Engineered NK Cells for Recurrent Glioblastoma

Overseen By Shiao-Pei Weathers, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Bevacizumab, Gliadel wafers

Disqualifiers: HIV, Hepatitis B/C, Autoimmune, others

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

Compensation: Varies

Number of Visits: 12

Duration: 32 weeks

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the optimal dose and assess the potential benefits and side effects of using specially engineered natural killer (NK) cells, known as Cord Blood-derived Expanded Allogeneic Natural Killer Cells, to treat recurrent glioblastoma, a type of brain cancer. The treatment involves injecting these modified immune cells directly into the tumor to help control its growth. The trial includes two groups: one receives the cells directly, while the other undergoes surgery before receiving the cells. Suitable candidates have experienced a recurrence of this specific brain cancer, have previously undergone radiation and treatment with temozolomide, and can manage daily tasks independently. As a Phase 1 trial, the 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 protocol does not specify if you need to stop taking your current medications. However, you must not be on immunosuppressive therapy within 7 days prior to the study, and you should not have had chemotherapy or targeted therapy within 2 weeks before starting the trial.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that specially designed natural killer (NK) cells, like those used in this trial, hold promise for treating certain cancers. These NK cells are unique immune cells engineered to locate and attack cancer. In earlier studies, NK cells were safely used in people, with some experiencing mild side effects such as tiredness, fever, or headaches, which usually don't last long.

Since this treatment is in an early phase trial, researchers are still learning about its safety. This phase primarily focuses on understanding how well people tolerate the treatment and determining the best dose. While more information is needed, early trials like this one help assess safety and guide future research. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for glioblastoma?

Unlike the standard treatments for recurrent glioblastoma, which often include surgery, radiation, and chemotherapy, the investigational treatment using Cord Blood-derived Expanded Allogeneic Natural Killer (CB-NK) Cells targets the tumor directly with immune cells. Researchers are excited about this approach because CB-NK cells are engineered to enhance their ability to attack and destroy cancer cells, potentially offering a more precise and potent treatment. Additionally, this method involves intratumoral delivery through an Ommaya catheter, allowing for direct application to the tumor site, which could improve effectiveness while minimizing systemic side effects. These unique features make this treatment a promising alternative to traditional therapies, which can be less targeted and more toxic.

What evidence suggests that this trial's treatments could be effective for recurrent glioblastoma?

Research has shown that specially designed natural killer (NK) cells can fight cancer by attacking and destroying tumor cells. Specifically, studies in mice found that NK cells with certain modifications can enhance the effects of other cancer treatments, such as bevacizumab and irinotecan, in treating glioblastoma, a type of brain cancer. This trial will evaluate the effects of Cord Blood-derived Expanded Allogeneic Natural Killer Cells, which participants may receive. Although researchers are still testing this treatment in humans, early results are promising and indicate potential benefits in managing recurring glioblastoma. ^{1 2 3 4 5}

Who Is on the Research Team?

Shiao-Pei S. Weathers

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with recurrent glioblastoma who've had prior radiation and temozolomide therapy can join this trial. They must have a stable health status, including normal organ function and blood counts, not be pregnant or breastfeeding, agree to use contraception, and understand the study's requirements. Excluded are those with severe allergies to monoclonal antibodies, certain infections or immunodeficiencies, recent immunosuppressive therapy, other active cancers requiring treatment, bleeding disorders or full-dose anticoagulation.

Inclusion Criteria

My blood counts meet the required levels for treatment.

I agree to use two effective birth control methods during and for 3 months after the study.

I have a tumor larger than 1cm2 that can be surgically removed.

Exclusion Criteria

I have been treated with Gliadel wafers before.

I have had cancer treatment directly into the tumor or nearby area.

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive CB-NK-TGF-betaR2-/NR3C1- intratumorally every 4 weeks for up to 8 doses

32 weeks

8 visits (in-person)

Surgical Resection (Group 2)

Participants undergo surgical resection of the tumor with Ommaya catheter management

2 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cord Blood-derived Expanded Allogeneic Natural Killer Cells
• Resection

Trial Overview The trial is testing genetically engineered NK cells designed to fight cancer by deleting TGF-betaR2 and NR3C1 in patients with recurrent glioblastoma. It aims to determine the optimal dose of these modified cells while monitoring for any potential benefits or side effects.

How Is the Trial Designed?

Group I: Group 2 (CB-NK-TGF-betaR2-/NR3C1-, resection) Experimental Treatment 2 Interventions

Ommaya catheter will be inserted prior to the 1st injection of NK cells (at the time of screening biopsy). Two weeks prior to Surgical resection participants will receive the 1st dose of CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over an additional 10 min via Ommaya catheter. Ommaya catheter will be taken out at the time of standard of care surgical resection of the tumor on day 15 and then another one will be inserted at the end of surgery for future IT injections. Beginning 2 weeks after surgery, participants will receive CB-NK-TGF-betaR2-/ NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every 4 weeks for up to 7 doses (total of 8 doses) in the absence of disease progression or unacceptable toxicity.

Group II: Group 1 (CB-NK-TGF-betaR2-/NR3C1- ) Experimental Treatment 1 Intervention

Participants will receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 10 minutes followed by 1 ml of Normal Saline injected over additional 10 min via Ommaya catheter every four weeks for up to 8 doses in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Glioblastoma stem cells (GSCs) are resistant to standard therapies but can be effectively targeted by healthy natural killer (NK) cells, highlighting a potential treatment avenue for glioblastoma multiforme (GBM).

