iCaspase9-transduced T cells + AP1903 for Blood Cancers

(DOTTI Trial)

Recruiting at 1 trial location

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Other investigational drugs

Disqualifiers: GvHD, Severe infection, Pregnancy, others

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

Compensation: Varies

Number of Visits: 5

15 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you cannot have taken other investigational drugs in the 30 days before the T cell infusion.

What data supports the effectiveness of the iCaspase9-transduced T cells treatment for blood cancers?

Research shows that iCaspase9-transduced T cells can be safely used in cancer treatments, as they allow for the removal of potentially harmful cells if needed. This safety feature has been successfully tested in other cancer types, showing promise for its use in blood cancers. ^{1 2 3 4 5}

Is iCaspase9-transduced T cell therapy safe for humans?

The iCaspase9 safety switch has been shown to effectively and safely eliminate T cells in clinical trials, reducing the risk of adverse effects in T-cell therapies for blood cancers. This system allows for the removal of potentially harmful T cells, making the treatment safer for patients. ^{2 3 4 6 7}

How does the iCaspase9-transduced T cells + AP1903 treatment differ from other treatments for blood cancers?

This treatment is unique because it includes a 'safety switch' using the inducible caspase 9 (iCasp9) gene, which allows for the selective removal of T cells if they become overactive and potentially harmful. This is achieved by administering a small molecule drug, AP1903, which triggers the death of these specific T cells, enhancing the safety of the therapy compared to traditional CAR T-cell treatments. ^{1 2 3 4 7}

What is the purpose of this trial?

Patients will be receiving a stem cell transplant as treatment for their disease. As part of the stem cell transplant, patients will be given very strong doses of chemotherapy, which will kill all their existing stem cells. A close relative of the patient will be identified, whose stem cells are not a perfect match for the patient's, but can be used. This type of transplant is called "allogeneic", meaning that the cells are from a donor. With this type of donor who is not a perfect match, there is typically an increased risk of developing GvHD, and a longer delay in the recovery of the immune system. GvHD is a serious and sometimes fatal side-effect of stem cell transplant. GvHD occurs when the new donor cells (graft) recognize that the body tissues of the patient (host) are different from those of the donor. In this study, investigators are trying to see whether they can make special T cells in the laboratory that can be given to the patient to help their immune system recover faster. As a safety measure, we want to "program" the T cells so that if, after they have been given to the patient, they start to cause GvHD, we can destroy them ("suicide gene"). Investigators will obtain T cells from a donor, culture them in the laboratory, and then introduce the "suicide gene" which makes the cells sensitive to a specific drug called AP1903. If the specially modified T cells begin to cause GvHD, the investigators can kill the cells by administering AP1903 to the patient. We have had encouraging results in a previous study regarding the effective elimination of T cells causing GvHD, while sparing a sufficient number of T cells to fight infection and potentially cancer. More specifically, T cells made to carry a gene called iCasp9 can be killed when they encounter the drug AP1903. To get the iCasp9 gene into T cells, we insert it using a virus called a retrovirus that has been made for this study. The AP1903 that will be used to "activate" the iCasp9 is an experimental drug that has been tested in a study in normal donors with no bad side-effects. We hope we can use this drug to kill the T cells. The major purpose of this study is to find a safe and effective dose of "iCasp9" T cells that can be given to patients who receive an allogeneic stem cell transplant. Another important purpose of this study is to find out whether these special T cells can help the patient's immune system recover faster after the transplant than they would have otherwise.

Research Team

Malcolm K Brenner, MB, PhD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for patients with certain blood disorders or immune system conditions like Non-Hodgkin's Lymphoma, Myelodysplastic Syndrome, and various forms of Leukemia. Participants must have a life expectancy over 30 days, stable organ function, and no severe infections. Pregnant individuals or those on other investigational drugs within the last 30 days cannot join.

Inclusion Criteria

My kidney function is normal, with creatinine levels not exceeding twice the upper limit.

Engrafted with an absolute neutrophil count > 500 cells/µL

My transplant shows at least 50% donor cells in blood or bone marrow, or my original disease has returned.

Exclusion Criteria

Other investigational drugs in the prior 30 days

Pregnancy*

Pregnancy test only required for at-risk individuals, defined as female patients of childbearing potential who have received a reduced-intensity conditioning regimen.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stem Cell Transplant

Patients receive a stem cell transplant as part of their treatment, involving high doses of chemotherapy

4-6 weeks

T Cell Infusion

Eligible patients receive iCasp9-modified T cells between Day 30 to 90 post-transplant

60 days

1 visit (in-person)

Follow-up

Participants are monitored weekly for side-effects and GvHD in the first month after T cell infusion

4 weeks

4 visits (in-person)

Long-term Follow-up

Participants are monitored for immune reconstitution and survival outcomes

Up to 15 years

Treatment Details

Interventions

• iCaspase9-transduced T cells

Trial Overview The study tests genetically modified T cells with a 'suicide gene' (iCasp9) in patients undergoing allogeneic stem cell transplants. If these T cells cause GvHD—a serious transplant complication—the drug AP1903 can be used to destroy them. The goal is to find a safe dose that helps immune recovery without causing harm.

Participant Groups

Group I: iCaspase9-transduced T cells Experimental Treatment 2 Interventions

The 5 dose levels are: 1. 1 x 10\^4 T cells/kg 2. 1 x 10\^5 T cells/kg 3. 5 x 10\^5 T cells/kg 4. 1 x 10\^6 T cells/kg 5. 5 x 10\^6 T cells/kg AP1903 will be administered if there is development of Grade 1 or greater GvHD.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Findings from Research

Adoptive T-cell therapy shows promise for treating various cancers and infections, but safety concerns remain due to potential on-target and off-target toxicities, which can sometimes be fatal.

The inducible caspase 9 (iCasp9) safety switch offers a solution by allowing for the rapid elimination of modified T cells if adverse effects occur, enhancing the safety of T-cell therapies, especially in cases like graft-versus-host disease in stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive T-cell therapy: adverse events and safety switches. Tey, SK.[2022]

The study explores the use of an inducible caspase 9 (iC9) suicide gene in CAR-T cells to enhance safety by allowing for the elimination of malignant CAR+ B cells, which can arise during treatment manufacturing.

In both in vitro and animal models, the activation of the iC9 suicide gene with the small molecule AP1903 effectively eliminated CAR+ leukemia and lymphoma cells, suggesting a promising strategy to mitigate adverse effects associated with CAR-T cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inclusion of the Inducible Caspase 9 Suicide Gene in CAR Construct Increases Safety of CAR.CD19 T Cell Therapy in B-Cell Malignancies. Guercio, M., Manni, S., Boffa, I., et al.[2022]

References

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

An inducible caspase 9 safety switch for T-cell therapy. [2023]

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

Phase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells. [2020]

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

Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The inducible caspase-9 suicide gene system as a "safety switch" to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. [2020]

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

Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation. [2020]

6. Australia pubmed.ncbi.nlm.nih.gov

Adoptive T-cell therapy: adverse events and safety switches. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Inclusion of the Inducible Caspase 9 Suicide Gene in CAR Construct Increases Safety of CAR.CD19 T Cell Therapy in B-Cell Malignancies. [2022]