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Safety of autologous NK cells with IL‑15 and CD45RA‑negative T cells with NKG2D CAR in children, adolescents and young adults with high‑grade brain tumors

Verified siteInvestigationalNo placebo

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What is this trial about?

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

The study focuses on children, adolescents and young adults who have central nervous system tumours that are classified as high‑grade, meaning they are aggressive and have returned after previous treatment. Two types of modified immune cells are being tested: one is a preparation of the patient’s own natural killer cells that have been grown in the laboratory with the help of interleukin-15 (a protein that boosts immune activity) and is referred to as NKIL15; the other is a preparation of the patient’s own T‑cells that have been altered using a lentiviral vector to add a chimeric antigen receptor that recognizes the protein NKG2D, and is called CART‑NKG2D. Both products are given directly into the area of the brain where the tumor is located.

The purpose of the trial is to determine whether these cell therapies can be given safely to the target group. Participants will first undergo basic health checks, then receive one or two doses of the assigned cell product through a small procedure that delivers the cells into the brain’s fluid spaces. After each dose, they will have regular clinic visits for a few weeks to monitor how they feel and to have simple tests, such as blood draws and fluid samples, to see how the cells behave in the body.

Throughout the study, doctors will closely watch for any side effects, especially reactions that affect the nervous system or cause inflammation. They will also check how long the infused cells remain in the brain’s fluid and whether they can be detected over time. The overall aim is to gather information that could help develop new treatments for these serious brain tumors.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Enrollment and initial consent
After joining the study, you sign the consent form that explains the purpose of the trial and the procedures you will undergo.
The study team records your basic information and confirms that you meet the eligibility criteria for children, adolescents, or young adults with a recurrent or refractory high‑grade central nervous system tumour.
Step 2
Baseline assessments
A series of examinations is performed before any treatment is given. this includes a physical exam, measurement of performance status (how well you are able to carry out daily activities), brain imaging, and collection of cerebrospinal fluid (csf) through a lumbar puncture.
The results create a reference point to compare later changes after the cell therapy.
Step 3
Blood collection for cell manufacturing
Blood is drawn from you to obtain peripheral blood cells that will be used to create the investigational product.
The cells are processed in a laboratory to produce either autologous nk cells stimulated with interleukin‑15 or cart‑nkg2d cells. "autologous" means the cells come from your own body, and "interleukin‑15" is a protein that helps activate nk cells.
Step 4
Cell processing period
The laboratory modifies the collected cells. for nk cells, interleukin‑15 is added to stimulate them; for cart‑nkg2d cells, a lentiviral vector is used to insert a chimeric antigen receptor that targets the nkg2d protein on tumour cells.
No action is required from you during this time; you will be notified when the cells are ready for infusion.
Step 5
First cell infusion into the central nervous system
The prepared cell suspension is injected directly into the central nervous system (cns) using a sterile solution for injection.
The specific product you receive will be one of the two study arms: autologous nk cells stimulated with interleukin‑15 or cart‑nkg2d cells. the protocol does not specify a fixed dose, frequency, or duration; the infusion is given as a single administration at this visit.
Step 6
Hospital monitoring after infusion (up to day 48)
After the infusion you remain in the hospital for close observation. medical staff watch for any adverse reactions, including fever, low blood pressure, or signs of cytokine release syndrome (crs), which is an immune reaction that can cause flu‑like symptoms.
They also monitor for neurotoxicity or icans (immune effector cell‑associated neurotoxicity syndrome), which can affect brain function. any severe reactions are treated promptly with medications such as tocilizumab or corticosteroids.
Step 7
Follow‑up assessments and possible second infusion
Between day 48 and the next scheduled visit, you undergo regular check‑ups that include performance‑status evaluation, csf sampling, and brain imaging to assess tumour response.
If the study protocol determines that a second treatment course is appropriate, a second infusion of the same cell product is administered in the same manner as the first.
Step 8
Long‑term follow‑up visits (3, 6, and 12 months)
At approximately three, six, and twelve months after the first treatment, you return for comprehensive assessments.
These visits include brain scans to evaluate progression‑free survival and overall survival, csf analysis to detect the presence of the infused cells and tumour‑derived cells, and measurement of cytokine levels in the csf.
The information collected helps determine the safety and effectiveness of the cell therapy over time.

Who can join the trial?

