapy in similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy. Gasnault, J., de Goër de Herve, MG., Michot, JM., et al.[2020]

The study demonstrated that MVA-hIL-7-Fc, a recombinant virotherapy, is safe for use in nonhuman primates, with no acute adverse reactions observed after a single intravenous injection.

The treatment effectively stimulated the immune system, leading to an expansion of various immune cells, including CD4 and CD8 T cells, indicating its potential for enhancing immune responses in sepsis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous injection of a novel viral immunotherapy encoding human interleukin-7 in nonhuman primates is safe and increases absolute lymphocyte count. Coupet, CA., Dubois, C., Evlachev, A., et al.[2023]

A 66-year-old man with progressive multifocal leukoencephalopathy (PML) and severe lymphocytopenia showed improvement after receiving three doses of interleukin-7 (IL-7), with no adverse effects reported.

IL-7 treatment led to a significant increase in lymphocyte counts, stabilizing MRI lesions and resulting in mild neurological improvement, suggesting its potential as a therapeutic option for PML in patients with idiopathic CD8+ lymphocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-7 treatment of PML in a patient with idiopathic lymphocytopenia. Miskin, DP., Chalkias, SG., Dang, X., et al.[2018]

In a study of 64 patients with progressive multifocal leukoencephalopathy (PML) treated with recombinant human IL-7 (rhIL-7), the one-year survival rate was 54.7%, with survival linked to increases in blood lymphocytes and CD4+ T cells, as well as decreases in JCV DNA in cerebrospinal fluid.

The treatment was generally well-tolerated, with side effects mostly being mild, such as local reactions and flu-like symptoms, indicating that rhIL-7 may be a safe option for restoring immunity against the JC virus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of Progressive Multifocal Leukoencephalopathy Treated by Interleukin-7. Lajaunie, R., Mainardi, I., Gasnault, J., et al.[2022]

A novel hybrid protein, TNFR-hyFc, was developed to reduce unwanted immune responses like antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which are concerns with existing TNF-α blockers like etanercept.

Pre-clinical evaluations showed that TNFR-hyFc has a similar biochemical profile to etanercept but is slightly larger and more acidic, suggesting it may offer a safer alternative with reduced side effects in treating conditions related to TNF-α.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical characterization of a new recombinant TNF receptor-hyFc fusion protein expressed in CHO cells. Lee, JH., Yeo, J., Park, HS., et al.[2015]

The hybrid Fc-fused long-acting recombinant human IL-7 (rhIL-7-hyFc) significantly enhances the antitumor response by expanding CD8+ T cells in the tumor microenvironment, leading to increased tumor-reactive T cells with improved effector functions.

When combined with chemotherapy and checkpoint inhibitors, rhIL-7-hyFc not only boosts the antitumor response but also restores CD8+ T cell levels even in conditions of low T lymphocyte counts, suggesting its potential as an effective immunotherapy strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy. Kim, JH., Kim, YM., Choi, D., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treatment of progressive multifocal leukoencephalopathy with interleukin 7. [2015]

2. United States pubmed.ncbi.nlm.nih.gov

Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Intravenous injection of a novel viral immunotherapy encoding human interleukin-7 in nonhuman primates is safe and increases absolute lymphocyte count. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Interleukin-7 treatment of PML in a patient with idiopathic lymphocytopenia. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Outcome of Progressive Multifocal Leukoencephalopathy Treated by Interleukin-7. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Biochemical characterization of a new recombinant TNF receptor-hyFc fusion protein expressed in CHO cells. [2015]

7. Australia pubmed.ncbi.nlm.nih.gov

Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy. [2022]