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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CART123 cells (Chimeric Antigen Receptor T-123 cells) for children and young adults with a challenging type of leukemia known as Acute Myeloid Leukemia (AML), particularly if it has recurred or resisted other treatments. Researchers aim to determine the safety of this treatment when combined with other medicines like cyclophosphamide and fludarabine. It suits patients whose AML has returned multiple times or has not responded to chemotherapy and who have a suitable stem cell donor available. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new therapy.

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.

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

Research has shown that CART123 cell treatment is being tested for safety in people with Acute Myeloid Leukemia (AML). In other studies, some patients experienced side effects such as fever and cytokine release syndrome (CRS), a strong immune response. However, strong evidence on its effectiveness against leukemia is still lacking.

As an early-phase study, the primary goal is to assess the treatment's safety. Researchers are still learning about its tolerability and potential side effects. Prospective participants should be aware that the treatment remains in early testing stages, meaning safety information is limited and not all possible side effects are known. ^{1 2 3 4 5}

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

Unlike the standard treatments for leukemia, which often involve chemotherapy or stem cell transplants, CART123 cells offer a cutting-edge approach by using genetically modified T cells that specifically target the CD123 antigen on leukemia cells. This targeted attack is designed to minimize damage to healthy cells, potentially leading to fewer side effects than traditional therapies. Researchers are excited because this method could provide a more precise and effective treatment option, with a mechanism of action that harnesses the body's own immune system to fight the cancer.

What evidence suggests that this trial's treatments could be effective for Acute Myeloid Leukemia?

Research has shown that CART123 cells, which participants in this trial will receive, might help treat acute myeloid leukemia (AML). These specially designed T cells can find and destroy leukemia cells in lab studies. By targeting CD123, a protein on leukemia cells, researchers have observed a significant reduction in the disease. In studies with mice, CART123 therapy caused the cancer to disappear, with the mice remaining cancer-free for at least 12 weeks. While these results are encouraging, it is important to note that most of this evidence comes from lab and animal studies, and researchers are still learning how well it works in humans. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

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.

My leukemia didn't respond to initial or re-induction chemotherapy.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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, 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10164930/

Outcomes with chimeric antigen receptor t-cell therapy in ... CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118475441

Efficient Termination of CD123-Redirected Chimeric ... Mice with CART123- or CART123/CD20-induced AML remission at time of T cell ablation remained leukemia-free for ≥12 weeks, and animal survival ...

3. ashpublications.org ashpublications.org/blood/article/123/15/2343/32257/Preclinical-targeting-of-human-acute-myeloid

Preclinical targeting of human acute myeloid leukemia and ... Key Points. Targeting of CD123 via CAR-engineered T cells results in rejection of human AML and myeloablation in mouse models.

4. nature.com nature.com/articles/s41467-022-29668-9

Allogeneic TCRαβ deficient CAR T-cells targeting CD123 ... Our data show that UCART123 is able to eliminate LSCs and preferentially eliminate AML versus normal cells in vitro and in vivo. UCART123 is a ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4624420/

T cells expressing CD123 chimeric antigen receptors for ... Preclinical data suggest that CD123 CAR T cells exhibit potent anti-leukemic activity and various impacts on normal hematopoiesis. Summary. CD123 is an ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04014881

NCT04014881 | Safety and Efficacy of Anti-CD123 CAR-T ... This study aims to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with relapsed/refractory CD123+ Acute Myeloid Leukemia. Official Title.

7. sciencedirect.com sciencedirect.com/science/article/pii/S014521262400064X

Safety and efficacy of chimeric antigen receptor T-cell ... The meta-analysis revealed a 48% incidence of complete remission with CAR T-cell therapy, varying significantly across subgroups based on study design, location ...

8. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04678336/

Clinical Trial: NCT04678336 - AML This is a Phase 1 study to determine the safety, manufacturing feasibility, and efficacy of CART123 cells following lymphodepleting chemotherapy ...

9. haematologica.org haematologica.org/article/view/8961/63690

Chimeric antigen receptor T-cell therapy for acute myeloid ... Though there was no measurable anti-leukemic activity responses in this trial, evidence of CART bioactivity was manifest by fever, CRS and ...