Genetically Modified T Cells for Acute Myeloid Leukemia

Overseen By EmergingMed

Age: 18+

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: 3 days

22 Participants Needed

Trial Summary

What is the purpose of this trial?

Phase 1 open-label study to estimate the safety, manufacturing feasibility, and efficacy 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 Acute Myeloid Leukemia (AML) subjects.

Will I have to stop taking my current medications?

The trial does not allow the use of systemic steroids or immunosuppressant medications, so you would need to stop these if you are currently taking them. However, inhaled steroids or physiologic replacement with hydrocortisone are allowed.

What data supports the effectiveness of this treatment for acute myeloid leukemia?

Research shows that genetically modified T cells targeting CD123, a protein found on most acute myeloid leukemia cells, can effectively eliminate leukemia in mice. This suggests that the treatment could be promising for patients with this type of cancer. ^{1 2 3 4 5}

Is the genetically modified T cell treatment for acute myeloid leukemia safe?

The safety of genetically modified T cells, like CART123, for acute myeloid leukemia is still being studied. Some research shows they can effectively target leukemia cells, but they may also harm normal blood cells, leading to potential risks. More studies are needed to ensure their safe use in humans. ^{1 3 6 7 8}

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

CART123 treatment is unique because it uses genetically modified T cells to specifically target and destroy leukemia cells by recognizing a protein called CD123 on their surface. This approach is different from traditional chemotherapy as it directly harnesses the body's immune system to fight the cancer, offering a novel option for patients who do not respond to standard treatments. ^{1 2 3 9 10}

Eligibility Criteria

This trial is for adults with Acute Myeloid Leukemia (AML) who haven't achieved remission or have relapsed, including after stem cell transplants. They must be over 18, have good organ function and performance status, not pregnant or breastfeeding, without severe active infections like HIV or hepatitis B/C, no history of certain heart conditions or other specific diseases.

Inclusion Criteria

My organs are functioning well.

- Creatinine ≤ 1.6 mg/dl

- ALT/AST must be ≤5 x upper limit of normal unless related to disease

Exclusion Criteria

I am HIV positive.

I do not have unstable heart rhythm issues.

My AML has returned and has a specific genetic feature (t(15:17)).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine prior to CART123 cell infusion

1 week

Treatment

Participants receive CART123 cell infusion with a split dosing approach or single administration

3 days

Follow-up

Participants are monitored monthly for safety and efficacy for up to 6 months post-infusion

6 months

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 a new therapy where patients' T cells are modified to target AML cells and then put back into the body. It's combined with two chemotherapy drugs: cyclophosphamide and fludarabine. The goal is to see if this approach is safe and effective against AML.

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 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]

CAR T-cell therapy has the potential to improve outcomes for patients with acute myeloid leukemia (AML) by specifically targeting leukemia cells, but there are significant challenges to its effectiveness and safety.

Strategies being explored to enhance CAR T-cell therapy in AML include targeting specific leukemia antigens to reduce side effects, using checkpoint inhibitors to counteract immune suppression caused by leukemia, and developing allogenic CAR T cells to make the treatment more accessible to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospect of CAR T-cell therapy in acute myeloid leukemia. Badar, T., Manna, A., Gadd, ME., et al.[2022]

CD123 is confirmed as a valid target for treating acute myeloid leukemia (AML), with both 41BB-based and CD28-based CAR T-cell therapies showing strong effectiveness in eliminating AML cells in laboratory and animal models.

However, these CAR T-cell therapies also destroy normal blood stem cells, which raises safety concerns and suggests they should primarily be used as a temporary solution before a stem cell transplant in patients with refractory or relapsed AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. Baroni, ML., Sanchez Martinez, D., Gutierrez Aguera, F., 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]

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]

CAR T-cell therapy for acute myeloid leukemia (AML) faces challenges due to the lack of specific surface antigens, but advancements are being made to improve its effectiveness.

Potential strategies to enhance the safety and efficacy of CAR T-cell therapy for AML include reducing the potency of CAR T cells, using transient CAR T cells during pre-transplant conditioning, and employing gene-edited allogeneic stem cell transplants to support sustained anti-AML activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How close are we to CAR T-cell therapy for AML? Gill, SI.[2021]

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]

CART33, a chimeric antigen receptor T cell therapy targeting CD33, showed significant effectiveness in eradicating acute myeloid leukemia (AML) in preclinical models, leading to prolonged survival.

To reduce the risk of long-term toxicity associated with permanent CART cell expression, a transiently expressed mRNA anti-CD33 CAR was developed, demonstrating potent but self-limited activity against AML, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Kenderian, SS., Ruella, M., Shestova, O., et al.[2022]

Adoptive transfer of genetically engineered T cells has shown significant and lasting responses in patients with blood cancers, highlighting its potential as a powerful treatment option.

The success of this therapy relies heavily on the quality of T cells produced, which is influenced by the methodologies and reagents used in their generation for preclinical studies, particularly in the context of chimeric antigen receptor T cell therapy for acute myeloid leukemia (AML).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generating and Expanding Autologous Chimeric Antigen Receptor T Cells from Patients with Acute Myeloid Leukemia. Kenderian, SS., June, CH., Gill, S.[2018]

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]

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. England pubmed.ncbi.nlm.nih.gov

Prospect of CAR T-cell therapy in acute myeloid leukemia. [2022]

3. England pubmed.ncbi.nlm.nih.gov

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. [2021]

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

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

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

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

6. Netherlands pubmed.ncbi.nlm.nih.gov

How close are we to CAR T-cell therapy for AML? [2021]

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

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

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

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. [2022]

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

Generating and Expanding Autologous Chimeric Antigen Receptor T Cells from Patients with Acute Myeloid Leukemia. [2018]

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

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