CD123 Redirected T Cells for Leukemia

Overseen By Brooke Leibfreid

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

18 Participants Needed

Trial Summary

What is the purpose of this trial?

Phase 1 open-label study to evaluate the safety of intravenously administered, lentivirally transduced T cells expressing anti-CD123 chimeric antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ /4-1BB) costimulatory domains in pediatric subjects with relapsed/refractory Acute Myeloid Leukemia (AML).

Will I have to stop taking my current medications?

The trial requires that patients do not take chronic systemic steroids or immunosuppressant medications, except for low-dose physiologic replacement therapy, topical steroids, and inhaled steroids. There may be specific washout requirements for these medications before starting the trial.

What data supports the effectiveness of the treatment CD123 Redirected T Cells for Leukemia?

Research shows that CD123 chimeric antigen receptor (CAR) T cells have strong antileukemic activity and can eradicate acute myeloid leukemia (AML) in experimental models. These CAR T cells target CD123, a marker found on most AML cells, and have shown promise in preclinical studies, although they may also affect normal blood cell production. ^{1 2 3 4 5}

Is CD123 Redirected T Cell therapy safe for humans?

CD123 Redirected T Cell therapy, also known as CART123, has shown potential in treating leukemia, but it can pose safety risks due to its effects on normal blood cells. A study demonstrated that a modified version, UniCAR-T, can control these risks better, showing reversible toxicity in pre-clinical tests, and is being further evaluated in a clinical trial. ^{1 2 5 6 7}

How is the CART123 treatment different from other treatments for leukemia?

CART123 treatment is unique because it uses specially engineered T cells to target and destroy leukemia cells that express a protein called CD123, which is often found on leukemia cells but not on normal cells. This approach is different from traditional chemotherapy as it specifically targets cancer cells, potentially reducing damage to healthy cells. ^{1 2 3 5 8}

Eligibility Criteria

This trial is for children and young adults aged 1 to 29 with Acute Myeloid Leukemia (AML) that has come back after treatment or hasn't responded to chemotherapy. They must have a stem cell donor ready, good heart and lung function, no serious infections like HIV, and not be pregnant.

Inclusion Criteria

Signed informed consent must be obtained.

My AML has returned after treatment or is not responding to chemotherapy.

I am between 1 and 29 years old.

Exclusion Criteria

It has been over 6 months since my stem cell transplant.

I am HIV positive.

I am currently receiving treatment for GVHD.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive lymphodepleting chemotherapy followed by CART123 cell infusion at varying dose levels

4 weeks

Multiple visits for dose administration and monitoring

Dose Limiting Toxicity Observation

Observation for dose-limiting toxicities (DLTs) for 28 days post-infusion

4 weeks

Weekly visits for safety follow-up

Follow-up

Participants are monitored monthly for safety and effectiveness after treatment

6 months

Monthly visits

Long-term Follow-up

Participants are transitioned into long-term follow-up for up to 15 years post-infusion

15 years

Treatment Details

Interventions

• CART123 cells
• Cyclophosphamide
• Fludarabine

Trial Overview The study tests CART123 cells combined with cyclophosphamide and fludarabine in patients. It's an early-phase trial assessing the safety of this gene therapy where T cells are modified to target leukemia cells in those who've had AML return or resist other treatments.

Participant Groups

Group I: Treatment Arm Experimental Treatment 1 Intervention

CART123 cells; cyclophosphamide; fludarabine

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Findings from Research

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]

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]

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]

In a phase-1/2 trial involving 13 adult patients with refractory acute lymphoblastic leukemia, third-generation CAR T cells (CARTs) demonstrated promising efficacy, with 80% of evaluable patients achieving complete remission, including 50% with no detectable residual disease.

The treatment was associated with remarkably low toxicity, as none of the patients experienced severe side effects like neurotoxicity or high-grade cytokine release syndrome, indicating a favorable safety profile for this innovative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial. Schubert, ML., Schmitt, A., Hückelhoven-Krauss, A., et al.[2023]

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]

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]

Genetically engineered T cells expressing chimeric antigen receptors (CARTs) have shown remarkable efficacy in treating relapsed/refractory acute lymphoblastic leukaemia (ALL), achieving not only remission but also long-term disease control.

Ongoing research aims to enhance the efficacy and safety of CART therapy, expanding its applicability to other types of cancers beyond leukaemias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The promise of chimeric antigen receptor T cells (CARTs) in leukaemia. Orlowski, RJ., Porter, DL., Frey, NV.[2018]

CD123, a receptor highly expressed in leukemic stem cells (LSCs) but not in normal stem cells, is a promising target for therapies aimed at treating refractory or relapsed leukemia, as it is linked to treatment response and prognosis.

Recent advancements in anti-CD123 therapies, including neutralizing antibodies and CAR-T cell therapies, show potential in effectively targeting LSCs, which could improve outcomes for patients with leukemia who do not respond to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD123: A Novel Biomarker for Diagnosis and Treatment of Leukemia. Shi, M., Su, RJ., Parmar, KP., et al.[2020]

References

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

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

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

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

3. 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]

4. England pubmed.ncbi.nlm.nih.gov

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial. [2023]

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

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

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

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

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

The promise of chimeric antigen receptor T cells (CARTs) in leukaemia. [2018]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

CD123: A Novel Biomarker for Diagnosis and Treatment of Leukemia. [2020]