Genetically Modified T-cell Therapy for Leukemia

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

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

Compensation: Varies

Number of Visits: 24

Duration: 1 day

31 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and the best dose of genetically modified T-cells after lymphodepleting chemotherapy in treating patients with acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm that has returned after a period of improvement or has not responded to previous treatment. An immune cell is a type of blood cell that can recognize and kill abnormal cells in the body. The immune cell product will be made from patient or patient's donor (related or unrelated) blood cells. The immune cells are changed by inserting additional pieces of deoxyribonucleic acid (DNA) (genetic material) into the cell to make it recognize and kill cancer cells. Placing a modified gene into white blood cells may help the body build an immune response to kill cancer cells.

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.

What data supports the effectiveness of the treatment Allogeneic CD123CAR-CD28-CD3zeta-EGFRt-expressing T-lymphocytes for leukemia?

Research shows that T cell therapies, like those engineered to target specific leukemia antigens, have been effective in treating leukemia by eradicating cancer cells and achieving remission. Similar treatments have demonstrated significant antitumor activity and improved outcomes in patients with leukemia. ^{1 2 3 4 5}

Is genetically modified T-cell therapy for leukemia safe for humans?

Research shows that genetically modified T-cell therapies, like CAR T-cells, have been used in clinical trials for leukemia and other conditions with some success. While there are potential risks, such as genotoxicity (damage to the genetic information within a cell), studies have reported achieving antileukemic activity without severe toxicities, indicating a generally positive safety profile. ^{1 3 6 7 8}

How is the Genetically Modified T-cell Therapy for Leukemia different from other treatments?

This treatment is unique because it uses genetically modified T-cells that are engineered to specifically target leukemia cells, potentially reducing relapse rates without causing graft-versus-host disease (a condition where donor cells attack the recipient's body). Unlike traditional treatments, this approach involves modifying the patient's own T-cells to enhance their ability to fight cancer. ^{1 4 9 10 11}

Research Team

Lihua E. Budde

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

I can lower my steroid use to only what's needed for basic body functions before starting treatment.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

References

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

T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. [2023]

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

CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. [2023]

3. England pubmed.ncbi.nlm.nih.gov

T cell receptor-engineered T cells for leukemia immunotherapy. [2022]

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

TCR Gene Therapy Improves AML Prognosis. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Antileukemia multifunctionality of CD4(+) T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma. [2022]

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

Sleeping Beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities. [2021]

8. United States 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. [2021]

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

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

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

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

11. Switzerland pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors. [2020]