CAR-NK Cell Therapy for Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Hypomethylating agents

Must not be taking: Calcineurin inhibitors

Disqualifiers: Cardiac failure, Active infection, CNS leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Phase I: Dose escalation; Phase II: Dose expansion

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine a safe dose of a new cell therapy for individuals with certain types of difficult-to-treat leukemia, such as relapsed or stubborn acute myeloid leukemia (AML). The treatment uses special immune cells, known as CAR-NK cells (CAR.70-Engineered IL15-Transduced Cord Blood-Derived NK Cells With TGF-beta Receptor 2 (TGFBR2) Knock Out), to assess their safety and effectiveness in fighting cancer. Suitable candidates for this trial include those with AML that has not improved after standard treatments and who meet specific test criteria required by the trial. As a Phase 1, Phase 2 trial, the study focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but you cannot use calcineurin inhibitors within the past 2 weeks or investigational antileukemic agents or chemotherapy agents in the last 7 days before lymphodepletion. You may continue non-investigational targeted therapies up until 3 days before lymphodepletion.

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

Research has shown that CAR-NK cell therapy, which uses specially modified natural killer cells from umbilical cord blood, may help treat certain cancers. These cells are altered to produce a substance called IL-15 and to resist another called TGF-beta, enhancing their activity and tumor-fighting ability.

Regarding safety, studies of similar NK cell therapies have found that patients generally tolerate them well. For instance, in trials where these cells were used with chemotherapy, side effects were manageable. The most common issues resembled those from standard treatments, such as mild to moderate flu-like symptoms.

This trial is in the early stages, with the main goal of assessing the treatment's safety. As a new therapy, there might be risks not yet fully understood. However, the treatment is designed to minimize serious side effects. Researchers will closely monitor participants to ensure their safety throughout the study. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for myeloid leukemia?

Researchers are excited about CAR-NK Cell Therapy for Myeloid Leukemia because it offers a new approach to targeting cancer cells. Unlike standard treatments like chemotherapy or bone marrow transplants, this therapy uses CAR.70-engineered IL15-transduced NK cells, which are natural killer cells derived from cord blood. These cells are further enhanced by knocking out the TGF-beta Receptor 2, potentially improving their ability to attack leukemia cells. This method aims to precisely target cancer cells while minimizing harm to healthy cells, potentially leading to fewer side effects and improved outcomes for patients.

What evidence suggests that this treatment might be an effective treatment for myeloid leukemia?

Research has shown that specially engineered NK cells, known as CAR.70 IL15-transduced NK cells, hold promise in fighting cancer. These cells have been modified to specifically target and destroy certain cancer cells in lab and animal studies. They demonstrate a strong ability to fight tumors and maintain their effectiveness over time. Early studies found these NK cells more effective at killing cancer cells than regular NK cells. In this trial, participants will receive CAR.70 IL15-transduced NK cells following lymphodepleting and primary chemotherapy. Tests have confirmed their safety and ability to target specific cancer markers, supporting their potential use in treating myeloid leukemia. ^{1 5 6 7 8}

Who Is on the Research Team?

Nicholas Short, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults aged 18-80 with relapsed/refractory AML, treated secondary AML, high-risk MDS, or CMML expressing CD70 can join. They must be physically stable (ECOG <2), have good organ function, and understand the consent form. Contraception is required for participants of childbearing potential.

Inclusion Criteria

Ability to understand and willingness to sign a written informed consent document

Willingness to sign informed consent to long-term follow-up on protocol PA17-0483

Willingness to use adequate contraception

Exclusion Criteria

Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection

Pregnant or breastfeeding women

I do not have severe heart failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy prior to NK cell infusion

1-2 weeks

Treatment

Participants receive TGFBR2 KO CAR27/IL-15 NK cells to determine safety and optimal dose

Phase I: Dose escalation; Phase II: Dose expansion

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• CAR.70-Engineered IL15-Transduced Cord Blood-Derived NK Cells With TGF-beta Receptor 2 (TGFBR2) Knock Out
• Cyclophosphamide

Trial Overview The trial tests TGFBR2 KO CAR27/IL-15 NK cells combined with lymphodepleting chemotherapy to find a safe dose for treating certain myeloid malignancies. It aims to determine the treatment's safety and effectiveness.

How Is the Trial Designed?

