NK Cell Therapy for Pediatric Brain Cancer

(PNOC028 Trial)

Recruiting at 6 trial locations

Overseen By Aubrie Dreschler

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Sabine Mueller, MD, PhD

Must not be taking: Anticoagulants

Disqualifiers: Disseminated disease, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: 7

Duration: 12 weeks

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment using natural killer (NK) cells to combat recurrent or worsening malignant brain tumors in children and young adults. NK cells, part of the immune system, can target and eliminate cancer cells. The trial aims to test the safety, side effects, and optimal dose of these cells. Participants must have a recurrent malignant brain tumor and be candidates for tumor surgery. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, if you are on dexamethasone, you need to be on a stable or decreasing dose for one week before joining the trial. Also, if you are taking any medication that increases bleeding risk, it must be stopped more than one week before NK cell infusion.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that natural killer (NK) cells can effectively target and destroy cancer cells. Lab tests have demonstrated that NK cells can attack various types of cancer, including brain tumors. When researchers carefully select and grow NK cells from healthy donors, they appear safe for use in cancer patients.

Current trials are testing different doses of NK cells. These early-stage trials focus on ensuring safety and determining the best dose. Early-phase studies help determine how well a treatment is tolerated. So far, these studies have not identified any major safety issues with NK cells. However, since these trials are in the early stages, the complete safety profile is still under investigation. Participants in these studies receive close monitoring for any side effects.

Overall, NK cell therapy shows promise, but researchers continue to learn about its safety. Participants considering joining a trial will be closely monitored to manage any risks. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for brain cancer?

Researchers are excited about using TGFβi NK cells for pediatric brain cancer because this approach targets the cancer differently than traditional treatments. Unlike standard options like surgery, radiation, and chemotherapy which attack cancer cells directly or halt their growth, TGFβi NK cells harness the body's own immune system to fight the tumor. This treatment involves a unique mechanism where natural killer cells are enhanced to recognize and destroy cancer cells, potentially leading to improved outcomes. Additionally, the method of delivering these cells directly into the brain through an Ommaya reservoir could enhance precision and reduce side effects, offering hope for a more effective and less invasive treatment option.

What evidence suggests that NK Cell Therapy might be an effective treatment for pediatric brain cancer?

Research has shown that natural killer (NK) cells can successfully attack and destroy cancer cells, including brain tumors, in lab experiments. These NK cells, part of the immune system, can find and remove abnormal cells. Early results suggest that NK cells from healthy, unrelated donors might help treat brain tumors in children. In this trial, participants will receive TGFβi NK cells, specially modified to enhance their cancer-fighting ability. Although more information from human trials is needed, these cells have shown promise in early studies. ^{2 3 5 6 7}

Who Is on the Research Team?

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 to 39 with recurrent or progressive non-metastatic brain tumors (WHO Grade III/IV). They must have completed initial treatments, be fit for surgery to place an Ommaya reservoir, and not be on chronic steroids. Participants need proper organ function, a performance score of at least 50, and agree to use contraception. Excluded are those with immune disorders, severe illnesses, bleeding risks, pregnancy/breastfeeding or unstable conditions.

Inclusion Criteria

I am mostly able to carry out daily activities.

I have finished my first round of treatment with radiation or chemotherapy.

Participants must agree to use adequate contraception

Exclusion Criteria

Specific criteria related to blood clotting

I have a bleeding disorder or am taking blood thinners.

I have a health condition that prevents me from having surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Surgery and Ommaya Placement

Participants undergo surgery for tumor resection and Ommaya reservoir placement

Up to 6 weeks

1 visit (in-person)

Treatment

Participants receive TGFβi NK cell infusions through the Ommaya reservoir once weekly for three weeks followed by one rest week, repeated for 3 cycles

12 weeks

3 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Implantation
• Universal Donor (UD) Transforming growth factor beta imprinting (TGFβi) Natural Killer (NK) Cells

Trial Overview The trial tests the safety and optimal dosage of NK cells from universal donors in treating malignant brain tumors that have returned after treatment. These NK cells are designed to fight tumor cells by being injected directly into the tumor site using an implanted reservoir.

