CAR T-Cell Therapy for Acute Myeloid Leukemia

Recruiting at 2 trial locations

Overseen By Swati Naik, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Systemic steroids, Rituximab

Disqualifiers: HIV, Severe infections, APL, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1-2 days

32 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before the CD123-CAR T-cell infusion. Specifically, you cannot be on systemic steroids exceeding a certain dose, systemic therapy that might interfere with the T cells, rituximab, or intrathecal chemotherapy within specified time frames before the infusion.

What data supports the effectiveness of the treatment CD123-CAR T-cell therapy for acute myeloid leukemia?

Research shows that CD123-CAR T-cell therapy has strong antileukemic effects, effectively targeting and destroying leukemia cells in both lab and animal studies. This treatment specifically targets the CD123 protein, which is found in high amounts on leukemia cells, making it a promising option for patients with acute myeloid leukemia. ^{1 2 3 4 5}

Is CD123-CAR T-cell therapy safe for humans?

CD123-CAR T-cell therapy has shown potential in treating acute myeloid leukemia, but it can cause side effects like myeloablation (reduction of bone marrow activity) and cytokine release syndrome (a severe immune reaction). A safety-switch mechanism in a related therapy, UniCAR-T, has shown reversible toxicity in pre-clinical models, suggesting efforts to improve safety are ongoing. ^{2 3 6 7 8}

How is CD123-CAR T-cell therapy different from other treatments for acute myeloid leukemia?

CD123-CAR T-cell therapy is unique because it uses genetically modified T cells to specifically target and attack leukemia cells that overexpress the CD123 protein, offering a novel approach compared to traditional chemotherapy. This therapy harnesses the body's immune system to fight the cancer, potentially providing a more targeted and effective treatment for high-risk acute myeloid leukemia. ^{2 3 5 9 10}

What is the purpose of this trial?

The CD123-CAR T-cell therapy is a new treatment that is being investigated for treatment of AML/myelodysplastic syndrome (MDS), T- or B- acute lymphoblastic leukemia (ALL) or blastic plasmacytoid dendritic cell neoplasia (BPDCN). The purpose of this study is to find the maximum (highest) dose of CD123-CAR T cells that is safe to give to these patients. This would include studying the side effects of the chemotherapy, as well as the CD123-CAR T-cell product on the recipient's body, disease and overall survival. Primary Objective To determine the safety of one intravenous infusion of escalating doses of autologous, CD123-CAR T cells in patients (≤21 years) with recurrent/refractory CD123+ disease (AML/MDS, B-ALL, T-ALL or BPDCN) after lymphodepleting chemotherapy. Secondary Objectives To evaluate the antileukemia activity of CD123-CAR T cells. Exploratory Objectives * To assess the immunophenotype, clonal structure and endogenous repertoire of CD123-CAR T cells and unmodified T cells * To characterize the cytokine profile in the peripheral blood and CSF after treatment with CD123-CAR T cells * To characterize tumor cells post CD123-CAR T-cell therapy

Research Team

Swati Naik, MD

Principal Investigator

St. Jude Children's Research Hospital

Paulina Velasquez, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for young people (21 or younger) with certain types of leukemia that have come back or didn't respond to treatment. They should be in a condition where they can live at least 12 more weeks, able to do some daily activities, and not pregnant or breastfeeding. They must also have a donor ready for cell therapy.

Inclusion Criteria

Relapsed/refractory CD123+ disease defined as follows: AML/MDS - Relapsed disease: Patients developing recurrent disease after a first complete remission (CR) Refractory disease: Patients not achieving a CR after 2 cycles of induction chemotherapy B-cell ALL - Relapsed disease that is CD123 positive and CD19 negative/dim or patients otherwise ineligible for CD19 directed therapies including Patients in 2nd or greater relapse Patients with relapse after allogeneic HSCT Refractory disease that is CD123 positive and CD19 negative/dim or patients otherwise ineligible for CD19 directed therapies T-cell All - Relapsed refractory disease that is CD123 positive BPDCN - Relapsed/refractory disease that has failed front-line therapy Estimated life expectancy of >12 weeks Karnofsky or Lansky (age-dependent) performance score ≥50 Patients with a history of prior allogeneic HCT must be clinically recovered from prior HCT therapy, have no evidence of active GVHD and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to apheresis Patient must have an identified, suitable HCT donor For females of child-bearing age: Not lactating with intent to breastfeed Not pregnant with negative serum pregnancy test within 7 days prior to enrollment Meets eligibility criteria to undergo autologous apheresis, or have previously undergone autologous apheresis

I am 21 years old or younger.

Exclusion Criteria

You are expected to live for at least 8 more weeks.

My bilirubin levels are within normal range, except I have Gilbert's syndrome.

I have not received rituximab therapy in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Collection and Manufacturing

Blood cells are collected via apheresis and modified to improve their ability to recognize and kill cancer cells

2-3 weeks

Chemotherapy

Lymphodepleting chemotherapy is administered to prepare the body for CD123-CAR T cell infusion

4 days

Daily visits for chemotherapy administration

Treatment

Infusion of CD123-CAR T cells following chemotherapy

1-2 days

1 visit for infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CD123-CAR T
• Cyclophosphamide
• Fludarabine
• Rituximab

Trial Overview The trial tests CD123-CAR T-cell therapy after chemotherapy to find the highest safe dose. It's given through an IV and aims to see how well it works against leukemia and what side effects it has on patients' bodies, disease control, and survival rates.