12 criteria

Age and tumor type: You must be 20 years old or younger and have a brain or spine tumor that has come back or did not respond to at least one prior chemotherapy, with no other curative treatment available. A tissue diagnosis (called histological verification) must have been made at the original diagnosis or at relapse.
Seizure disorder: If you have seizures, they must be well‑controlled with medicines called anticonvulsants.
Informed consent: You (or your parent/guardian) must be able to sign a written consent form agreeing to take part in the study.
Birth‑control requirement: If you are sexually active, you must agree to use an effective birth‑control method for 6 months after the cell infusion, and any male partner must use a condom.
NKG2DL expression: Your tumor tissue must be tested and show the presence of a protein called NKG2DL, which the study drug targets.
Measurable or evaluable tumor: Your tumor must be either measurable (at least one spot that can be measured in two dimensions, each at least 10 mm) or evaluable (a spot that cannot be measured accurately, or cancer cells found in spinal fluid, known as CSF cytology).
Neurosurgical assessment: A neurosurgeon must determine that you can safely receive the cell infusion either through an implanted device called an Ommaya reservoir or directly into the spinal fluid (intrathecally), whichever is best for you.
Ventricular catheter eligibility: You must be a candidate for an implanted catheter in the brain’s ventricles (using an Ommaya reservoir) if the infusion will be given into the ventricles.
Performance score: You need a score of at least 50 on the Lansky scale (for children under 16) or the Karnofsky scale (for those 16 and older). These scores measure how well you can carry out daily activities.
Recovery from previous treatment side effects: You must have recovered from the acute toxic effects of prior cancer therapies to no worse than grade 2 (mild to moderate) according to the standard toxicity grading system called CTCAE v5.0.
Time since prior therapies: At least 12 weeks must have passed since the end of radiation therapy; at least 2 weeks since the end of any chemotherapy; at least 2 weeks since the last dose of targeted drugs; at least 6 weeks after any bevacizumab; and at least 12 weeks after any immunotherapy or cell therapy.
Organ function: Your bone‑marrow (blood‑forming), liver (hepatic), and kidney (renal) function must be adequate as judged by the investigators.

Who cannot join the trial?

13 criteria

Being enrolled in another treatment study within the past 4 weeks.
Having a ventriculoperitoneal (VP) shunt (a tube that drains fluid from the brain to the abdomen) that is not programmable or cannot be set to the lowest setting before the infusion and for 3 hours afterward.
Having any other cancer at the same time (concomitant neoplasia) or cancer that has spread outside the brain (extra‑cranial metastasis).
Having any other medical disease that is not under control (uncontrolled medical disease).
Having disease that is too extensive, located in a risky area, or having other health problems (co‑morbid conditions) that doctors consider unsafe for the infusion.
Having an untreated active infection or a serious overall illness (systemic illness), including:
- a heart problem where the heart’s pumping ability (left ventricular ejection fraction) is less than 55% as measured by an ultrasound of the heart (LVEF < 55% determined by ECHO);
- a positive test for Human Immunodeficiency Virus (HIV);
- current or past infection with CMV, EBV, hepatitis B or C (viruses that can affect the body);
- significant problems with the lungs (pulmonary), liver (hepatic), or other organs.
- Currently taking corticosteroids (except when used as hormone replacement therapy).
- Having severe nerve damage from previous cancer treatments, defined as neurological toxicity grade 4 or higher according to the standard grading system (CTCAE).
- Being pregnant or breastfeeding (pregnant or lactating).
- Any other condition that doctors believe could affect the safety or results of the trial.

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Fundacion Para La Investigacion Biomedica Del Hospital Universitario La Paz
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Madrid, Spain

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Investigated drugs

Unexpanded autologous peripheral blood adult differentiated NK cells stimulated with IL-15
is a therapy that uses natural killer (NK) cells taken from the patient’s own blood. These cells are not grown in large numbers in the lab, but they are treated outside the body with a protein called interleukin‑15, which helps the NK cells become more active. The activated NK cells are then placed in a liquid that can be injected directly into the brain or spinal fluid, where they are expected to seek out and kill tumor cells. In this trial the main purpose is to see whether delivering these boosted NK cells to the central nervous system is safe for children and young adults with high‑grade brain tumors.
CART45RA‑NKG2D CELLS
are another type of personalized cell therapy. Blood is drawn from the patient and a specific group of T‑cells (the CD45RA‑ subset) is isolated. These T‑cells are then genetically modified using a harmless virus to add a “chimeric antigen receptor” (CAR) that recognizes a protein called NKG2D, which is often found on the surface of tumor cells. After this modification, the engineered T‑cells are suspended in a solution that can be injected into the central nervous system. The goal of the trial is to determine whether delivering these CAR‑engineered T‑cells locally is safe for children and young adults with recurrent or refractory high‑grade CNS tumors.

What is already known about the treatment

Unexpanded autologous peripheral blood adult differentiated NK cells stimulated with IL-15
This product is a cell suspension for injection that is given directly into the brain area of the patient. It is an experimental therapy still in early clinical studies and not yet approved for general use. The cells are natural killer (NK) cells taken from the patient’s own blood and grown with a protein called interleukin‑15, which makes them more active in finding and killing tumor cells. It is classified as an autologous cellular immunotherapy for high‑grade central nervous system tumours.
CART45RA-NKG2D CELLS
This therapy is provided as a solution for injection and is administered locally to the central nervous system. It is also an experimental product being evaluated in early‑phase trials and has no regulatory approval at this time. The treatment uses the patient’s own T‑cells that are genetically modified with a viral vector to add a chimeric antigen receptor that targets the NKG2D protein on cancer cells, helping the immune cells recognize and destroy the tumour. It belongs to the class of autologous CAR‑T cell immunotherapies for recurrent or refractory high‑grade CNS tumours.

Investigated diseases

Central nervous system tumor - A central nervous system tumor is an abnormal growth of cells that originates in the brain or spinal cord. High‑grade forms tend to grow quickly, expanding within the protective coverings of the nervous system. As the tumor enlarges, it can press on surrounding brain tissue, leading to changes in neurological function. Over time, the tumor may infiltrate nearby structures, causing further disruption of normal brain activity.