CAR T-cell Therapy for Acute Myeloid Leukemia

Overseen By LaQuisa HIll, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: High dose steroids

Disqualifiers: APL, Active infection, Second cancer, others

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

Compensation: Varies

Number of Visits: 5

18 Participants Needed

Trial Summary

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 cannot be on systemic chemotherapy at least 2 weeks before the study treatment and must not be on high-dose steroids or certain immune-suppressing drugs. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment CLL-1.CAR T cells for acute myeloid leukemia?

Research shows that CLL-1 CAR-T cells can effectively target and kill leukemia cells in both lab settings and animal models. In a clinical trial with children who had a difficult-to-treat form of leukemia, the treatment helped some patients achieve a state where no leukemia was detectable, suggesting it can be a promising option for treating this condition. ^{1 2 3 4 5}

Is CAR T-cell therapy targeting CLL-1 safe for humans?

CAR T-cell therapy targeting CLL-1 has been tested in children with acute myeloid leukemia and showed that it can be well-tolerated, with some patients experiencing mild side effects like cytokine release syndrome (a condition where the immune system releases too many proteins into the blood too quickly). No severe or lethal side effects were reported in the studies. ^{1 2 3 5 6}

How is the CLL-1 CAR-T cell treatment different from other treatments for acute myeloid leukemia?

The CLL-1 CAR-T cell treatment is unique because it targets a specific protein, CLL-1, found on leukemia cells but not on normal stem cells, reducing the risk of damaging healthy cells. This targeted approach allows for effective leukemia cell killing while sparing normal blood-forming cells, which is a significant advantage over traditional treatments. ^{1 2 3 4 5}

What is the purpose of this trial?

Patients eligible for this study have a type of blood cancer Acute Myeloid Leukemia (AML) which has come back or has not gone away after treatment. The body has different ways of fighting disease and infection, and this research study combines two different ways of fighting cancer with antibodies and T cells with the hope that they will work together. T cells (also called T lymphocytes) are special infection-fighting blood cells that can kill other cells including tumor cells. Antibodies are types of proteins that protect the body from bacterial and other infectious diseases. Both antibodies and T cells have been used to treat patients with cancers; they have shown promise, but have not been strong enough to cure most patients when used alone. T lymphocytes can kill tumor cells but there normally are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person. The antibody used in this study targets CLL-1. This antibody sticks to AML cells because of a substance (protein) on the outside of these cells called CLL-1. For this study, the antibody to CLL-1 has been changed so that instead of floating free in the blood, it is now joined to the T cells. When T-cells contain an antibody that is joined to them, they are called chimeric antigen receptor T-cells or CAR-T cells. In the laboratory, the investigators have also found that T cells work better if proteins that stimulate T cells are also added, such as one called CD28. Adding the CD28 makes the cells grow better and last longer in the body, thus giving the cells a better chance of killing the leukemia or lymphoma cells. In this study we are going to attach the CLL-1 chimeric receptor that has CD28 added to it to the patient's T cells. We will then test how long the cells last. These CLL-1 chimeric antigen receptor T cells with CD28 are investigational products not approved by the Food and Drug Administration.

Research Team

LaQuisa Hill, MD

Principal Investigator

Cell and Gene Therapy, Baylor College of Medicine

Eligibility Criteria

This trial is for adults up to 75 years old with Acute Myeloid Leukemia (AML) that's resistant or returned after treatment. They must have a certain level of CLL-1 protein on their cancer cells, good kidney and liver function, no active infections, HIV or HTLV, not be taking high-dose steroids for GVHD, and not have another active cancer.

Inclusion Criteria

Serum Creatinine < 1.5 x ULN

PT and APTT <1.5x ULN

AST < 1.5 x ULN

Exclusion Criteria

I do not have an active HIV or HTLV infection.

I am currently on high-dose steroids or other immune-suppressing drugs for GVHD.

I have an ongoing infection that isn't getting better despite treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-treatment Chemotherapy

Participants receive cyclophosphamide and either fludarabine or clofarabine to lower T cell counts before CAR-T cell infusion

1 week

3 visits (in-person)

CAR-T Cell Infusion

Participants receive an infusion of CLL-1 chimeric antigen receptor T-cells

1 day

1 visit (in-person)

Initial Monitoring

Participants are monitored closely for side effects and response to treatment, including potential hospital admission for 72 hours

4 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with regular blood tests and imaging

15 years

Regular visits (in-person)

Treatment Details

Interventions

• CLL-1.CAR T cells

Trial Overview The study tests CAR-T cells targeting the CLL-1 antigen in AML patients. These modified T-cells are equipped with an antibody against CLL-1 and a CD28 stimulator to enhance their growth and persistence in the body. This investigational therapy aims to improve the immune system's ability to fight leukemia.

