CD83 CAR T Cells for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Roswell Park Cancer Institute

Must not be taking: Glucocorticoids, Investigational therapies

Disqualifiers: APL, CNS leukemia, HIV, others

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

Compensation: Varies

Number of Visits: 9

26 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use systemic glucocorticoids above a certain dose or be on certain investigational therapies close to the time of treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment Autologous Anti-CD83 CAR T-cells for Acute Myeloid Leukemia?

Research on similar CAR T-cell treatments, like those targeting CD33 and CD123, shows they can effectively fight acute myeloid leukemia by targeting specific markers on cancer cells, suggesting potential for CD83 CAR T-cells as well. ^{1 2 3 4 5}

Is CD83 CAR T-cell therapy safe for humans?

While specific safety data for CD83 CAR T-cell therapy is not available, similar CAR T-cell therapies for acute myeloid leukemia (AML) have shown potential risks such as myeloablation (bone marrow suppression) and cytokine release syndrome (a severe immune reaction). However, these therapies are being studied to find ways to reduce these risks. ^{3 5 6 7 8}

How is the CD83 CAR T-cell treatment different from other treatments for acute myeloid leukemia?

The CD83 CAR T-cell treatment is unique because it uses a patient's own immune cells, which are modified to specifically target and attack leukemia cells expressing the CD83 protein. This personalized approach is different from traditional chemotherapy or other CAR T-cell therapies that target different proteins, offering a novel way to potentially prevent relapse and improve outcomes in acute myeloid leukemia. ^{1 6 9 10 11}

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of genetically engineered cells (CD83 chimeric antigen receptor \[CAR\] T cells) in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or has not responded to previous treatment (refractory). CD83 is a protein that is found on AML blasts. Blasts are abnormal immature white blood cells that can multiply uncontrollably: filling up the bone marrow and preventing the production of other cells important for survival. CD83 CAR T cells represent a new cell therapy to eliminate AML blasts, while avoiding the risk for graft versus host disease (GVHD) after stem cell transplant to replace bone marrow or, tumor toxicity like myeloid aplasia where the body's own immune system causes damage to the bone marrow stem cells. Therefore, human CD83 CAR T cells are a promising cell-based approach to preventing two critical complications of stem-cell transplant - GVHD and relapse. Giving CD83 CAR T cells may be safe, tolerable, and/or effective in treating patients with relapsed or refractory AML.

Research Team

Shernan G Holtan

Principal Investigator

Roswell Park Cancer Institute

Eligibility Criteria

This trial is for patients with acute myeloid leukemia (AML) that has returned after treatment or hasn't responded to previous treatments. Participants must have AML blasts with CD83 protein and meet other health criteria not specified here.

Inclusion Criteria

Creatinine clearance: ≥ 40 mL/min (Cockroft-Gault)

Total bilirubin: ≤ 2mg/dL except for patients with Gilbert's syndrome, hemolysis, or related to disease

AST and ALT < 3.0 x upper limit of normal (ULN)

Exclusion Criteria

Enrollment in another investigational therapy protocol within specific timeframe

Requirement for treatments other than specified agents

Unwilling or unable to follow protocol requirements

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-3 weeks

1 visit (in-person)

Leukapheresis and Pre-treatment

Leukapheresis to obtain PBMCs for CD83 CAR T cell product manufacturing and optional hydroxyurea administration

3 weeks

1 visit (in-person)

Conditioning and Treatment

Patients receive fludarabine and cyclophosphamide followed by CD83 CAR T cells infusion

1 week

Daily visits (in-person) for 5 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Every 2 weeks for 2 months, then at 3, 6, and 12 months

Treatment Details

Interventions

• Autologous Anti-CD83 CAR T-cells

Trial Overview The trial tests genetically engineered cells called CD83 CAR T cells, aiming to treat relapsed/refractory AML safely. It includes determining the best dose while monitoring side effects using various medical procedures and imaging techniques.

Participant Groups

Group I: Treatment (fludarabine, cyclophosphamide, CD83 CAR T-cells) Experimental Treatment 12 Interventions

Patients undergo leukapheresis to obtain PBMCs for CD83 CAR T-cell product manufacturing on day -21 and may receive hydroxyurea at the discretion of the treating physician on study. Patients then receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients then receive CD83 CAR T-cells IV over 15 minutes on day 0. Patients also undergo ECHO and chest x-ray during screening, blood sample collection throughout the study, and CT and/or PET, as well as lumbar puncture as clinically indicated. In addition, patients may undergo bone marrow aspiration throughout the study.

