Not yet recruitingRare disease

Autologous CD4+ T-Cell Gene Therapy for X-linked Hyper-IgM Syndrome Type 1 in Patients with X-linked Hyper-IgM Syndrome Type 1

Verified siteRegistered drugNo placebo

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This clinical trial is studying X-linked immunodeficiency with hyper-IgM type 1 (HIGM1), a rare inherited disease in which the immune system does not work properly and cannot make enough effective antibodies to fight infections. The treatment being tested is FT018, made from the person’s own CD4+ T-cells (a type of white blood cell) that are collected, changed in the laboratory using CRISPR/Cas9 and an IDLV-based vector (a tool used to carry genetic changes into cells), and then given back by intravenous infusion.

The purpose of the study is to evaluate the safety of FT018 in people with HIGM1. The study is open label, which means that both the study team and the participants know which treatment is being given, and it has one treatment group. The treatment course includes one or more infusions of the modified cells, followed by regular follow-up visits over time to watch for side effects, signs of immune system recovery, infections, and overall health. Some participants may receive an additional dose later if needed.

The study also includes several background vaccines used as standard care, including Rabipur, TICOVAC, and Infanrix hexa. These are vaccines against rabies, tick-borne encephalitis, and a group of childhood infections including diphtheria, tetanus, pertussis, hepatitis B, polio, and Haemophilus influenzae type b. The study follows people for up to 2 years after treatment.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Study treatment with edited cd4+ t-cells
You receive autologous peripheral blood-derived CD4+ t-cells, which are your own cd4+ t-cells (a type of white blood cell) that have been edited outside the body at the cd40lg site using crispr/cas9 and an idlv-based vector.
These cells are given by intravenous infusion (through a vein). The study does not state the dose, frequency, or exact duration of this infusion.
Step 2
Follow-up after each dose
After each dose of the study treatment, you are monitored for dose-limiting toxicities (dlt, meaning side effects serious enough to limit the dose that can be given).
The study also checks for adverse events (ae, any unwanted medical problem), serious adverse events (sae, a severe medical problem), adverse events of special interest (aesi, specific side effects the study is watching for), and side effects related to the study treatment.
The study checks for immune reconstitution inflammatory syndrome (iris, a reaction that can happen when the immune system begins to recover and causes inflammation) at 28 days after each dose.
Step 3
Possible boost dose
Some patients may receive a boost dose of the study treatment. The study measures the proportion of patients who receive this additional dose.
The source data do not specify the dose, frequency, or timing of the boost dose.
Step 4
Long-term follow-up
You are followed after treatment at 6 months, 1 year, and 2 years.
At these time points, the study checks for side effects, including ae, sae, aesi, treatment-related side effects, and iris.
Step 5
Infection and survival assessment
The study reviews the number, length, and share of days with moderate to severe infection during the 2 years after treatment.
This review is done in consecutive 6-month periods, including assessments at 6 months, 1 year, 1.5 years, and 2 years.
The study also checks overall survival at 6 months, 1 year, and 2 years after treatment.
Step 6
Background vaccines used in the study
The study lists background vaccines given by intramuscular injection (into a muscle). These are rabipur, ticovac 0.25 ml for pediatric use, infanrix hexa, and ticovac 0.5 ml.
Rabipur is a vaccine against rabies (a serious infection that affects the brain and nervous system) and contains inactivated rabies virus. The source data do not provide a dose, frequency, or duration.
Ticovac 0.25 ml for pediatric use is a vaccine against tick-borne encephalitis (a brain infection spread by ticks) and contains inactivated tick-borne encephalitis virus. The source data do not provide a dose, frequency, or duration.
Infanrix hexa is a vaccine against diphtheria, tetanus, whooping cough (pertussis), hepatitis b, polio, and haemophilus influenzae type b (hib, a germ that can cause serious infections). The source data do not provide a dose, frequency, or duration.
Ticovac 0.5 ml is also a vaccine against tick-borne encephalitis and contains inactivated tick-borne encephalitis virus. The source data do not provide a dose, frequency, or duration.

Who can join the trial?

8 criteria

Signed informed consent is required. This means the patient, or a legal guardian when appropriate, must agree in writing to take part in the study.
The patient must be male.
The patient must be at least 1 year old.
The patient must have a Lansky/Karnofsky score of 80% or higher. This is a measure of how well a person can do normal daily activities and how independent they are.
The patient must have a genetic diagnosis of HIGM1. This means the condition has been confirmed by testing the genes.
The patient must have absent or reduced CD40L expression or function on CD4+ T-cells after stimulation with PMA/ionomycin. In simple terms, blood cells must show that this protein, called CD40L, is missing or does not work well when tested in the laboratory.
The patient must need chronic IgRT. IgRT means immunoglobulin replacement therapy, a regular treatment that gives antibodies to help protect against infections.
The patient must show good adherence to IgRT. This means the patient has been able to follow the antibody treatment regularly and as prescribed.

Who cannot join the trial?

