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

Trial Summary

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.

What data supports the effectiveness of the treatment CAR.70-Engineered IL15-Transduced Cord Blood-Derived NK Cells With TGF-beta Receptor 2 (TGFBR2) Knock Out, Cyclophosphamide for myeloid leukemia?

Research shows that engineered NK cells, which are a type of immune cell, can effectively target and kill leukemia cells. These NK cells are modified to produce IL-15, a protein that helps them survive longer and work better against cancer, and have shown promising results in prolonging survival in animal models of leukemia. ^{1 2 3 4 5}

Is CAR-NK cell therapy safe for humans?

CAR-NK cell therapy has shown promising safety results in studies, with engineered NK cells effectively targeting leukemia cells without causing harm to healthy cells. Some studies have reported no observable side effects, while others mention systemic toxicities, indicating that while generally safe, there may be risks involved. ^{1 2 3 5 6}

What makes CAR-NK Cell Therapy for Myeloid Leukemia unique?

This treatment uses engineered natural killer (NK) cells derived from cord blood, which are modified to express a chimeric antigen receptor (CAR) and interleukin-15 (IL-15) to enhance their ability to target and kill leukemia cells. Additionally, the NK cells have a TGF-beta receptor 2 (TGFBR2) knock out, which may help them overcome immune suppression in the tumor environment, making this approach distinct from traditional therapies. ^{1 2 3 5 7}

What is the purpose of this trial?

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 relapsed/refractory disease. The safety and effectiveness of this treatment will also be studied.

Research Team

Nicholas Short, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Phase 2A: Dose Expansion with CAR.70 for AML Patients Experimental Treatment 1 Intervention

Expansions of 2 arms: 1.) patients with relapsed/refractory AML and 2.) patients with MDS/CMML after HMA failure.

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

The study will have a phase I dose-escalation portion using a standard "BOIN" approach to determine the MTD of the TGFBR2 KO CAR27/IL-15 NK cells

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

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]

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-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]

References

1. England pubmed.ncbi.nlm.nih.gov

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. [2022]

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

Natural killer cells generated from cord blood hematopoietic progenitor cells efficiently target bone marrow-residing human leukemia cells in NOD/SCID/IL2Rg(null) mice. [2021]

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

Off-the-shelf CAR-engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia. [2023]

4. United States 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. [2021]

5. England 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. [2021]

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

Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123. [2021]