Engineered T Cells + Chemotherapy for Myeloid Leukemia

Overseen By Jeremy Ramdial, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Systemic steroids, Immunosuppressants

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

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4-6 weeks

44 Participants Needed

Trial Summary

What is the purpose of this trial?

To find a recommended dose of PRAME-TCR-NK cells that can be given to patients with AML or MDS.

Will I have to stop taking my current medications?

The trial requires that participants stop taking certain medications before starting the study. You must be at least three weeks from your last cytotoxic chemotherapy, but you can continue taking Hydroxyurea until the day before starting lymphodepleting chemotherapy. Tyrosine kinase inhibitors or other targeted therapies can be continued until three days before starting lymphodepleting chemotherapy.

What data supports the effectiveness of the treatment Engineered T Cells + Chemotherapy for Myeloid Leukemia?

Research shows that engineered natural killer (NK) cells, which are part of the immune system, can be modified to better target and kill leukemia cells. These modified NK cells have been shown to improve survival in animal models of acute myeloid leukemia (AML) and have demonstrated enhanced anti-leukemia activity in both laboratory and patient-derived models. ^{1 2 3 4 5}

Is the treatment with engineered T cells and chemotherapy for myeloid leukemia safe?

Studies have shown that engineered natural killer (NK) cells, which are similar to T cells, have a favorable safety profile in treating acute myeloid leukemia (AML). In trials, these NK cells did not cause significant adverse effects, and no dose-limiting toxicities or severe side effects were observed with CAR T cells targeting NKG2D ligands in AML patients. ^{1 5 6 7 8}

What makes the PRAME-TCR-NK cell treatment unique for myeloid leukemia?

The PRAME-TCR-NK cell treatment is unique because it combines engineered T cells with natural killer (NK) cells that are designed to target specific leukemia antigens, potentially improving the immune system's ability to fight the cancer. This approach is novel compared to traditional chemotherapy or other immunotherapies, as it specifically targets leukemia cells while minimizing damage to healthy cells. ^{1 9 10 11 12}

Research Team

Jeremy Ramdial, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for patients with relapsed or refractory myeloid malignancies, such as AML (acute myeloid leukemia) or MDS (myelodysplastic syndromes), who have not responded to standard treatments. Participants must be able to receive lymphodepleting chemotherapy.

Inclusion Criteria

I can do most of my daily activities by myself.

It has been at least 3 weeks since my last strong chemotherapy before starting the next treatment.

Life Expectancy >=3 months

Exclusion Criteria

I am currently on steroids or have recently had immunosuppressive therapy.

I have not had an active autoimmune disease in the last year.

I have an active neurological disorder.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy prior to NK cell infusion

1-2 weeks

Treatment

Participants receive TCR-NK cell infusion at assigned dose level

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Cyclophosphamide
• Decitabine
• Fludarabine phosphate
• PRAME-TCR-NK cells

Trial Overview The study is testing a new therapy that uses engineered T cell receptor-modified NK cells targeting PRAME, combined with lymphodepleting chemotherapy drugs: Cyclophosphamide, Fludarabine phosphate, and Decitabine.

Participant Groups

Group I: Phase 1 (Dose Escalation and Dose Expansion) Experimental Treatment 4 Interventions

Participants will be assigned to a dose level of the NK cell treatment based on when you join this study. Up to 4 dose levels of the treatment will be tested. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of the NK cell treatment is found.

PRAME-TCR-NK cells is already approved in United States for the following indications:

Approved in United States as PRAME TCR/IL-15 NK for:

• Acute Myeloid Leukemia (AML)
• Myelodysplastic Syndromes (MDS)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

Engineered allogeneic NK cells targeting the FLT3 antigen showed enhanced effectiveness against acute myeloid leukemia (AML) cells, demonstrating higher cytotoxicity and interferon gamma secretion compared to standard NK cells.

These FLT3 CAR_sIL-15 NK cells not only prolonged survival in AML models but also exhibited no harmful effects on healthy blood cells, suggesting a promising and safe treatment option for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-the-shelf CAR-engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia. Mansour, AG., Teng, KY., Li, Z., et al.[2023]

Engineering NK-92 cells with a third-generation CAR targeting the CD123 receptor significantly enhances their ability to kill acute myeloid leukemia (AML) cells, as demonstrated in both in vitro and in vivo models.

The inclusion of IL-15 in the CAR design improves the persistence of these modified NK-92 cells in the body, suggesting that this approach could lead to more effective treatments for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123. Morgan, MA., Kloos, A., Lenz, D., et al.[2021]

Engineering NK cells to express CD123-specific chimeric antigen receptors (CARs) and interleukin-15 (IL-15) significantly enhances their anti-AML activity and persistence, particularly with the 2B4.ζ CAR, which showed improved efficacy in vitro and in vivo.

While the 2B4.ζ/sIL-15 CAR-NK cells demonstrated potent anti-AML effects, they also caused lethal toxicity in some models, highlighting the need for careful management of cytokine expression in future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. Christodoulou, I., Ho, WJ., Marple, A., et al.[2022]

The study successfully developed CAR-NK cells targeting NKG2D ligands using a non-viral piggyBac transposon technology, showing effective cancer cell lysis in vitro and tumor growth inhibition in an in vivo AML model.

