Anti-FLT3 CAR-T Cells for AML

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Hemogenyx Pharmaceuticals LLC

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Pregnancy, Active malignancy, Hepatitis, others

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

Compensation: Varies

Number of Visits: 14

Duration: 4 weeks

18 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are using certain immunosuppressant medications or high doses of systemic steroids.

What data supports the effectiveness of the Anti-FLT3 CAR-T cell treatment for AML?

Research shows that Anti-FLT3 CAR-T cells can effectively target and kill AML cells with a specific mutation (FLT3-ITD), especially when used with another drug called crenolanib. This combination enhances the ability of the CAR-T cells to recognize and attack the cancer cells, suggesting a promising approach for treating this type of leukemia. ^{1 2 3 4 5}

Is Anti-FLT3 CAR-T cell therapy safe for humans?

The safety of Anti-FLT3 CAR-T cell therapy is still being studied. Early research in animals shows it can target leukemia cells but may also affect some normal bone marrow cells, which could lead to side effects. More clinical trials are needed to fully understand its safety in humans. ^{3 5 6 7 8}

How is the Anti-FLT3 CAR-T cell treatment different from other treatments for AML?

The Anti-FLT3 CAR-T cell treatment is unique because it uses genetically engineered T-cells to specifically target and kill AML cells with the FLT3 mutation, offering a novel approach compared to traditional chemotherapy. This treatment can be combined with FLT3 inhibitors like crenolanib to enhance its effectiveness, and it includes an 'off-switch' to help manage potential side effects, such as myelotoxicity (damage to bone marrow). ^{2 3 4 7 9}

What is the purpose of this trial?

This is a phase 1 dose escalation study to determine the safety of anti-FLT3 CAR-T in subjects with R/R AML. The primary objective is to assess safety. Up to 18 evaluable subjects will be enrolled. Evaluable subjects are defined as those who have received an infusion of HG-CT-1. Primary clinical objectives: i. Determine the safety of HG-CT-1 based on the proportion of subjects infused with HG-CT-1 who experience a dose limiting toxicity (DLT). Secondary clinical objectives: i. Estimate the efficacy of HG-CT-1 according to standard clinical response criteria for AML. ii. Estimate overall survival of evaluable subjects. iii. Estimate progression-free survival of evaluable subjects. iv. Estimate duration of response in evaluable subjects who achieve a response. Secondary scientific objectives: i. Describe the persistence and trafficking of HG-CT-1. ii. Describe HG-CT-1 bioactivity and its predictors.

Eligibility Criteria

This trial is for individuals with relapsed or refractory Acute Myeloid Leukemia (AML), including childhood cancer and granulocytic leukemia. Participants must have previously received treatments that are no longer effective.

Inclusion Criteria

Subjects must have a suitable stem cell transplant donor

I had a transplant, am not on immunosuppressants for 1 month, and have no GvHD needing them.

I am fully active or can carry out light work.

Exclusion Criteria

I had a stem cell transplant from a donor under specific conditions.

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

Known history of allergy or hypersensitivity to study product excipients

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an infusion of HG-CT-1 CAR-T cells, with dose escalation to determine safety

4 weeks

Multiple visits for infusion and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of dose-limiting toxicities and clinical response

12 months

Regular visits at Day 14, Day 28, Month 3, Month 6, and Month 12

Treatment Details

Interventions

• Anti-FLT3 CAR-T cells

Trial Overview The study tests a new therapy called Anti-FLT3 CAR-T cells, aiming to determine its safety at different doses in up to 18 subjects who will receive an infusion of HG-CT-1, the study drug.

Participant Groups

Group I: Dose level 3: 3.5x10^8 Transduced CAR+ HG-CT-1 Experimental Treatment 1 Intervention

Group II: Dose level 2: 1.4x10^8 Transduced CAR+ HG-CT-1 Experimental Treatment 1 Intervention

Group III: Dose level 1: 7x10^7 Transduced CAR+ HG-CT-1 Experimental Treatment 1 Intervention

Group IV: Dose level -1: 3.5 x 10^7 Transduced CAR+ HG-CT-1 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Hemogenyx Pharmaceuticals LLC

Lead Sponsor

Trials

1

Recruited

20+

MD Anderson Cancer Center University of Texas

Collaborator

Trials

1

Recruited

20+

Findings from Research

FLT3 is a key receptor involved in the survival and proliferation of blood cells, and its mutations are linked to poor outcomes in acute myeloid leukemia (AML), making it a critical target for treatment.

Several small molecule tyrosine kinase inhibitors (TKIs) targeting FLT3 have shown promise in early clinical trials, particularly when combined with traditional chemotherapy, indicating a potential strategy for improving responses in patients with FLT3-mutant AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting FLT3 for the treatment of leukemia. Small, D.[2021]

The study developed a chimeric antigen receptor (CAR) targeting the Flt3 tyrosine kinase, which is associated with poor outcomes in acute myeloid leukemia (AML), demonstrating specific killing of Flt3-positive cancer cells without harming Flt3-negative cells.

