CAR-T Therapy for Leukemia

Overseen By Kelly Hoye

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must not be taking: Corticosteroids, Investigational drugs

Disqualifiers: Pregnancy, Active HIV, HBV, HCV, 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: 8

Duration: 2-14 days

54 Participants Needed

Trial Summary

What is the purpose of this trial?

The body has different ways of fighting infection and disease. No single way is effective at fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to try to create a more effective treatment. This investigational treatment is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. In previous studies, it has been shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical structure carrying the genetic information that may determine human characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells makes a piece of an antibody called anti-CD19. This antibody can flow through the blood and can find and stick to leukemia cells because these leukemia cells have a substance on their surface called CD19. Anti-CD19 antibodies have been used to treat people with leukemia but have not been strong enough to cure most patients. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood a piece of it is now joined to the surface of the T cells. Only the part of the antibody that sticks to the leukemia cells is attached to the T cells instead of the entire antibody. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown. Preliminary results of giving ATLCAR.CD19 cells to leukemia patients have been encouraging; however, many subjects receiving this treatment have experienced unwanted side effects including neurotoxicity and/or cytokine release syndrome (also referred to as cytokine storm or an infusion reaction). Cytokines are small proteins that interreact as e signals to other cells and are the way cells talk to one another. During cytokine release syndrome, too many cytokines are released and too many cells in your body react to their release. Symptoms resulting from cytokine release syndrome vary from flu-like symptoms to more severe side effects such as cardiac arrest, multi-system organ failure or death. We predict that about 50% of patients on this study will experience mild to severe cytokine release syndrome. To help reduce cytokine release syndrome symptoms in future patients, a safety switch has been added to the ATLCAR.CD19 cells that can cause the cells to become dormant or "go to sleep". The safety switch is called inducible caspase 9 or iC9. The modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. The purpose of this study is to determine whether receiving the iC9-CAR19 cells is safe and tolerable (there are not too many unwanted effects). Researchers has previously tested different doses of the iC9-CAR19. An effective dose that had the least number of unwanted side effects in patients was identified. It was planned to test this dose in more patients to learn more about its effect in the body. This type of research study is called a dose expansion study. It will allow the investigators to collect more information about the effect of this dose in treating of certain type of cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but certain drugs must be stopped before lymphodepleting chemotherapy, such as tyrosine kinase inhibitors and some chemotherapy drugs. Maintenance doses of specific chemotherapy drugs are allowed, and corticosteroids are permitted only under certain conditions.

What data supports the effectiveness of the treatment iC9-CAR19 cells, iC9-CAR19 cells, ATLCAR.CD19 cells with inducible safety switch for leukemia?

Research shows that CAR-T cells targeting CD19 are effective in treating B-cell malignancies like leukemia, with some patients achieving long-term remission. The inclusion of the iC9 safety switch in these CAR-T cells helps manage side effects, making the treatment safer by allowing controlled elimination of the cells if needed. ^{1 2 3 4 5}

Is CAR-T therapy for leukemia safe for humans?

CAR-T therapy for leukemia has shown promising results, but it can have serious side effects like cytokine release syndrome (a severe immune reaction) and neurological issues. To improve safety, researchers have developed a 'safety switch' using a gene called inducible caspase 9 (iC9), which can help control or eliminate the CAR-T cells if severe side effects occur, making the treatment safer. ^{2 5 6 7 8}

What makes the iC9-CAR19 cell treatment unique for leukemia?

The iC9-CAR19 cell treatment is unique because it includes an inducible safety switch that allows doctors to control the therapy's activity, reducing the risk of severe side effects like cytokine release syndrome (CRS) while maintaining its effectiveness against leukemia. ^{2 4 7 9 10}

Research Team

Natalie S. Grover

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Eligibility Criteria

This trial is for people aged 3-70 with relapsed/refractory B cell ALL, who've had some prior treatment. They must have a certain level of health and organ function, agree to contraception methods if applicable, and not be pregnant or breastfeeding. Those with severe infections or other active cancers aren't eligible.

