NK Cell Therapy for Pediatric Brain Cancer

(PNOC028 Trial)

Recruiting at 4 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

Trial Summary

What is the purpose of this trial?

This trial uses enhanced immune cells called natural killer cells to treat children and young adults with recurring or worsening brain tumors. The treatment involves injecting these cells directly into the tumor to help destroy cancer cells. Natural killer (NK) cells are a promising option in cancer immunotherapy, showing potential in treating various solid tumors, including brain tumors.

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.

What data supports the effectiveness of this treatment for pediatric brain cancer?

Research shows that natural killer (NK) cells can effectively target and destroy cancer cells, including those in neuroblastoma and medulloblastoma, which are types of pediatric brain cancers. By modifying NK cells to resist the suppressive effects of TGFβ, a protein that usually weakens their function, these cells can maintain their ability to attack tumors more effectively. ^{1 2 3 4 5}

Is NK Cell Therapy generally safe for humans?

The research does not provide specific safety data for NK Cell Therapy in humans, but it discusses how TGF-beta can affect NK cell function and development, which is relevant to understanding potential impacts on safety. ^{3 6 7 8 9}

How is the NK Cell Therapy for Pediatric Brain Cancer different from other treatments?

This treatment uses specially engineered natural killer (NK) cells that are modified to resist the suppressive effects of TGFβ, a protein that usually weakens NK cells in the tumor environment. This makes them more effective in attacking brain cancer cells, offering a novel approach compared to traditional therapies that may not target the immune-suppressive environment. ^{1 2 10 11 12}

Research Team

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

Engineering the TGFβ Receptor to Enhance the Therapeutic Potential of Natural Killer Cells as an Immunotherapy for Neuroblastoma. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Medulloblastoma rendered susceptible to NK-cell attack by TGFβ neutralization. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

TGFβ Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion. [2020]

4. United States 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. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Overcoming the UCB HSCs -Derived NK cells Dysfunction through Harnessing RAS/MAPK, IGF-1R and TGF-β Signaling Pathways. [2021]

6. United States 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. [2016]

7. England pubmed.ncbi.nlm.nih.gov

Downregulation of NKG2DLs by TGF-β in human lung cancer cells. [2022]

8. United States 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. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

TGF-β affects development and differentiation of human natural killer cell subsets. [2021]

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

Monitoring of intracerebellarly-administered natural killer cells with fluorine-19 MRI. [2020]

11. England pubmed.ncbi.nlm.nih.gov

NK cells in the brain: implications for brain tumor development and therapy. [2023]

12. England 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. [2021]