Allodepleted T Cells for Leukemia

(CASPALLO 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: Pregnancy, GvHD, Severe infection, others

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

Compensation: Varies

Number of Visits: Unknown

10 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients are being asked to participate in this study because they will be receiving a stem cell transplant as treatment for their disease. As part of the stem cell transplant, they will be given very strong doses of chemotherapy, which will kill off all their existing stem cells. Stem cells are created in the bone marrow. They grow into different types of blood cells that we need, including red blood cells, white blood cells, and platelets. We have identified a close relative of the patients whose stem cells are not a perfect match for the patient, but can be used. This type of transplant is called "allogeneic", meaning that the cells come from a donor. With this type of donor who is not a perfect match, there is typically an increased risk of developing graft-versus-host disease (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 recognize that the body tissues of the patient are different from those of the donor. In the laboratory, we have seen that cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. To get the iCasp9 into the T cells, we insert it using a virus called a retrovirus that has been made for this study. 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. We hope we can use this drug to kill the T cells. Other drugs that kill or damage T cells have helped GvHD in many studies. However we do not yet know whether AP1903 will kill T cells in humans, even though it has worked in our experimental studies on human cells in animals. Nor do we know whether killing the T cells will help the GvHD. Because of this uncertainty, patients who develop significant GvHD will also receive standard therapy for this complication, in addition to the experimental drug. We hope that having this safety switch in the T cells will let us give higher doses of T cells that will make the immune system recover faster. These specially treated "suicide gene" T cells are an investigational product not approved by the Food and Drug Administration.

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 treatment Allodepleted T Cells Transduced With Inducible Caspase 9 Suicide Gene for leukemia?

Research shows that T cells engineered with specific receptors and safety switches, like the inducible caspase 9 suicide gene, have been effective in targeting leukemia cells while minimizing harmful side effects. This approach has demonstrated significant anti-leukemia activity and the ability to control potential toxicities, making it a promising treatment option. ^{1 2 3 4 5}

Is the use of allodepleted T cells with an inducible caspase 9 suicide gene safe for humans?

The use of allodepleted T cells with an inducible caspase 9 suicide gene has been shown to be generally safe in humans. This safety feature allows for the elimination of the modified T cells if needed, reducing the risk of adverse effects. Studies have demonstrated that this system can effectively remove transduced T cells without affecting other cells, making it a promising safety measure in T-cell therapies. ^{4 5 6 7 8}

How is the treatment with Allodepleted T Cells Transduced With Inducible Caspase 9 Suicide Gene different from other leukemia treatments?

This treatment is unique because it uses specially modified T cells that can be controlled to self-destruct if they cause harmful side effects, like graft-versus-host disease (a condition where donor cells attack the recipient's body). This approach aims to harness the cancer-fighting ability of donor T cells while minimizing risks, which is different from traditional treatments that don't have this built-in safety mechanism. ^{1 2 3 9 10}

Research Team

Malcolm K Brenner, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for patients with certain blood disorders like leukemia, who are getting a stem cell transplant and have no perfect match donor. They should not be pregnant, must have a life expectancy over 30 days, stable liver and kidney function, good oxygen levels without assistance, and an ability to consent. It's not for those with severe infections or recent other investigational drug use.

Inclusion Criteria

I don't have a closely matched donor or my disease is worsening too quickly.

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

Engrafted with ANC greater than 500

Exclusion Criteria

I have graft-versus-host disease.

You have taken any experimental drugs within the last 30 days.

I do not have a severe ongoing infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Treatment

High-dose chemotherapy to prepare the body for transplantation

Varies

Stem Cell Transplantation

Patients receive haploidentical stem cell transplantation

1 day

T Cell Infusion

Specially selected and treated T cells are infused between Day 30 and Day 90 post-transplant

60 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring for GvHD and the effects of AP1903

1 year

Long-term Follow-up

Participants are followed for long-term side effects of the gene transfer

15 years

Treatment Details

Interventions

• Allodepleted T Cells Transduced With Inducible Caspase 9 Suicide Gene

Trial Overview The study tests allodepleted T cells modified with the iCasp9 'suicide gene' in patients receiving non-matched stem cell transplants. If GvHD occurs—a common serious side effect—the modified T cells can be targeted and killed using the experimental drug AP1903 to prevent harm.

Participant Groups

Group I: Dose Level 1-3 Experimental Treatment 1 Intervention

Administration of suicide gene-modified allodepleted T cells.

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

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]

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]

Engineered natural killer T cells (NKT) expressing a functional T-cell receptor (TCR) demonstrated effective antitumor activity in mouse models without causing graft-versus-host disease, suggesting a safer alternative for adoptive T-cell therapy.

The study revealed that the engineered TCR can displace the invariant TCR (iTCR) in NKT cells, allowing for effective targeting of cancer cells while minimizing the risk of autoreactivity, making these cells promising candidates for 'off-the-shelf' immunotherapy products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A High-Avidity T-cell Receptor Redirects Natural Killer T-cell Specificity and Outcompetes the Endogenous Invariant T-cell Receptor. Landoni, E., Smith, CC., Fucá, G., et al.[2020]

References

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

CD28 costimulation and immunoaffinity-based selection efficiently generate primary gene-modified T cells for adoptive immunotherapy. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Inducible T-cell receptor expression in precursor T cells for leukemia control. [2018]

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

TCR Gene Therapy Improves AML Prognosis. [2020]

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

Multi-cistronic vector encoding optimized safety switch for adoptive therapy with T-cell receptor-modified T cells. [2013]

5. 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]

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

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

7. Australia pubmed.ncbi.nlm.nih.gov

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

8. 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]

9. England pubmed.ncbi.nlm.nih.gov

Human T cells engineered with a leukemia lipid-specific TCR enables donor-unrestricted recognition of CD1c-expressing leukemia. [2021]

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

A High-Avidity T-cell Receptor Redirects Natural Killer T-cell Specificity and Outcompetes the Endogenous Invariant T-cell Receptor. [2020]