Inclusion Criteria

I am mostly independent in my daily activities.

Written informed consent for procurement signed by subject or legal guardian of a pediatric subject and HIPAA authorization

I have Ph+ ALL and have not responded to at least 2 treatments, had a relapse after a stem cell transplant, or have minimal residual disease.

Exclusion Criteria

I haven't had any cancer except for skin cancer in the last 5 years.

My tumor is not located where it could block my airway if it grows.

My aggressive leukemia is worsening with over half of my white blood cells being cancerous.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Procurement

Peripheral blood is collected for cell procurement, and leukapheresis may be performed if necessary.

1-2 weeks

Up to 3 visits (in-person)

Lymphodepleting Regimen

Subjects receive a lymphodepleting regimen of fludarabine and cyclophosphamide.

1 week

4 visits (in-person)

Treatment

Administration of iC9-CAR19 T cells post lymphodepletion.

2-14 days

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment.

4 weeks

Weekly visits (in-person)

Long-term Follow-up

Subjects are followed for up to 15 years for RCR evaluation or until death.

15 years

Treatment Details

Interventions

• iC9-CAR19 cells

Trial Overview The study tests autologous T cells modified with a CD19 antigen (iC9-CAR19 cells) to treat leukemia. It includes an 'off switch' to reduce side effects like cytokine release syndrome. The goal is to find the safest dose that works best against cancer.

Participant Groups

Group I: iC9-CAR19 cells Experimental Treatment 4 Interventions

The 3+3 design in adult subjects and an independent study using 3+3 design in pediatric subjects. The starting dose of 5 x 10\^5 transduced cells/kg will enroll 3 adult subjects in the initial cohort. If there are no dose limiting toxicities w/in 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x10\^6 transduced cells/kg in adults. If there is toxicity in 1/3 patients in the initial cohort, the cohort will be expanded to enroll up to 6 adult patients. If the dose level 1 is determined to be above the tolerated cell dose, de-escalation would occur to dose level -1 where subjects would receive 1 x 10\^5 transduced cells/kg. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before administration of iC9-CAR19 T cells.

Group II: Expansion Cohort Second Administration of iC9-CAR19 cells Experimental Treatment 4 Interventions

After the recommended phase 2 dose (RP2D) of iC9-CAR19 T cells has been determined in adults, up to 18 additional adult subjects will be enrolled in an expansion cohort at the RP2D. In the expansion cohort, subjects will be offered a second infusion of iC9-CAR19 T cells based on B-cell recovery and minimal residual disease (MRD) status. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before second administration of iC9-CAR19 T cells. Subjects in the expansion cohort who experience ≥grade 2 CRS or ICANS, did not respond to the initial dose of the standard of care treatment will be enrolled in a sub-study of rimiducid.

iC9-CAR19 cells is already approved in United States for the following indications:

Approved in United States as iC9-CAR19 cells for:

• Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Bellicum Pharmaceuticals

Industry Sponsor

Trials

28

Recruited

1,400+

Findings from Research

CAR T cell therapy, which modifies T cells to target the CD19 antigen on B cells, has shown significant clinical effectiveness in treating various B cell malignancies, including chronic lymphocytic leukemia and acute lymphoblastic leukemia, with some patients experiencing long-term remissions.

The FDA has recognized the potential of CD19-directed CAR T cells by granting 'breakthrough' designation for their use in treating relapsed or refractory acute lymphoblastic leukemia in both adults and children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-Targeted CAR T Cells: A New Tool in the Fight against B Cell Malignancies. Miller, BC., Maus, MV.[2023]

Immunotherapy using CD19.CAR-T cells is highly effective for treating B cell malignancies, but it can lead to serious side effects like B cell aplasia and cytokine release syndrome (CRS).