Group I: Phase 2A: Dose Expansion with CAR.70 for AML Patients Experimental Treatment 5 Interventions

Participants will receive lymphodepleting and primary chemotherapy, followed by a one-time infusion of TGFR KO-CAR27/IL-15 NK cells using the maximum tolerated dose found in escalation

Group II: Phase 1: Dose Escalation with CAR.70 Experimental Treatment 5 Interventions

Participants will receive lymphodepleting and primary chemotherapy, followed by a one-time infusion of TGFR KO-CAR27/IL-15 NK cells. Dose of the cells will be a different dose until a maximum tolerated dose is found.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

The study successfully developed CAR-NK cells targeting NKG2D ligands using a non-viral piggyBac transposon technology, showing effective cancer cell lysis in vitro and tumor growth inhibition in an in vivo AML model.

Co-expressing interleukin-15 (IL-15) with the NKG2D CAR significantly enhanced the persistence and antileukemic activity of the CAR-NK cells, leading to improved tumor control and extended survival in treated mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

piggyBac system to co-express NKG2D CAR and IL-15 to augment the in&#160;vivo persistence and anti-AML activity of human peripheral blood NK cells. Du, Z., Ng, YY., Zha, S., et al.[2021]

Engineered cord blood-derived natural killer (NK) cells, modified with CAR-CD19 and IL-15, showed effective targeting and killing of leukemia cells in laboratory tests and improved survival in a mouse model of lymphoma.

This approach not only enhances the efficacy of NK cells in treating cancers but also includes a safety mechanism (the iC9 suicide gene) to eliminate the cells if necessary, reducing the risk of adverse effects like graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Liu, E., Tong, Y., Dotti, G., et al.[2021]

Engineering NK cells to express CD123-specific chimeric antigen receptors (CARs) and interleukin-15 (IL-15) significantly enhances their anti-AML activity and persistence, particularly with the 2B4.ζ CAR, which showed improved efficacy in vitro and in vivo.

While the 2B4.ζ/sIL-15 CAR-NK cells demonstrated potent anti-AML effects, they also caused lethal toxicity in some models, highlighting the need for careful management of cytokine expression in future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. Christodoulou, I., Ho, WJ., Marple, A., et al.[2022]

Engineered allogeneic NK cells targeting the FLT3 antigen showed enhanced effectiveness against acute myeloid leukemia (AML) cells, demonstrating higher cytotoxicity and interferon gamma secretion compared to standard NK cells.

These FLT3 CAR_sIL-15 NK cells not only prolonged survival in AML models but also exhibited no harmful effects on healthy blood cells, suggesting a promising and safe treatment option for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-the-shelf CAR-engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia. Mansour, AG., Teng, KY., Li, Z., et al.[2023]

Engineering NK-92 cells with a third-generation CAR targeting the CD123 receptor significantly enhances their ability to kill acute myeloid leukemia (AML) cells, as demonstrated in both in vitro and in vivo models.

The inclusion of IL-15 in the CAR design improves the persistence of these modified NK-92 cells in the body, suggesting that this approach could lead to more effective treatments for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123. Morgan, MA., Kloos, A., Lenz, D., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6063081/

Cord blood NK cells engineered to express IL-15 and a ... Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent anti-tumor activity.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05092451

NCT05092451 | Phase I/II Study of CAR.70- Engineered ... To determine the safety, efficacy and optimal cell dose of CAR.70/IL15-transduced CB-NK cells in patients with relapsed/refractory hematological malignances.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06930651

NCT06930651 | A Phase I/II Study of CAR.70-Engineered ... The goal of this clinical research study is to find the recommended safe dose of TGFBR2 KO CAR27/IL-15 NK cells that can be given to patients with ...

4. ashpublications.org ashpublications.org/bloodadvances/article/8/11/2635/515576/CD70-specific-CAR-NK-cells-expressing-IL-15-for

CD70-specific CAR NK cells expressing IL-15 for the ... CD70-CAR NK cells displayed superior cytotoxic activity in vitro and in vivo against CD19-negative B-cell lymphoma when compared with nontransduced NK cells ...

5. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2021-0386.html

engineered IL15-transduced cord blood-derived NK cells ... The goal of this clinical research study is to learn about the safety of giving immune cells called natural killer (NK) cells with chemotherapy to patients ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8655609/

Engineering CAR-NK cells to secrete IL-15 sustains their ... Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 2018;32:520–31.

7. withpower.com withpower.com/trial/phase-2-neoplasms-9-2025-f7803

CAR-NK Cell Therapy for Myeloid Leukemia The goal of this clinical research study is to find the recommended safe dose of TGFBR2 KO CAR27/IL-15 NK cells that can be given to patients with ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT05703854

NCT05703854 | Study of CAR.70-engineered IL15 ... Primary Objective: To determine the safety, tolerability, and optimal cell dose of chimeric antigen receptor (CAR).70/interleukin (IL)15-transduced cord ...