Genetically Modified T-cell Therapy for Leukemia

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: HIV, Active hepatitis, Other malignancy, others

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

Compensation: Varies

Number of Visits: 24

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment using modified T-cells, a type of immune cell, to combat leukemia, a cancer of the blood. The goal is to determine the optimal dose and assess side effects of these modified cells, which are designed to target and destroy cancer cells. The trial targets individuals with acute myeloid leukemia (AML) or a rare blood cancer called blastic plasmacytoid dendritic cell neoplasm (BPDCN) that hasn't improved with other treatments. It may suit those whose cancer has returned or isn't responding to treatment and who meet specific medical criteria, such as having CD123 positive cancer cells, indicating a marker that the T-cells can target. As a Phase 1 trial, this research aims to understand how the treatment works 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?

Participants must stop taking all anti-leukemic drugs at least 7 days before the CAR T cell infusion, except for the lymphodepleting regimens. If you are on corticosteroids, you must reduce them to no more than physiological replacement doses before starting lymphodepletion.

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

Research has shown that genetically modified T-cells, like those used in this trial, have been extensively studied for safety in treating certain blood cancers. These treatments modify a patient's or donor's immune cells to help fight cancer. This approach has achieved some success in managing relapsed or hard-to-treat acute myeloid leukemia.

Earlier studies found that these T-cell therapies were generally well-tolerated. Common side effects included fever, low blood pressure, and tiredness, which are often manageable with medical care. More serious side effects, such as a strong immune reaction called cytokine release syndrome, have been reported but are less common and closely monitored by medical teams.

The safety of this treatment remains under active study in these trials. Since this study is in its early stages, it focuses on understanding these side effects and determining the safest dose. Participants can expect close monitoring to ensure any adverse reactions are quickly addressed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these T-cell therapies for leukemia because they use genetically modified T-lymphocytes that target the CD123 antigen, a marker commonly found on leukemia cells. Unlike traditional chemotherapy and stem cell transplants, which can affect healthy cells, these therapies offer a targeted approach, aiming specifically at cancer cells. This precision could lead to fewer side effects and better outcomes. Additionally, the flexibility of using either allogeneic (donor-derived) or autologous (patient-derived) cells provides more options for individuals based on their unique needs and circumstances.

What evidence suggests that this genetically modified T-cell therapy could be an effective treatment for leukemia?

Research has shown that CD123CAR T-cell therapy could be promising for treating certain types of leukemia. This therapy uses specially modified immune cells to target and fight cancer. In this trial, participants will receive either autologous or allogeneic CD123CAR T-cells. Studies have found moderate success in treating relapsed or hard-to-treat acute myeloid leukemia (AML), with about 49.5% of patients responding to the treatment. These modified T-cells are designed to find and attack leukemia cells by focusing on a protein called CD123, often present on these cancer cells. While early results are encouraging, researchers continue to study the treatment to ensure safety and determine the best dosage. ^{1 2 3 5 6}

Who Is on the Research Team?

Lihua E. Budde

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with certain blood cancers that have come back or didn't respond to treatment. It's open to those who meet specific health criteria like normal liver and kidney function, a good performance status score (able to carry out daily activities), and no severe active infections. They must not be pregnant, agree to use birth control, and can't have other active cancers or HIV.

Inclusion Criteria

My last cancer treatment was at least 2 weeks ago.

I stopped taking immunosuppressants for GVHD 2 weeks before leukapheresis.

I had a stem cell transplant and have not taken any immunosuppressants for GVHD in the last 7 days.

Exclusion Criteria

Research participants with uncontrolled intercurrent illness including, but not limited to ongoing or active or poorly controlled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled pulmonary disease or psychiatric illness/social situations that would limit compliance with study requirements; such social situations include but are not limited to lack of reliable means of transportation for follow up, inability to make time for required clinic visits due to work or family needs, or lack of reliable ways of communication with the study team in the event that the participant is seriously ill

Research participants who have tested human immunodeficiency virus (HIV) positive, or have active hepatitis B or C infection based on testing performed within 4 weeks of enrollment

Research participants will be excluded, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Patients undergo a lymphodepleting regimen 3-10 days prior to CD123+ CAR T cell infusion

1-2 weeks

In-person visits for chemotherapy administration

Treatment

Patients receive autologous or allogeneic CD123+ CAR T cells IV over 15 minutes on day 0

1 day

In-person visit for T-cell infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

Follow-up at 24 hours, then every 2 days for up to 14 days, every week for 1 month, every month for 1 year, and then yearly

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic CD123CAR-CD28-CD3zeta-EGFRt-expressing T-lymphocytes
• Autologous CD123CAR-CD28-CD3zeta-EGFRt-expressing T Lymphocytes
• Cyclophosphamide
• Fludarabine Phosphate

Trial Overview The trial tests genetically modified T-cells after chemotherapy in patients with acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm. The T-cells are engineered from the patient's or donor's blood cells to target and kill cancer cells.

