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 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 NR3C1 (cord blood \[CB\]-NK-TGF-betaR2-/NR3C1-) in treating patients with glioblastoma that has come back (recurrent). CB-NK-TGF-betaR2-/NR3C1- cells are genetically changed immune cells that may help to control the disease.

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 the treatment with engineered NK cells generally safe for humans?

Research indicates that cord blood-derived natural killer (NK) cells, including those engineered with chimeric antigen receptors (CARs), have shown a robust safety profile in humans, making them a promising option for cancer treatment. ^{1 2 3 4 5}

How is the treatment with engineered NK cells for recurrent glioblastoma different from other treatments?

This treatment uses engineered natural killer (NK) cells derived from cord blood, which are modified to resist the suppressive effects of the tumor environment, specifically targeting the TGF-β pathway that often hinders immune response in glioblastoma. Unlike traditional therapies, these NK cells do not require prior antigen presentation, making them a potentially more effective option for targeting glioblastoma stem cells that are resistant to standard treatments. ^{3 5 6 7 8}

What data supports the effectiveness of the treatment using engineered NK cells for recurrent glioblastoma?

Research shows that natural killer (NK) cells, which are part of the body's immune system, can be activated to attack glioblastoma cells, a type of aggressive brain cancer. Studies have found that NK cells from cord blood can be expanded and enhanced to improve their ability to target and kill cancer cells, suggesting potential effectiveness in treating glioblastoma. ^{2 6 7 8 9}

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.

Signed and dated informed consent

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]

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]

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]

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]

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]

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]

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]

Citations

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

Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Cytokines impact natural killer cell phenotype and functionality against glioblastoma in vitro. [2023]

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

Umbilical Cord Blood and iPSC-Derived Natural Killer Cells Demonstrate Key Differences in Cytotoxic Activity and KIR Profiles. [2021]

4. China pubmed.ncbi.nlm.nih.gov

[Enhanced cytotoxicity against leukemia cells of natural Killer cells from cord blood after expansion in vitro]. [2013]

5. Switzerland pubmed.ncbi.nlm.nih.gov

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy. [2020]

6. Netherlands 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. [2023]

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

Emerging NK cell therapies for cancer and the promise of next generation engineering of iPSC-derived NK cells. [2022]

8. United States 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. [2021]

9. United States 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. [2022]