Participant Groups

Group I: CD123-CAR T cell therapy Experimental Treatment 5 Interventions

CD123-CAR T-cell dose and infusion Up to 4 Dose levels will be evaluated with a maximum dose of 2.5 x 10\^8 CAR+ T cells. If dose limiting toxicities (DLTs) are observed on Dose level 1 then the cell dose is de- escalated.

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

CD123 is identified as a promising target for CAR T-cell therapy in acute myeloid leukemia (AML), as its expression increases over time in tumor cells, making it a viable option for treatment.

While CART123 T cells effectively eliminate AML cells in mice, they also destroy normal blood cell production, highlighting the need for careful management and potential rescue strategies during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Gill, S., Tasian, SK., Ruella, M., et al.[2021]

CD123 chimeric antigen receptor (CAR) redirected T cells have shown strong antileukemic activity, indicating a promising new approach for treating acute myeloid leukemia.

The development of CD123 CARs provides insights into enhancing immunotherapy strategies, highlighting the need for novel treatments in this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myeloid leukemia therapeutics: CARs in the driver's seat. Mardiros, A., Brown, CE., Budde, LE., et al.[2021]

CD123 CAR T cells, designed to target the interleukin-3 receptor α chain (CD123) overexpressed in acute myeloid leukemia (AML), showed strong effectiveness against AML cell lines and primary patient samples, indicating their potential as a powerful immunotherapy.

These CAR T cells did not harm normal blood cell formation in vitro and demonstrated the ability to kill AML cells from patients, suggesting a targeted approach that minimizes damage to healthy cells while effectively treating high-risk AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Mardiros, A., Dos Santos, C., McDonald, T., et al.[2023]

CD123 is a promising target for CAR T-cell therapy in leukemia because it is highly expressed in leukemic stem cells while being minimally present in normal blood stem cells, which may reduce potential side effects.

Preclinical studies indicate that CD123 CAR T cells show strong anti-leukemic effects, making them a potential effective treatment option for patients with relapsed or refractory acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells expressing CD123 chimeric antigen receptors for treatment of acute myeloid leukemia. Mardiros, A., Forman, SJ., Budde, LE.[2018]

Engineered CAR T cells targeting CD123, which is overexpressed in acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL), show promise in treating these cancers while minimizing damage to normal hematopoietic stem cells.

The study demonstrated that a specific combination of antibody chains in CAR T cells can maintain anti-tumor activity without significantly harming normal cells, suggesting a safer approach for immunotherapy in hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of VL and VH Domains Targeting CD123+ Tumors. Thokala, R., Olivares, S., Mi, T., et al.[2020]

The UniCAR-T platform, designed to target CD123, effectively eliminated CD123+ leukemia cells in both laboratory and animal models, demonstrating strong anti-leukemic efficacy.

This innovative CAR-T approach includes a safety-switch mechanism that allows for controllable toxicity, reducing the risk of harm to healthy hematopoietic cells, which is a significant improvement over traditional CD123 CAR-T therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapidly Switchable Universal CAR-T Cells for Treatment of CD123-Positive Leukemia. Loff, S., Dietrich, J., Meyer, JE., et al.[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]

The study developed a new type of T cell, called CD123-CAR-VST, which can target both acute myeloid leukemia (AML) cells and viral infections like EBV, adenovirus, and CMV, potentially addressing two major complications after hematopoietic stem cell transplantation (HSCT).

CD123-CAR-VST cells were shown to effectively recognize and attack both AML cells and viral antigens in laboratory tests, suggesting they could be a promising treatment option for preventing relapse and viral infections in patients who have undergone HSCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD123 redirected multiple virus-specific T cells for acute myeloid leukemia. Zhou, L., Liu, X., Wang, X., et al.[2016]

CAR-modified T cells, specifically those expressing anti-CD123, have shown effectiveness in treating Acute Myeloid Leukemia (AML) by eradicating AML cells.

This innovative immunotherapeutic approach highlights the potential of genetically modified T cells as a promising strategy in the development of AML treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD123 AML targeting by chimeric antigen receptors: A novel magic bullet for AML therapeutics? Tettamanti, S., Biondi, A., Biagi, E., et al.[2022]

Modified Vγ9Vδ2 T cells expressing anti-CD123 CAR showed significantly improved ability to kill acute myeloid leukemia (AML) cells in laboratory tests, indicating their potential effectiveness as a treatment.

In a mouse model of AML, these modified T cells demonstrated enhanced tumor control, suggesting they could be a promising alternative therapy for patients with this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A CD123-specific chimeric antigen receptor augments anti-acute myeloid leukemia activity of Vγ9Vδ2 T cells. Zhang, X., Ang, WX., Du, Z., et al.[2022]

References

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

Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. [2021]

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

Acute myeloid leukemia therapeutics: CARs in the driver's seat. [2021]

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

T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. [2023]

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

T cells expressing CD123 chimeric antigen receptors for treatment of acute myeloid leukemia. [2018]

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

Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of VL and VH Domains Targeting CD123+ Tumors. [2020]

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

Rapidly Switchable Universal CAR-T Cells for Treatment of CD123-Positive Leukemia. [2020]

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

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

8. England pubmed.ncbi.nlm.nih.gov

CD123 redirected multiple virus-specific T cells for acute myeloid leukemia. [2016]

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

CD123 AML targeting by chimeric antigen receptors: A novel magic bullet for AML therapeutics? [2022]

10. England pubmed.ncbi.nlm.nih.gov

A CD123-specific chimeric antigen receptor augments anti-acute myeloid leukemia activity of Vγ9Vδ2 T cells. [2022]