Flt3-CAR T cells showed strong antitumor effects in vitro and low off-target cytotoxicity, suggesting a promising new approach for treating relapsed/refractory AML with potentially fewer side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines. Maiorova, V., Mollaev, MD., Vikhreva, P., et al.[2021]

Engineered T-cells targeting FLT3 show strong effectiveness against acute myeloid leukemia (AML) cells, including those with the FLT3-ITD mutation, indicating a promising new treatment approach for high-risk AML patients.

Combining FLT3-CAR T-cell therapy with the FLT3-inhibitor crenolanib enhances the recognition and destruction of AML cells, suggesting a synergistic effect that could improve treatment outcomes, although caution is needed due to potential damage to normal hematopoietic stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Jetani, H., Garcia-Cadenas, I., Nerreter, T., et al.[2019]

Dual-target FLT3scFv/NKG2D-CAR T cells effectively kill acute myeloid leukaemia (AML) cells in both laboratory tests and in a mouse model, showing promise as a treatment option.

The FLT3 inhibitor gilteritinib enhances the effectiveness of these CAR T cells by increasing the expression of NKG2D ligands on AML cells through the NF-κB2 signaling pathway, suggesting a synergistic approach to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib. Li, KX., Wu, HY., Pan, WY., et al.[2022]

Anti-FLT3 CAR T-cell therapies are being developed as a promising treatment for acute myeloid leukemia (AML), especially for patients with limited options after relapse, showing effectiveness in both laboratory and animal studies.

While these therapies demonstrate potential efficacy, their safety profiles require further investigation, and initial clinical trials have begun to assess their effectiveness in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in the Development of Anti-FLT3 CAR T-Cell Therapies for Treatment of AML. Pedersen, MG., Møller, BK., Bak, RO.[2022]

FLT3L CAR-T cells specifically target and kill FLT3+ leukemia cells, including those with the FLT3-ITD mutation, showing strong potential for treating acute myeloid leukemia (AML).

In mouse models, FLT3L CAR-T therapy significantly prolonged survival without harming normal hematopoietic stem cells, indicating a promising safety profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells. Wang, Y., Xu, Y., Li, S., et al.[2019]

The study presents a promising off-the-shelf CAR T cell therapy targeting FLT3 for treating acute myeloid leukemia (AML), showing effective elimination of AML cells in preclinical models.

While the therapy demonstrated strong efficacy, it also posed a risk of myelotoxicity by affecting healthy hematopoietic stem cells; however, a rituximab-responsive off-switch was developed to allow for safe depletion of CAR T cells after treatment, enabling bone marrow recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic FLT3 CAR T Cells with an Off-Switch Exhibit Potent Activity against AML and Can Be Depleted to Expedite Bone Marrow Recovery. Sommer, C., Cheng, HY., Nguyen, D., et al.[2021]

AMG 553, a CAR T-cell therapy targeting FLT3, shows promise in selectively targeting acute myeloid leukemia (AML) cells while demonstrating limited toxicity to healthy cells, based on studies in cynomolgus monkeys.

Nonclinical safety assessments indicate that while AMG 553 effectively targets FLT3-positive AML cells, it may also affect some normal hematopoietic stem and progenitor cells, suggesting a need for careful monitoring in clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia. Karbowski, C., Goldstein, R., Frank, B., et al.[2021]

Monovalent FLT3-targeted CAR T cells (FLT3CART) and bispecific CD19xFLT3CART show strong anti-leukemia activity in preclinical models of FLT3-mutant acute myeloid leukemia (AML) and KMT2A-rearranged acute lymphoblastic leukemia (ALL), indicating their potential as effective treatments.

These CAR T-cell therapies demonstrated minimal cross-reactivity with normal tissues and significant in vivo inhibition of leukemia proliferation, suggesting a promising safety profile and efficacy for further clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent preclinical activity of FLT3-directed chimeric antigen receptor T-cell immunotherapy against FLT3- mutant acute myeloid leukemia and KMT2A-rearranged acute lymphoblastic leukemia. Niswander, LM., Graff, ZT., Chien, CD., et al.[2023]

References

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

Targeting FLT3 for the treatment of leukemia. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Natural Flt3Lg-Based Chimeric Antigen Receptor (Flt3-CAR) T Cells Successfully Target Flt3 on AML Cell Lines. [2021]

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

CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. [2019]

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

A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Recent Advances in the Development of Anti-FLT3 CAR T-Cell Therapies for Treatment of AML. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells. [2019]

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

Allogeneic FLT3 CAR T Cells with an Off-Switch Exhibit Potent Activity against AML and Can Be Depleted to Expedite Bone Marrow Recovery. [2021]

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

Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia. [2021]

9. Italy pubmed.ncbi.nlm.nih.gov

Potent preclinical activity of FLT3-directed chimeric antigen receptor T-cell immunotherapy against FLT3- mutant acute myeloid leukemia and KMT2A-rearranged acute lymphoblastic leukemia. [2023]