The study shows that an inducible caspase-9 (iC9) safety switch can selectively eliminate CD19.CAR-T cells in a controlled manner, allowing for management of CRS while preserving antitumor activity and enabling normal B cell recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inducible Caspase-9 Selectively Modulates the Toxicities of CD19-Specific Chimeric Antigen Receptor-Modified T Cells. Diaconu, I., Ballard, B., Zhang, M., et al.[2019]

The study developed a novel CAR T-cell therapy targeting CD33 in acute myeloid leukemia (AML) that incorporates an inducible Caspase9 (iC9) suicide gene system, allowing for controlled elimination of T-cells to manage adverse effects like myelosuppression.

In preclinical models, these iC9 CAR T-cells effectively controlled leukemia growth and could be partially eliminated by 76% using a chemical inducer, suggesting a promising approach to enhance safety while maintaining therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of Suicide Gene-Modified Chimeric Antigen Receptor-Redirected T-Cells for Cancer Immunotherapy. Minagawa, K., Al-Obaidi, M., Di Stasi, A.[2019]

In a study of 59 children receiving CAR-T therapy for B-cell acute lymphoblastic leukemia, 40.7% required admission to the Pediatric Intensive Care Unit (PICU), primarily due to cytokine release syndrome (CRS), indicating that while CAR-T is effective, it can lead to serious side effects that need intensive monitoring.

Despite the high rate of PICU admissions and associated complications, including severe neurotoxicity in some patients, supportive treatments like tocilizumab were effective in managing these toxicities, resulting in a high survival rate among the patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk factors and outcome of Chimeric Antigen Receptor T-Cell patients admitted to Pediatric Intensive Care Unit: CART-PICU study. Caballero-Bellón, M., Alonso-Saladrigues, A., Bobillo-Perez, S., et al.[2023]

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]

The study found that high levels of leukemia blast contamination in the starting material did not negatively impact the manufacturing of CAR T-cells or their ability to expand, suggesting that CAR T-cell therapy can be safely produced even from contaminated samples.

Using a specific CAR design with a short linker (CAR.CD19 SL) enhances the ability of CAR T-cells to target and kill CD19+ leukemia cells, providing a potential safety advantage in preventing leukemic relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts. Quintarelli, C., Guercio, M., Manni, S., et al.[2022]

CAR-T cell therapy has shown great promise in treating hematological cancers, with two Anti-CD19 CAR-T therapies already approved for CD19-positive leukemia and lymphoma.

However, the therapy can cause serious side effects like cytokine release syndrome and on-target off-tumor toxicity, leading to some patients discontinuing treatment; researchers are exploring various safety strategies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Yu, S., Yi, M., Qin, S., et al.[2020]

In a study of 27 pediatric patients receiving CD19 CAR-T therapy for relapsed or refractory B-cell acute lymphoblastic leukemia, only 22% experienced infections in the first 100 days, indicating a lower infection rate than previously reported.

The most common infections were bacterial bloodstream infections, but importantly, there were no infection-related deaths, suggesting that the antimicrobial prophylaxis used was effective in managing infection risks in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infections in children following chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia. Diamond, Y., Gilsenan, M., Wang, SS., et al.[2023]

CAR T cell therapy targeting CD19 has shown remarkable efficacy, achieving complete remission in up to 90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), compared to a 30% response rate with traditional chemotherapy.

The therapy involves genetically modifying T cells to express a chimeric antigen receptor, allowing them to effectively target and eliminate cancer cells, although it is important to note that there are unique toxicities associated with this treatment that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Davila, ML., Brentjens, RJ.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

CD19-Targeted CAR T Cells: A New Tool in the Fight against B Cell Malignancies. [2023]

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

Inducible Caspase-9 Selectively Modulates the Toxicities of CD19-Specific Chimeric Antigen Receptor-Modified T Cells. [2019]

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

Generation of Suicide Gene-Modified Chimeric Antigen Receptor-Redirected T-Cells for Cancer Immunotherapy. [2019]

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

Risk factors and outcome of Chimeric Antigen Receptor T-Cell patients admitted to Pediatric Intensive Care Unit: CART-PICU study. [2023]

5. 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]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. [2020]

9. Denmark pubmed.ncbi.nlm.nih.gov

Infections in children following chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia. [2023]

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

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. [2023]