9 criteria

A CD40LG gene change located before the vector insertion site in CD40LG intron 1, or any other gene change that cannot be fixed with the gene-editing treatment.
A medical reason that makes vaccination unsafe, if the study protocol requires vaccination, or a medical reason that prevents use of other medicines or procedures planned in the study.
Any previous treatment with cell therapy or gene therapy.
Positive tests for HIV RNA (human immunodeficiency virus genetic material in the blood), HCV RNA (hepatitis C virus genetic material in the blood), or HBV DNA (hepatitis B virus genetic material in the blood), or the presence of total syphilis antibodies (blood markers showing past or current syphilis infection), if this does not meet the required tissue donation rules for manufacturing.
Severe organ dysfunction (poor working of a body organ such as the heart, liver, or kidneys) or another serious illness or medical condition that the study doctor thinks would make the person unsuitable for the study.
Previous allogeneic hematopoietic stem cell transplantation (a transplant of blood-forming stem cells from another person) with evidence that some donor cells are still present.
Being enrolled in another clinical trial.
Not being able to donate enough lymphocytes (a type of white blood cell) to make the study treatment.
Using systemic corticosteroids (steroid medicines that work throughout the body) or other immunosuppressive drugs (medicines that lower the immune system) that could interfere with apheresis (a procedure that collects blood cells) or with making the drug product.

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Ospedale San Raffaele S.r.l.
Verified
Milan, Italy

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Investigated drugs

Autologous peripheral blood-derived CD4+ T-cells CRISPR-edited at the CD40LG locus
These are the patient’s own CD4 T-cells, which are a type of white blood cell. They are taken from the blood, changed in the lab using CRISPR gene editing to fix the CD40LG gene area, and then given back by vein. The goal is to help the immune system work better in people with X-linked Hyper IgM syndrome type 1.
Rabipur
This is an inactivated rabies vaccine given by injection into a muscle. It is included as a background vaccine, meaning it is part of the routine care or vaccination history and not the main study treatment.
TICOVAC
This is an inactivated tick-borne encephalitis vaccine given by injection into a muscle. It is included as a background vaccine, meaning it is part of the routine care or vaccination history and not the main study treatment.
Infanrix hexa
This is a combination vaccine that helps protect against diphtheria, tetanus, whooping cough, hepatitis B, polio, and Haemophilus influenzae type b. It is given by injection into a muscle and is listed as background treatment, meaning it is not the main study therapy.
TICOVAC
This is another presentation of the inactivated tick-borne encephalitis vaccine given by injection into a muscle. It is also background treatment and not the main study therapy.

What is already known about the treatment

Rabipur
Rabipur is a vaccine given by intramuscular injection, usually in the upper arm, to help the body build protection against rabies. It is an inactivated vaccine, which means it contains killed rabies virus and cannot cause rabies, but it can teach the immune system to recognize the virus and make protective antibodies. It is widely used in medicine and is well established in medical literature for both pre-exposure and post-exposure rabies prevention. It belongs to the pharmacological class of inactivated viral vaccines, specifically a whole-virus rabies vaccine.
TICOVAC
TICOVAC is a vaccine given by intramuscular injection as a suspension for injection, used to protect against tick-borne encephalitis. It contains an inactivated form of the virus, so it cannot cause the disease, but it helps the immune system learn to defend against future infection. This vaccine is well known and commonly described in medical literature as a preventive medicine for people at risk of exposure in areas where the disease is present. It belongs to the pharmacological class of inactivated viral vaccines, specifically a whole-virus tick-borne encephalitis vaccine.
Infanrix hexa
Infanrix hexa is a combination vaccine given by intramuscular injection to protect against six serious infections: diphtheria, tetanus, whooping cough, hepatitis B, polio, and infections caused by Haemophilus influenzae type b. It is an established medicine in current medical practice and is widely discussed in medical literature as a routine childhood vaccine. The vaccine contains harmless pieces or inactivated forms of the germs, which stimulate the immune system to make protective antibodies without causing the diseases. It belongs to the pharmacological class of combination vaccines, including toxoid, acellular pertussis, inactivated polio, hepatitis B, and Hib conjugate vaccine components.
Autologous Peripheral Blood-Derived CD4+ T-Cells CRISPR-Edited at the CD40LG Locus
This treatment is given by intravenous infusion and uses the patient’s own CD4+ T cells, which are collected from blood, edited in the laboratory with CRISPR/Cas9, and then returned to the body. It is an experimental therapy and is currently under clinical investigation, with limited information in medical literature because it is still being studied in early-phase trials. The main goal is to help people with X-linked hyper-IgM syndrome type 1 by restoring the function of the CD40LG gene, which is needed for normal immune signaling and antibody production. It belongs to the pharmacological class of gene-edited cell therapy and is an orphan investigational product.

Investigated diseases

X-linked hyper-IgM syndrome type 1 - A rare inherited immune system disorder caused by a change in the CD40 ligand gene, which affects the normal development of immune defenses. People with this disease have low levels of some protective antibodies and may have higher levels of immunoglobulin M. It usually begins in early childhood and can lead to repeated infections, especially in the lungs, ears, sinuses, and gut. Over time, ongoing immune weakness can cause infections to happen more often and become harder to clear.