Modified Stem Cell Transplant + CAR T Cells for Acute Myeloid Leukemia

(CART33 Trial)

Overseen By Abramson Cancer Center Clinical Trials Service

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Systemic steroids, Immunosuppressants

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

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

Compensation: Varies

Number of Visits: Unknown

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for acute myeloid leukemia (AML) by combining a modified stem cell transplant with CAR T-cell therapy. The approach uses stem cells from a healthy donor, modified to work alongside CAR T-cells, which target and destroy leukemia cells. This method aims to improve outcomes for those whose AML doesn't respond to existing treatments or has returned after a previous transplant. Suitable candidates have AML that hasn't fully gone into remission or has returned after treatment and 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 opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial requires that participants do not use systemic steroids or immunosuppressant medications. If you are currently taking these, you would need to stop before joining the trial.

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

A previous study demonstrated that the CD33KO-HSPC treatment, involving a gene-edited stem cell transplant, was generally safe. It quickly produced new, healthy blood cells, suggesting good patient tolerance.

For the CART-33 treatment, which uses specially designed immune cells to target leukemia, research has shown it effectively fights leukemia cells. It caused limited harm, meaning it didn't damage the stem cells needed for blood production.

Both treatments have shown promising safety in early research. However, since this trial is in its initial phase, the complete safety profile is still being determined. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute myeloid leukemia (AML) because they offer a novel approach that could improve outcomes. Unlike traditional chemotherapy and stem cell transplants, which are the standard treatments for AML, this approach uses a combination of modified stem cell transplants and CAR T-cell therapy. The CD33KO-HSPC treatment involves genetically modifying stem cells to be resistant to certain chemotherapy agents, potentially allowing for more aggressive treatment without damaging healthy cells. Meanwhile, the CART-33 therapy uses engineered T-cells that specifically target and destroy leukemia cells expressing the CD33 protein. This dual approach aims to enhance the immune system's ability to fight the cancer more effectively, offering hope for better remission rates.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that CD33KO-HSPC is a promising treatment for acute myeloid leukemia (AML). Studies have found that it helps the bone marrow rebuild while resisting certain harmful drugs, potentially reducing the risk of leukemia returning. Meanwhile, CART-33 specifically targets and destroys AML cells. Early results suggest it can effectively eliminate leukemia cells and extend patient survival. This trial studies both treatments together to determine if they can be more effective against AML. ^{1 2 3 4 5}

Who Is on the Research Team?

Noelle Frey

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for adults over 18 with Acute Myeloid Leukemia (AML) that's hard to cure with existing treatments. Candidates must have a suitable stem cell donor, good kidney and liver function, no severe heart or lung issues, and can't be on systemic immunosuppression if they've had a transplant before.

Inclusion Criteria

My AML is not expected to be cured with existing treatments.

Subjects must have a suitable stem cell donor

Satisfactory organ function: Creatinine clearance > 40 ml/min, ALT/AST must be ≤ 5x upper limit of normal unless related to disease and < 20 x upper limit of normal if related to disease, Direct bilirubin < 2.0 mg/dl, unless subject has Gilbert's syndrome (≤ 3.0 mg/dL), Left ventricular ejection fraction ≥ 40% as confirmed by echocardiogram or MUGA, DLCO > 45% predicted, ECOG performance status 0-1, Written informed consent is given, Subjects of reproductive potential must agree to use acceptable birth control methods

Exclusion Criteria

Pregnant or lactating (nursing) women

I have severe limitations due to heart problems.

I do not have active hepatitis B, C, or HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stem Cell Transplant

Participants receive a modified stem cell transplant using blood-forming stem cells from a healthy donor

1 month

CAR T-Cell Infusion

Participants receive 1-3 infusions of CAR T-cells engineered to attack AML cells

3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term Follow-up

Participants are monitored for long-term outcomes such as overall survival and progression-free survival

15 years

What Are the Treatments Tested in This Trial?

Interventions

• CART-33
• CD33KO-HSPC

Trial Overview The study tests a new AML treatment combining modified stem cell transplants from donors with CAR T-cell therapy. The CAR T-cells are designed to target leukemia cells without affecting the newly transplanted 'invisible' healthy blood cells.

How Is the Trial Designed?

Group I: CD33KO-HSPC followed by CART33 Experimental Treatment 1 Intervention

All subjects will receive CD33KO-HSPC, followed by 1-3 CART-33 infusions

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 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]

The study introduces a new third-generation CAR T-cell therapy (3G.CAR33-T) targeting CD33 for treating acute myeloid leukemia (AML), showing improved viability, proliferation, and cytotoxicity compared to second-generation CAR T-cells.

3G.CAR33-T cells effectively kill CD33-positive leukemia cells while sparing normal hematopoietic stem and progenitor cells, suggesting a safer treatment option that could be combined with genome-edited stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells. Liu, Y., Wang, S., Schubert, ML., et al.[2022]

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]

The clinical trial involved a 41-year-old male patient with refractory acute myeloid leukemia (AML) who received 1.12 billion CD33-directed CAR-modified T cells, resulting in a significant reduction of leukemia cells in the bone marrow within 2 weeks.

Despite initial positive effects, the patient experienced severe side effects, including fever and fluctuations in blood cell counts, and the leukemia progressed again by 9 weeks, indicating the need for further research on CART-33 therapy in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Wang, QS., Wang, Y., Lv, HY., et al.[2021]

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]

A novel second-generation chimeric antigen receptor (CAR) targeting CD33 has been developed, showing effectiveness in redirecting T cells to kill acute myeloid leukemia (AML) cells, which express CD33 in about 90% of cases.

In pre-clinical studies, this CAR therapy demonstrated significant anti-leukemia effects both in vitro and in vivo, effectively preventing leukemia development and delaying disease progression in mice, supporting its potential as a clinical treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. O'Hear, C., Heiber, JF., Schubert, I., 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]

The study developed tremtelectogene empogeditemcel (trem-cel), a genetically modified hematopoietic stem cell product that lacks the CD33 protein, which is targeted by certain AML therapies, thus reducing the risk of toxicity to healthy cells.

Preclinical studies demonstrated that trem-cel can be manufactured with over 70% efficiency without affecting cell viability or function, and it showed resistance to the CD33-targeted drug gemtuzumab ozogamicin, supporting its potential safety and efficacy for treating acute myeloid leukemia in upcoming clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a gene edited next-generation hematopoietic cell transplant to enable acute myeloid leukemia treatment by solving off-tumor toxicity. Lydeard, JR., Lin, MI., Ge, HG., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39748428/

Safety and efficacy of CD33-targeted CAR-NK cell therapy ... Conclusions: Our preclinical and clinical data demonstrated the primary efficacy and safety of CD33 CAR-NK cells for patients with R/R AML.

2. ehoonline.biomedcentral.com ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00592-6

Safety and efficacy of CD33-targeted CAR-NK cell therapy for ... We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4644600/

CD33-specific chimeric antigen receptor T cells exhibit ... CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts.

4. sciencedirect.com sciencedirect.com/science/article/pii/S1525001625002618

CAR-T cell therapy for treatment of acute myeloid leukemia ... This review discusses the advances of CAR-T cell therapy in AML, targets, and outcomes in preclinical and clinical studies.

5. nature.com nature.com/articles/s41375-021-01232-2

Autologous CD33-CAR-T cells for treatment of relapsed/ ... Acute myelogenous leukemia (AML) is a potentially curable disease; 70% of newly diagnosed patients achieve complete remission with ...