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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of a new cancer treatment called PRAME-TCR-NK cells for individuals with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Researchers are testing various doses to identify the most effective one that minimizes severe side effects. This trial suits individuals with AML or MDS who have undergone certain treatments and are not in full remission. Participants should possess specific genetic markers and be capable of managing daily activities. As a Phase 1 trial, this research seeks to understand how the treatment functions in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

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

Research shows that the FDA has approved PRAME-TCR-NK cells for clinical trials, indicating they have passed initial safety checks for testing in people. Other studies found that these cells release small amounts of IL-15, a protein that supports their growth without additional help from the body. This suggests they might function more controllably, potentially reducing the risk of serious side effects. However, this trial remains in the early stages. The goal is to determine the safest and most effective dose, so some side effects might still occur as testing continues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for myeloid leukemia, which often involve chemotherapy and stem cell transplants, the PRAME-TCR-NK cell therapy introduces a cutting-edge approach by leveraging engineered T cells. This treatment targets the PRAME antigen, a protein commonly expressed in cancer cells but not in most normal tissues, allowing for a more precise attack on the leukemia cells while sparing healthy ones. Researchers are excited because this method not only enhances the body's natural immune response but also aims to significantly reduce the side effects associated with traditional treatments. By potentially offering a more targeted and less toxic therapy, this approach represents a promising shift in leukemia treatment strategies.

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

Research has shown that PRAME-TCR-NK cells, which participants in this trial may receive, are designed to target a protein called PRAME, often found in high amounts in leukemia cells. This protein aids cancer cell survival and growth. By focusing on PRAME, these specially engineered cells can potentially attack and kill cancer cells in acute myeloid leukemia (AML) without harming normal cells. Early studies suggested that these cells might find and destroy cancer cells more effectively than traditional treatments. While research continues, the specific targeting of PRAME makes this approach promising for treating AML. ^{1 2 3 6 7}

Who Is on the Research Team?

Jeremy Ramdial, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

Citations

1. targetedonc.com targetedonc.com/view/fda-clears-ind-of-prame-tcr-il-15-nk-program-for-r-r-myeloid-malignancies

FDA Clears IND of PRAME TCR-IL-15 NK Program for R ... A phase 1/2 open-label study will assess PRAME TCR/IL-15 NK in patients with relapsed/refractory acute myeloid leukemia (AML) and ...

2. mdanderson.org mdanderson.org/newsroom/novel-PRAME-targeted-TCR-NK-cell-therapy-receives-FDA-IND-clearance-hematologic-cancers.h00-159696756.html

Novel PRAME-targeted TCR NK cell therapy receives FDA ... The Phase I/II open-label study will assess the safety, tolerability and preliminary efficacy of PRAME TCR/IL-15 NK (SY-307) in patients with ...

3. ecancer.org ecancer.org/en/news/24666-fda-clearance-announced-for-ind-application-for-first-in-class-prame-targeted-tcr-nk-cell-therapy-for-haematological-malignancies

FDA clearance announced for IND application for first-in- ... The Phase I/II open-label study will assess the safety, tolerability and preliminary efficacy of PRAME TCR/IL-15 NK (SY-307) in patients with ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11002138/

Targeting PRAME for acute myeloid leukemia therapy This paper reviews the structure and function of PRAME, its effects on normal cells and AML blasts, its implications in prognosis and follow-up,

5. synapse.patsnap.com synapse.patsnap.com/article/replay-secures-ind-approval-for-prame-t-cell-therapy

Replay Secures IND Approval for PRAME T Cell Therapy The trial, a Phase I/II study, will explore the efficacy of T cell receptor natural killer (TCR-NK) cell therapy in patients suffering from ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11058644/

Self-sufficient primary natural killer cells engineered to ... This study showed that NK:TCR/IL-15 cells secrete low levels of IL-15 and can proliferate in an environment lacking cytokines.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06660420

Phase 1 Dose Escalation and Expansion Study of PRAME ... To find the highest tolerable dose and recommended dose of PRAME-TCR-NK cells that can be given to participants with recurrent and/or refractory melanoma.