Participant Groups

Group I: CLL-1.CAR Experimental Treatment 1 Intervention

Group A

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Findings from Research

CAR-T cells targeting CLL-1 were successfully developed and showed a high transduction rate of 77.82%, effectively killing CLL-1-expressing acute myeloid leukemia (AML) cells in both in vitro and in vivo models.

In a human xenograft mouse model, CLL-1 CAR-T cells significantly improved survival compared to untransduced T cells, demonstrating potent antileukemic activity with a median survival of not reached versus 22 days for the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Development and functional verification of CAR-T cells targeting CLL-1]. Chai, X., Jin, X., Zhao, MF.[2022]

In a phase 1/2 clinical trial involving 8 children with relapsed or refractory acute myeloid leukemia (R/R-AML), anti-CLL1 CAR-T cell therapy demonstrated a favorable safety profile, with only mild cytokine release syndrome observed and no fatal events reported.

The treatment showed promising efficacy, with 4 out of 8 patients achieving a morphologic leukemia-free state and minimal residual disease negativity, indicating that anti-CLL1 CAR-T cell therapy could be a viable option for these young patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of anti-CLL1 based CAR-T therapy for children with relapsed or refractory acute myeloid leukemia: the multi-center efficacy and safety interim analysis. Zhang, H., Bu, C., Peng, Z., et al.[2023]

In a trial involving four pediatric patients with refractory/relapsed acute myeloid leukemia (R/R-AML), three patients achieved complete remission and were free of minimal residual disease after receiving anti-CLL1 CAR T-cell therapy, indicating promising efficacy.

The treatment was associated with low-grade and manageable adverse events, suggesting that this CAR T-cell therapy could be a safe alternative for children with R/R-AML, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CLL1 Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed/Refractory Acute Myeloid Leukemia. Zhang, H., Wang, P., Li, Z., et al.[2022]

CLL-1.CAR-T cells specifically target and kill acute myeloid leukemia (AML) cells while sparing normal hematopoietic stem cells, which is crucial for reducing the risk of severe toxicity during treatment.

The introduction of an inducible caspase-9 suicide gene system allows for controlled elimination of CLL-1.CAR-T cells, providing a safety mechanism to manage potential side effects from cytotoxic activity against normal myeloid cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Acute Myeloid Leukemia with T Cells Expressing Chimeric Antigen Receptors Directed to C-type Lectin-like Molecule 1. Tashiro, H., Sauer, T., Shum, T., et al.[2022]

CAR T-cell therapy shows promise in improving outcomes for patients with acute myeloid leukemia (AML), a condition with historically poor prognosis.

A significant challenge for the effectiveness of CAR T-cell therapy in AML is the identification of specific target antigens on leukemia cells, as well as the risk of immune escape due to changes in these antigens and a suppressive tumor environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current challenges for CAR T-cell therapy of acute myeloid leukemia. Sauer, T., Rooney, CM.[2020]

Up to 30% of patients with acute myeloid leukemia (AML) show some response to CAR T-cell therapy, but these responses are often not deep or long-lasting, indicating a need for improved treatment strategies.

Common targets for CAR T-cells in AML include CD123, CD33, and CLL-1, but while these therapies can lead to myeloablation and cytokine release syndrome, they rarely cause neurotoxicity, suggesting a relatively safe profile for certain side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia. Cummins, K., Gill, S.[2023]

References

1. China pubmed.ncbi.nlm.nih.gov

[Development and functional verification of CAR-T cells targeting CLL-1]. [2022]

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

Characteristics of anti-CLL1 based CAR-T therapy for children with relapsed or refractory acute myeloid leukemia: the multi-center efficacy and safety interim analysis. [2023]

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

Anti-CLL1 Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed/Refractory Acute Myeloid Leukemia. [2022]

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

Treatment of Acute Myeloid Leukemia with T Cells Expressing Chimeric Antigen Receptors Directed to C-type Lectin-like Molecule 1. [2022]

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

Current challenges for CAR T-cell therapy of acute myeloid leukemia. [2020]

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

Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia. [2023]