How Is the Trial Designed?

Group I: Dose Level 4 (3x10^8) Experimental Treatment 4 Interventions

If no safety or toxicity events are demonstrated by the previous dose cohort, enrolled participants in the next dosing cohort must proceed to surgery for tumor resection and Ommaya placement into the resection cavity within 14 days of enrollment. The dose of 3x10\^8 of TGFβi NK cells (first dose) may be administered at least 14 days after the Ommaya reservoir placement and may not start until all acute surgical complications have resolved (maximum of 6 weeks after enrollment). TGFβi NK cell infusions through the Ommaya reservoir will occur once weekly for three weeks followed by one rest week. If participants have stable or improved disease, participants may continue to receive therapy for a total of 3 cycles.

Group II: Dose Level 3 (3x10^7) Experimental Treatment 4 Interventions

If no safety or toxicity events are demonstrated by the starting dose cohort, enrolled participants in the next dosing cohort must proceed to surgery for tumor resection and Ommaya placement into the resection cavity within 14 days of enrollment. The dose of 3x10\^7 of TGFβi NK cells (first dose) may be administered at least 14 days after the Ommaya reservoir placement and may not start until all acute surgical complications have resolved (maximum of 6 weeks after enrollment). TGFβi NK cell infusions through the Ommaya reservoir will occur once weekly for three weeks followed by one rest week. If participants have stable or improved disease, participants may continue to receive therapy for a total of 3 cycles.

Group III: Dose Level 2 (3x10^6) - Starting Dose Experimental Treatment 4 Interventions

Enrolled participants must proceed to surgery for tumor resection and Ommaya placement into the resection cavity within 14 days of enrollment. Starting dose of 3x10\^6 of TGFβi NK cells (first dose) may be administered at least 14 days after the Ommaya reservoir placement and may not start until all acute surgical complications have resolved (maximum of 6 weeks after enrollment). TGFβi NK cell infusions through the Ommaya reservoir will occur once weekly for three weeks followed by one rest week. If participants have stable or improved disease, participants may continue to receive therapy for a total of 3 cycles.

Who Is Running the Clinical Trial?

Sabine Mueller, MD, PhD

Lead Sponsor

Trials

9

Recruited

440+

Washington University School of Medicine

Collaborator

Trials

2,027

Recruited

2,353,000+

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

Rally Foundation

Collaborator

Trials

2

Recruited

8,000+

CureSearch

Collaborator

Trials

3

Recruited

130+

Tommy Strong Foundation

Collaborator

Trials

1

Recruited

20+

Published Research Related to This Trial

TGF-β reduces the expression of activating molecules (NKG2DLs) on lung cancer cells, which may weaken the immune response by natural killer (NK) cells, but this effect can be reversed by the TGF-β inhibitor Galunisertib.

The study suggests that inhibiting TGF-β could enhance NK cell-mediated anti-cancer responses by restoring the levels of NKG2DLs, although it did not affect the expression of PD-L1 and PD-L2 in lung cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Downregulation of NKG2DLs by TGF-β in human lung cancer cells. Lee, YS., Choi, H., Cho, HR., et al.[2022]

NK cells derived from umbilical cord blood (UCB) hematopoietic stem cells can be effectively enhanced for cancer immunotherapy by manipulating specific signaling pathways, resulting in higher cytotoxicity against cancer cells.

The study demonstrated that NK cells induced in a specific culture medium showed over 90% cytotoxicity against K562 leukemia cells and over 65% against SKOV3 ovarian carcinoma cells, indicating their potential as a powerful treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming the UCB HSCs -Derived NK cells Dysfunction through Harnessing RAS/MAPK, IGF-1R and TGF-β Signaling Pathways. Shokouhifar, A., Anani Sarab, G., Yazdanifar, M., et al.[2021]

TGFβ imprinting (TGFβi) during the activation of NK cells enhances their ability to secrete important cytokines like interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) for at least one month after TGFβ is removed, indicating a long-lasting effect on NK cell function.