The study identified that GSCs impair NK cell function through a mechanism involving αv integrin-mediated TGF-β activation, suggesting that targeting this pathway could enhance NK cell efficacy and reduce tumor growth in GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. Shaim, H., Shanley, M., Basar, R., et al.[2021]

Natural Killer (NK) cells from cord blood, when expanded in vitro for 21 days, showed significantly increased expression of activated receptors, enhancing their ability to kill leukemia cells compared to fresh NK cells.

The expanded NK cells demonstrated higher cytotoxicity against leukemia cell lines, indicating their potential effectiveness in cell therapy for tumors, while maintaining specificity for their target ligands.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Enhanced cytotoxicity against leukemia cells of natural Killer cells from cord blood after expansion in vitro]. Zhou, F., Han, WM., Jia, ZX., et al.[2013]

Natural killer (NK) cells, which are often suppressed by glioblastoma (GB) tumors, can be activated ex vivo with cytokines to restore their ability to attack GB cells, suggesting their potential for immunotherapy.

Current research includes a phase I clinical trial using CAR-NK cells targeting the ErbB2 (HER2) antigen in glioblastoma patients, highlighting a promising approach to enhance NK cell specificity and efficacy against this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy. Burger, MC., Zhang, C., Harter, PN., et al.[2020]

A new cytokine-based culture system allows for the efficient expansion of natural killer (NK) cells from umbilical cord blood, achieving over 15,000-fold expansion with nearly 100% purity, making it suitable for cancer immunotherapy.

The expanded NK cells effectively target and kill myeloid leukemia and melanoma cells, demonstrating their potential as a powerful treatment option for these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High log-scale expansion of functional human natural killer cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. Spanholtz, J., Tordoir, M., Eissens, D., et al.[2021]

Adoptive cell therapy using natural killer (NK) cells shows promise in cancer treatment, particularly for solid tumors, as they can effectively clear tumors without needing prior antigen presentation, unlike T or B cells.

The review discusses various sources for NK cells, including peripheral blood, umbilical cord blood, and induced pluripotent stem cells (iPSCs), highlighting the potential of engineered iPSC-derived NK cells for enhanced and sustained antitumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging NK cell therapies for cancer and the promise of next generation engineering of iPSC-derived NK cells. Maddineni, S., Silberstein, JL., Sunwoo, JB.[2022]

Genetically engineered natural killer (NK) cells derived from cord blood, expressing a chimeric antigen receptor (CAR) targeting B7H3, show strong potential as a safe and effective off-the-shelf therapy for treating glioblastoma multiforme (GBM), a challenging brain tumor.

To counteract the immune suppression caused by transforming growth factor (TGF)-β in the tumor environment, co-expressing a TGF-β dominant negative receptor (DNR) with the B7H3 CAR in NK cells helps maintain their ability to kill GBM cells, suggesting a promising strategy for enhancing the efficacy of CAR-NK cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-transducing B7H3 CAR-NK cells with the DNR preserves their cytolytic function against GBM in the presence of exogenous TGF-β. Chaudhry, K., Geiger, A., Dowlati, E., et al.[2022]

The study identified optimal conditions for expanding and activating natural killer (NK) cells from human blood, achieving significant increases in their viability and cytotoxicity against glioblastoma cells, with the best results from a specific cytokine combination (IL-12/18/15) and pre-activation protocols.

The research demonstrated that the effectiveness of NK cells can be enhanced through specific activation and re-activation strategies, which could lead to improved outcomes in immunotherapy for cancer, particularly glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokines impact natural killer cell phenotype and functionality against glioblastoma in vitro. Sivonen, M., Sirviö, KA., Wojciechowski, S., et al.[2023]

NK cells derived from umbilical cord blood (UCB56) exhibit stronger cytotoxicity compared to those derived from hematopoietic stem/progenitor cells (UCB34), highlighting the potential of UCB56 cells in cancer therapies.

The expression of killer Ig-like receptors (KIRs) on NK cells, including those derived from induced pluripotent stem cells (iPSCs), does not significantly affect their ability to kill tumor cells when HLA class I is present, suggesting that in vitro conditions may enhance their effectiveness regardless of KIR expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Umbilical Cord Blood and iPSC-Derived Natural Killer Cells Demonstrate Key Differences in Cytotoxic Activity and KIR Profiles. Goldenson, BH., Zhu, H., Wang, YM., et al.[2021]

The study successfully developed a feeder-free expansion system that produces large quantities of highly purified and cytotoxic natural killer cells (NKCs) from cord blood, which could be used for cancer immunotherapy.

Expanded cord blood NKCs demonstrated significant cytotoxicity against glioblastoma cells, indicating their potential effectiveness in treating certain cancers, although their cytotoxicity decreased with longer expansion periods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An efficient feeder-free and chemically-defined expansion strategy for highly purified natural killer cells derived from human cord blood. Nakazawa, T., Maeoka, R., Morimoto, T., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04991870

NCT04991870 | Phase I CB-NK-TGF-ßR2-/NR3C1- in rGBM This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 ...

2. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04991870/

Clinical Trial: NCT04991870 Beginning 2 weeks after surgery, patients receive CB-NK-TGF-betaR2-/NR3C1- intratumorally over 5-10 minutes weekly for up to 5 doses (total of 8 ...

3. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2020-0960.html

A Phase I clinical trial with a window-of-opportunity ... This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 and ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-00598

Engineered NK Cells Containing Deleted TGF-BetaR2 and ... This phase I trial is to find out the best dose, possible benefits and/or side effects of engineered natural killer (NK) cells containing deleted TGF-betaR2 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9871756/

Natural killer cell therapy potentially enhances the antitumor ... Natural killer cell therapy potentially enhances the antitumor effects of bevacizumab plus irinotecan in a glioblastoma mouse model.