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

Trial Summary

What is the purpose of this trial?

The purpose of this study is to provide a new type of treatment for AML. This treatment combines a new type of stem cell transplant along with treatment using chimeric antigen receptor (CAR) T cells that have been engineered to recognize and attack your AML cells. The first treatment is a modified stem cell transplant, using blood-forming stem cells donated from a healthy donor. From the same donor, we will also make CAR T-cells, which are leukemia fighting cells, which will be given to the patient via an infusion into the vein after the transplanted stem cells have started to grow healthy blood cells. The modification of the stem cell transplant means that the healthy bone marrow cells will be "invisible" to the CAR T-cells that are trying to kill the leukemia cells.

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.

What data supports the effectiveness of the treatment Modified Stem Cell Transplant + CAR T Cells for Acute Myeloid Leukemia?

Research shows that CD33-targeted CAR T-cell therapy, like CART-33, has demonstrated strong anti-leukemia activity in preclinical studies, effectively killing leukemia cells and prolonging survival in animal models. This suggests potential effectiveness in treating acute myeloid leukemia. ^{1 2 3 4 5}

What safety data exists for CD33-targeted CAR T-cell therapy in humans?

CD33-targeted CAR T-cell therapy has shown some safety concerns, such as causing chills, fevers, and changes in blood cell levels in a patient with acute myeloid leukemia. Preclinical studies suggest that permanently expressed CD33-specific CAR T-cells could have unacceptable toxicity, but using a temporary version might avoid long-term issues. A gene-edited stem cell product, trem-cel, showed no adverse effects in preclinical studies, supporting its safety in early human trials. ^{1 2 3 6 7}

What makes the Modified Stem Cell Transplant + CAR T Cells treatment unique for acute myeloid leukemia?

This treatment is unique because it combines a modified stem cell transplant with CAR T-cell therapy targeting CD33, which is a protein found on most acute myeloid leukemia cells. By editing the CD33 gene in stem cells, the therapy aims to target leukemia cells while sparing healthy cells, potentially reducing side effects compared to other treatments. ^{1 2 3 5 8}

Research Team

Noelle Frey

Principal Investigator

University of Pennsylvania

Eligibility Criteria

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

Subjects must have a suitable stem cell donor

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

References

1. United States 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

5. Italy pubmed.ncbi.nlm.nih.gov

Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. [2021]

6. United States 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. [2023]

7. United States 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. [2021]

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

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