Co-expressing interleukin-15 (IL-15) with the NKG2D CAR significantly enhanced the persistence and antileukemic activity of the CAR-NK cells, leading to improved tumor control and extended survival in treated mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells. Du, Z., Ng, YY., Zha, S., et al.[2021]

In a phase 1 trial involving 9 pediatric and young adult patients with relapsed acute myeloid leukemia (AML) after hematopoietic cell transplantation, donor-derived memory-like natural killer (ML NK) cells showed significant antileukemic activity, leading to complete remission in 4 out of 8 evaluable patients by day 28.

The ML NK cells expanded and persisted for over 3 months without significant toxicity, suggesting that this approach, combined with donor lymphocyte infusions, could be a promising new immunotherapy for relapsed AML in a post-transplant setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. Bednarski, JJ., Zimmerman, C., Berrien-Elliott, MM., et al.[2023]

In a study testing CD33-CAR NK cells in patients with relapsed and refractory acute myeloid leukemia (AML), no significant adverse effects were observed at doses up to 5 billion cells per patient, suggesting a favorable safety profile.

CAR NK-92 cells can be produced at a lower cost than CAR T cells, indicating that with further optimization, they could become a more accessible treatment option for cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Tang, X., Yang, L., Li, Z., et al.[2021]

The study involved 7 pediatric patients with acute myeloid leukemia (AML) who received activated and expanded natural killer (NK) cells as a treatment after chemotherapy, showing that this approach is safe and feasible.

After a median follow-up of 33 months, 85.7% of patients remained in complete remission, and the 3-year overall survival rate was 83.3%, although the small sample size limits definitive conclusions about efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Clinical Trial of Infusing Haploidentical K562-mb15-41BBL-Activated and Expanded Natural Killer Cells as Consolidation Therapy for Pediatric Acute Myeloblastic Leukemia. Gómez García, LM., Escudero, A., Mestre, C., et al.[2022]

The phase I study involving 12 subjects with acute myeloid leukemia or relapsed/refractory multiple myeloma demonstrated that NKG2D-CAR T cells were safe, with no dose-limiting toxicities or significant adverse events observed, indicating a favorable safety profile for this treatment approach.

While no objective tumor responses were achieved, there were transient improvements in hematologic parameters in one AML patient, suggesting potential for disease stability, but further modifications to enhance CAR T-cell expansion and effectiveness may be necessary for better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. Baumeister, SH., Murad, J., Werner, L., et al.[2021]

In a small trial, T cells modified to target the Wilms tumor antigen 1 were effective in preventing relapse in patients with acute myeloid leukemia after they underwent an allogeneic stem-cell transplant.

This approach highlights the potential of engineered T cell therapies in enhancing post-transplant outcomes for leukemia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR Gene Therapy Improves AML Prognosis. [2020]

The article discusses a clinical trial for a new adoptive immunotherapy using gene-modified T cells that target the Wilms Tumor 1 (WT1) antigen, showing promise for treating refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

While this innovative approach has demonstrated clear and lasting clinical efficacy against tumors, it also poses risks of serious treatment-related adverse events, highlighting the need for careful management in developing powerful gene-modified T cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy utilizing cancer antigen-specific T-cell receptors. Tanimoto, K., Fujiwara, H.[2017]

A new modular T cell therapy platform has been developed that targets acute myeloid leukemia (AML) by using synthetic agonistic receptor (SAR) T cells combined with AML-specific antibody fragments, allowing for selective targeting of cancer cells.

This approach demonstrated effective killing of AML cells in laboratory models and showed durable responses in xenograft models, suggesting it could be a promising treatment option for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A modular and controllable T cell therapy platform for acute myeloid leukemia. Benmebarek, MR., Cadilha, BL., Herrmann, M., et al.[2023]

CAR-T cells from patients with Acute Myeloid Leukemia (AML) show a more exhausted phenotype compared to those from healthy donors, which may limit their effectiveness in treating the disease.

The study developed a new CAR-T cell product using CRISPR and transposon technologies to create HLA-IKO/TCRKO CAR-T cells, which demonstrated similar efficacy to non-edited CAR-T cells and a safe integration profile, making them a promising option for allogeneic AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of universal allogeneic CAR-T cells combining CRISPR and transposon-based technologies for treatment of acute myeloid leukemia. Calviño, C., Ceballos, C., Alfonso, A., et al.[2023]

References

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

Off-the-shelf CAR-engineered natural killer cells targeting FLT3 enhance killing of acute myeloid leukemia. [2023]

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

Improved Activity against Acute Myeloid Leukemia with Chimeric Antigen Receptor (CAR)-NK-92 Cells Designed to Target CD123. [2021]

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

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. [2022]

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

piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells. [2021]

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

Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. [2023]

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

First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. [2021]

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

Phase 2 Clinical Trial of Infusing Haploidentical K562-mb15-41BBL-Activated and Expanded Natural Killer Cells as Consolidation Therapy for Pediatric Acute Myeloblastic Leukemia. [2022]

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

Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma. [2021]

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

TCR Gene Therapy Improves AML Prognosis. [2020]

10. Japan pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy utilizing cancer antigen-specific T-cell receptors. [2017]

11. England pubmed.ncbi.nlm.nih.gov

A modular and controllable T cell therapy platform for acute myeloid leukemia. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Optimization of universal allogeneic CAR-T cells combining CRISPR and transposon-based technologies for treatment of acute myeloid leukemia. [2023]