While TGFβi NK cells show increased cytokine secretion, they also exhibit changes in their cytotoxic capabilities, such as downregulating certain activating receptors and upregulating TRAIL, which could influence their effectiveness against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TGFβ Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion. Foltz, JA., Moseman, JE., Thakkar, A., et al.[2020]

Natural killer (NK) cells have strong antitumor capabilities and are being explored as potential therapies for brain tumors, despite their low presence in the tumor-infiltrating immune cells.

The review discusses various strategies to enhance NK cell effectiveness against brain malignancies, including sourcing therapeutic NK cells, combining them with other treatments, and engineering them to improve their ability to kill cancer cells, supported by preclinical and clinical trial evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK cells in the brain: implications for brain tumor development and therapy. Balatsoukas, A., Rossignoli, F., Shah, K.[2023]

The study successfully administered intraventricular infusions of autologous natural killer (NK) cells to 9 out of 12 pediatric patients with recurrent medulloblastoma and ependymoma, demonstrating the feasibility and safety of this treatment with no dose-limiting toxicities observed.

While all patients showed progressive disease, one patient experienced stable disease for one month and another had a transient radiographic response, indicating potential for NK cell therapy to impact tumor progression, warranting further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of intraventricular infusions of autologous ex vivo expanded NK cells in children with recurrent medulloblastoma and ependymoma. Khatua, S., Cooper, LJN., Sandberg, DI., et al.[2021]

Genetically modified natural killer (NK) cells, designed to counteract the inhibitory effects of TGFβ in the tumor microenvironment, showed enhanced ability to kill neuroblastoma cells in laboratory tests and improved survival rates in animal models.

This research supports the potential for using 'off-the-shelf' NK cell therapies derived from umbilical cord blood to treat neuroblastoma and other cancers that secrete TGFβ, making them a promising option for immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering the TGFβ Receptor to Enhance the Therapeutic Potential of Natural Killer Cells as an Immunotherapy for Neuroblastoma. Burga, RA., Yvon, E., Chorvinsky, E., et al.[2020]

Natural killer (NK) cells can effectively suppress the growth of medulloblastoma (MB) tumors in vivo, as demonstrated in a study using immunodeficient mice, where both labeled and unlabeled NK cells showed similar efficacy in reducing tumor size.

The use of a fluorine-19 (19F) MRI probe allowed for accurate tracking of NK cell delivery to the tumor site, confirming their presence and association with tumor cell apoptosis, which highlights the potential of NK cells as a promising treatment strategy for MB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring of intracerebellarly-administered natural killer cells with fluorine-19 MRI. Kennis, BA., Michel, KA., Brugmann, WB., et al.[2020]

Cytokines TGF-β and TNFα can decrease the ability of natural killer (NK) cells to attack pancreatic adenocarcinoma cells (MiaPaCa2), which may hinder the body's immune response against tumors.

The reduction in NK cell activity is linked to changes in the expression of specific ligands on tumor cells, such as decreased ULBP-1 and increased HLA-E, HLA-G, CD155, and CD112, suggesting that these cytokines help tumors evade immune detection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transforming Growth Factor-β and Tumor Necrosis Factor-α Reduce the Sensitivity of MiaPaCa2 Pancreatic Cancer Cells to Lysis by NK Cells. Ostapchuk, EO., Kali, A., Belyaev, NN.[2018]

TGF-beta 1 plays a crucial role in regulating NK cell proliferation during acute viral infections, with its levels correlating with the decline in NK cell activity as observed in a mouse model infected with lymphocytic choriomeningitis virus.