How Is the Trial Designed?

Group I: Treatment (lymphodepletion, T-cell immunotherapy) Experimental Treatment 5 Interventions

Patients undergo a lymphodepleting regimen 3-10 days prior to CD123+ CAR T cell infusion as determined by the principal investigator and the protocol team. Patients receive either cyclophosphamide IV on days -4 and/or -3; fludarabine phosphate and cyclophosphamide IV on days -5 to -3; fludarabine phosphate IV on days -5 to -3 and cyclophosphamide IV on days -4 and/or -3. Patients receive autologous or allogeneic CD123+ CAR Tcells IV over 15 minutes on day 0. Patients with evidence of disease at \> 28 days, continuing expression of the CD123 antigen, and not having experienced a DLT may receive a second infusion of CD123+ CAR T cells after 28 days.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Mustang Bio, Inc.

Industry Sponsor

Trials

1

Recruited

30+

Published Research Related to This Trial

In a study involving five adults with relapsed B cell acute lymphoblastic leukemia (B-ALL), treatment with autologous T cells modified to express a CD19-specific CAR (19-28z) led to rapid tumor eradication and complete remissions without minimal residual disease (MRD), indicating strong efficacy of this therapy.

The treatment was generally well tolerated, although patients with higher tumor burdens experienced significant cytokine elevations, which required management with steroids, highlighting the need for monitoring and potential intervention during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Brentjens, RJ., Davila, ML., Riviere, I., et al.[2023]

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 study demonstrated that using CRISPR/Cas9 to knock out the TCR gene in ARI-0001 CAR-T cells can effectively disrupt the TCR without significantly altering the T cell phenotype, achieving over 80% efficiency.

While this method shows promise for creating allogeneic CAR-T cells with maintained anti-tumor activity, there are potential safety risks due to possible large deletions in the genome that require careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. Maldonado-Pérez, N., Tristán-Manzano, M., Justicia-Lirio, P., et al.[2022]

A new Phase I clinical trial at MD Anderson Cancer Center is investigating the safety and feasibility of using autologous T cells modified to express a CD19-specific chimeric antigen receptor (CAR) in patients with high-risk B-lymphoid malignancies undergoing hematopoietic stem-cell transplantation (HSCT).

This approach combines cell and gene therapies, utilizing a nonviral gene transfer method to create tumor-specific T cells, which may enhance treatment efficacy while minimizing the toxicities associated with traditional chemotherapy and radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies. Kebriaei, P., Huls, H., Jena, B., et al.[2021]

In a phase I/II trial involving 13 patients with B cell acute lymphoblastic leukemia (B-ALL) who relapsed after stem cell transplantation, donor-derived CD19 CAR T cells showed promising results, with 6 out of 7 patients receiving the highest doses achieving complete remission (CR) or CR with incomplete blood count recovery (CRi) by day 28.

The CAR T cell therapy demonstrated a favorable safety profile, with only mild cytokine-release syndrome reported and no severe toxicities such as graft-versus-host disease or neurotoxicity, indicating that this approach could be a viable treatment option for relapsed B-ALL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sleeping Beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities. Magnani, CF., Gaipa, G., Lussana, F., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10164930/

Outcomes with chimeric antigen receptor t-cell therapy in ... We conducted a systematic review and meta-analysis to evaluate outcomes following chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory acute ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02159495

Study Details | NCT02159495 | Genetically Modified T-cell ... This phase I trial studies the side effects and the best dose of genetically modified T-cells after lymphodepleting chemotherapy in treating patients with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8257483/

T-cell-based immunotherapy of acute myeloid leukemia Innovative T-cell-based treatment strategies aim to achieve robust antileukemic activity while avoiding T-cell cytotoxicity against healthy tissues.

4. cancer.gov cancer.gov/publications/dictionaries/cancer-drug/def/allogeneic-cd123car-cd28-cd3zeta-egfrt-expressing-t-lymphocytes

allogeneic CD123CAR-CD28-CD3zeta-EGFRt-expressing ... CD123 is normally expressed on committed blood progenitor cells in the bone marrow; its overexpression is associated with increased leukemic cell proliferation ...

5. researchgate.net researchgate.net/publication/370713830_Outcomes_with_chimeric_antigen_receptor_t-cell_therapy_in_relapsed_or_refractory_acute_myeloid_leukemia_a_systematic_review_and_meta-analysis

Outcomes with chimeric antigen receptor t-cell therapy in ... Conclusion CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable antigen ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6701025/

Next generation chimeric antigen receptor T cells This review summarized the preclinical studies and clinical trials of the safety strategies of CAR-T cells and their respective strengths and weaknesses.