iCaspase9-transduced T cells + AP1903 for Blood Cancers

(DOTTI Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to help the immune system recover faster after a stem cell transplant, particularly when there is a risk of developing GvHD, a condition where donor cells attack the body. Researchers use iCaspase9-transduced T cells, specially modified T cells that can be easily removed with a specific drug if they cause problems. This approach is designed for individuals with certain blood cancers or disorders who cannot find a perfect stem cell match from a donor. For those with blood cancers like leukemia that have returned or are not responding to treatment, this trial may be suitable. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that iCaspase9-transduced T cells are likely to be safe for humans?

Research has shown that iCaspase9-modified T cells include a built-in safety feature to help reduce risks. An earlier study found the use of the iCasp9 "suicide gene" promising for removing harmful T cells that might cause GvHD, a serious issue after a stem cell transplant, while retaining enough T cells to fight infections and possibly cancer. The drug AP1903, which activates this safety switch, was tested in healthy individuals and did not cause any adverse side effects.

This approach aims to make therapy safer for patients receiving a stem cell transplant from a donor who isn't a perfect match. Although this trial remains in the early stages, these initial findings suggest that the treatment is well-tolerated and could offer a safer option for patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about iCaspase9-transduced T cells for blood cancers because this treatment introduces a unique safety switch mechanism. Unlike traditional therapies, which might not offer a quick way to manage complications, this method allows doctors to control the activity of the T cells using a drug called AP1903. If patients develop complications like Graft-versus-Host Disease (GvHD), AP1903 can rapidly deactivate the T cells, potentially reducing side effects. This innovative approach not only targets cancer more precisely but also provides a significant safety advantage over current treatments.

What evidence suggests that iCaspase9-transduced T cells might be an effective treatment for blood cancers?

Research has shown that specially modified T cells, called iCaspase9-transduced T cells, can help manage GvHD, a complication in stem cell transplants. In earlier studies, these T cells were safely destroyed by a drug called AP1903, reducing GvHD without major side effects. This method retains enough T cells to support the immune system, aiding in the fight against infections and cancer. In this trial, participants will receive iCaspase9-transduced T cells, and AP1903 will be administered if Grade 1 or greater GvHD develops. Tests of AP1903 in healthy individuals found it to be safe with no serious side effects. This treatment aims to speed up immune recovery and includes a safety feature to manage any adverse reactions. ^{2 3 5 6 7}

Who Is on the Research Team?

Malcolm K Brenner, MB, PhD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

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

Life expectancy > 30 days

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. synapse.patsnap.com synapse.patsnap.com/drug/7a447fda66c4462b8df0a288237bddad

iCaspase9-transduced T cells(Baylor College of Medicine) Clinical Results associated with iCaspase9-transduced T cells(Baylor College of Medicine). Login to view more data. 100 Translational Medicine ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5318250/

Recent Advances in T-Cell Immunotherapy ... - PubMed Central (Sadelain 2015) Several groups have reported CR rates as high as 90% in ALL after administration of a single dose of CD19-CAR T-cells following lymphodepleting ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1106152

Inducible Apoptosis as a Safety Switch for Adoptive Cell ... We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT00710892?cond=Suicide%20gene&viewType=Table&rank=8

Allodepleted T Cells Transduced With Inducible Caspase 9 ... The drug (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.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01494103?term=gene%20therapy&cond=%22Familial%20Hemophagocytic%20Lymphohistiocytosis%22&viewType=Table&rank=2

Administration of Donor T Cells With the Caspase-9 ... 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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9226391/

CAR-T Cell Therapy in Hematological Malignancies Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0301472X16305136

Improving the safety of T-Cell therapies using an inducible ... The inducible caspase-9 safety switch is designed to increase the safety of immunotherapy. It is based on the fusion of human proteins and non-immunogenicity.