While TGF-beta 1 significantly inhibits NK cell proliferation, it does not affect T cell proliferation even at much higher concentrations, suggesting a differential sensitivity that may help coordinate immune responses during viral infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A role for transforming growth factor-beta 1 in regulating natural killer cell and T lymphocyte proliferative responses during acute infection with lymphocytic choriomeningitis virus. Su, HC., Leite-Morris, KA., Braun, L., et al.[2016]

Cord blood-derived natural killer (NK) cells modified to express a dominant negative TGF-β receptor (DNRII) maintained their cytotoxic ability against medulloblastoma cells even in the presence of immune-suppressive TGF-β, unlike unmodified NK cells which showed reduced effectiveness.

These DNRII-transduced NK cells not only preserved their function but also reduced TGF-β levels in the tumor microenvironment, suggesting they could protect surrounding immune cells and enhance immunotherapy for high-risk medulloblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medulloblastoma rendered susceptible to NK-cell attack by TGFβ neutralization. Powell, AB., Yadavilli, S., Saunders, D., et al.[2020]

The study shows that using a TGF-beta receptor kinase inhibitor, LY2157299, can help maintain the cancer-fighting ability of natural killer (NK) cells when exposed to high levels of TGF-beta, which usually weakens their effectiveness.

In a mouse model of colon cancer, combining LY2157299 with adoptive NK cell therapy significantly improved the elimination of liver metastases compared to using NK cells or TGF-beta inhibition alone, suggesting that targeting TGF-beta could enhance the success of NK cell treatments in cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models. Otegbeye, F., Ojo, E., Moreton, S., et al.[2023]

TGF-β inhibits the development of natural killer (NK) cells from CD34(+) progenitor cells and specifically suppresses the differentiation of CD16(+) NK cells, which are important for immune responses.

The study also found that TGF-β can convert some CD56(bright)CD16(+) NK cells into CD56(bright)CD16(-) cells, suggesting that TGF-β plays a significant role in shaping the different subsets of NK cells in the blood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TGF-β affects development and differentiation of human natural killer cell subsets. Allan, DS., Rybalov, B., Awong, G., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05887882?locStr=United+States&country=United+States

Intra-Tumoral Injections of Natural Killer Cells for Recurrent ... This phase I trial tests the safety, side effects, and best dose of ex vivo expanded natural killer cells in treating patients with cancerous (malignant) ...

2. pediatricsnationwide.org pediatricsnationwide.org/2025/09/15/universal-donor-car-nk-cells-a-new-platform-technology-for-cancer/

Universal Donor CAR NK Cells: A New Platform ... These universal donor CAR NK cells were developed and are produced completely in house at Nationwide Children's Hospital. “This trial represents ...

3. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT05887882

Intra-Tumoral Injections of Natural Killer Cells for Recurrent ... This phase I trial tests the safety, side effects, and best dose of ex vivo expanded natural killer cells in treating patients with cancerous (malignant) ...

4. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/universal-donor-expanded-tgf-beta-imprinted-nk-cells?pn=1

Clinical Trials Using Universal Donor Expanded TGF-beta- ... Donor Immune Cells (Ex Vivo Expanded Natural Killer Cells) for the Treatment of Recurrent or Progressive Malignant Brain Tumors in Children and Young Adults.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06026657

Study Details | NCT06026657 | Gemcitabine and Ex Vivo ... This phase Ib/II trial tests the safety, best dose and how well gemcitabine and ex vivo expanded allogenic universal donor TGFBi NK cells with or without ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04254419

NCT04254419 | Phase 1 Study of Locoregional Injections ... After 2 weeks, the TGFβi NK cells are washed and cryopreserved for future use. The expanded donor NK cell product will be manufactured prior to subject ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7465121/

Natural Born Killers: NK Cells in Cancer Therapy - PMC Natural killer (NK) cells are crucial for tumor surveillance and exhibit potent killing capacity of aberrant cells in an antigen-independent manner.