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

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]

The study introduces a new third-generation CAR T-cell therapy (3G.CAR33-T) targeting CD33 for treating acute myeloid leukemia (AML), showing improved viability, proliferation, and cytotoxicity compared to second-generation CAR T-cells.

3G.CAR33-T cells effectively kill CD33-positive leukemia cells while sparing normal hematopoietic stem and progenitor cells, suggesting a safer treatment option that could be combined with genome-edited stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells. Liu, Y., Wang, S., Schubert, ML., et al.[2022]

A novel method was developed to generate large numbers of reactive T-cell lines specifically targeting acute myeloid leukemia (AML), with an estimated frequency of 6 AML-reactive T cells per million peripheral blood mononuclear cells from patients.

These T-cell lines demonstrated the ability to specifically kill autologous AML cells and induce apoptosis, particularly through CD4(+) T cells, suggesting their potential for effective adoptive immunotherapy in AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of T-cell lines to autologous acute myeloid leukemia cells by competitive limiting dilution culture of acute myeloid leukemia mononuclear cells. Zhong, RK., Lane, TA., Ball, ED.[2008]

CD123 CAR T cells, designed to target the interleukin-3 receptor α chain (CD123) overexpressed in acute myeloid leukemia (AML), showed strong effectiveness against AML cell lines and primary patient samples, indicating their potential as a powerful immunotherapy.

These CAR T cells did not harm normal blood cell formation in vitro and demonstrated the ability to kill AML cells from patients, suggesting a targeted approach that minimizes damage to healthy cells while effectively treating high-risk AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Mardiros, A., Dos Santos, C., McDonald, T., et al.[2023]

In a study testing CD33-CAR NK cells in patients with relapsed and refractory acute myeloid leukemia (AML), no significant adverse effects were observed at doses up to 5 billion cells per patient, suggesting a favorable safety profile.

CAR NK-92 cells can be produced at a lower cost than CAR T cells, indicating that with further optimization, they could become a more accessible treatment option for cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Tang, X., Yang, L., Li, Z., et al.[2021]

Up to 30% of patients with acute myeloid leukemia (AML) show some response to CAR T-cell therapy, but these responses are often not deep or long-lasting, indicating a need for improved treatment strategies.

Common targets for CAR T-cells in AML include CD123, CD33, and CLL-1, but while these therapies can lead to myeloablation and cytokine release syndrome, they rarely cause neurotoxicity, suggesting a relatively safe profile for certain side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia. Cummins, K., Gill, S.[2023]

The compound CAR (cCAR) T-cell therapy, which targets both CD123 and CD33 antigens in acute myeloid leukemia (AML), demonstrated strong anti-tumor activity and improved survival in four different leukemia mouse models.

The inclusion of a safety-switch using alemtuzumab allows for the rapid termination of cCAR therapy if needed, enhancing the safety profile of this dual-targeting approach against AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. Petrov, JC., Wada, M., Pinz, KG., et al.[2021]

Engineered T-cells targeting FLT3 show strong effectiveness against acute myeloid leukemia (AML) cells, including those with the FLT3-ITD mutation, indicating a promising new treatment approach for high-risk AML patients.

Combining FLT3-CAR T-cell therapy with the FLT3-inhibitor crenolanib enhances the recognition and destruction of AML cells, suggesting a synergistic effect that could improve treatment outcomes, although caution is needed due to potential damage to normal hematopoietic stem cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Jetani, H., Garcia-Cadenas, I., Nerreter, T., et al.[2019]

References

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

TCR Gene Therapy Improves AML Prognosis. [2020]

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

CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells. [2022]

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

Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Generation of T-cell lines to autologous acute myeloid leukemia cells by competitive limiting dilution culture of acute myeloid leukemia mononuclear cells. [2008]

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

T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. [2023]

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

CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells. [2023]

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

First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. [2021]

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

Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia. [2023]

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

Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. [2021]

10. England pubmed.ncbi.nlm.nih.gov

CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. [2019]

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

Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML. [2021]