Clinical Study of DC-AML Cells in the Treatment of Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The primary aim of this innovative immunotherapy using WT1/hTERT/Survivin-loaded DCs is to determine whether this novel DC vaccination is safe and can significantly prevent clinical relapse and increase survival of acute myeloid leukemia (AML) patients by eradicating minimal residual disease, while maintaining its safety profile in this phase I trial.

Detailed Description
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we will conduct a single-arm phase I clinical study in 20 patients with acute myeloid leukemia (AML) at the stage of minimal residual disease (MRD) following standard chemotherapy, and these patients are not the subjects of stem cell transplantation. Adult patients between18 and 70 years old with AML who have entered morphological remission after induction, consolidation or intensive chemotherapy with molecular signature of increased WT1 molecule levels and pathological characteristics of bone marrow biopsy, together with fulfilling all other eligibility criteria, will be vaccinated with dendritic cells loaded with tri-antigens (WT1/TERT/survivin) in the absence of any additional therapeutic measurements. The primary aim of this innovative immunotherapy study is to determine whether the anti-leukemic effects seen in our preclinical study can be confirmed in patients and whether such DC vaccination can significantly prevent relapse and increase survival of AML patients by eradicating minimal residual disease. Patients will be recruited at 307 Hospital in Beijing. Recruitment will start in the second half of 2021 and will last for two years or until 20 safety and efficacy-evaluable AML patients are included. This is a single-arm trial. The patients who present MRD after complete chemotherapy will receive a conditioning regimen of cyclophosphamide, followed by six infusions of autologous or HLA-matched donor-derived DCs loaded with tri-antigens including WT1/TERT/survivin. The dendritic cell therapy product will be administered in the stem cell transplantation center at 307 Hospital headed by Dr. Liang-Ding Hu. After inclusion of 20 safety/feasibility-evaluable patients, relapse rate, relapse-free survival and overall survival analysis will be performed. Tumor marker levels and immune signature molecules will also be monitored at molecular and immunological levels, and general and disease-specific quality of life will be evaluated using quality of life questionnaires at various time points.

Official Title
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Safety and Feasibility Study of Dendritic Cell (DC) Vaccination Expressing WT1/hTERT/Survivin in AML Patients With Minimal Residual Disease (MRD)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: DC vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute myeloid leukemia (AML) according to the 2008 criteria of the World Health Organization (WHO). Patients completed induction and consolidation chemotherapy and have achieved complete remission (CR) by bone marrow biopsy criteria but with persistent MRD (defined by upregulated WT1 level and less than 5% of blast cells in bone marrow biopsy) and are not eligible for stem cell transplant Patients have MRD molecular relapse (defined by upregulated WT1 level and less than 5% of blast cells in bone marrow biopsy) after achieved CR following induction and consolidation chemotherapy. Patients with molecular relapse (define by upregulated WT1 level and less than 5% of blast cells in bone marrow biopsy) after allogeneic stem cell transplant Leukemic cells express at least one of the following antigens: WT1, hTERT or survivin detected by qRT-PCR and/or flow cytometry or immunohistochemistry Karnofsky PS ≥60% or ECOG PS≤2. Patients must have organ and marrow function as defined below: leukocytes >=3,000/mcL absolute neutrophil count >=1,500/mcL platelets >=100,000/mcL hemoglobin >=9.0 g/dL total bilirubin within normal institutional limits except in patients with Gilberts Syndrome who must have a total bilirubin < 3.0 mg/dL AST(SGOT)/ALT(SGPT) Serum ALT/AST < 2.5X ULN creatinine clearance Calculated creatinine clearance (CrCl) >=50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation) Adequate cardiac function: LVEF ≥50% by MUGA Ability of subject to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Participation in any other interventional clinical trial during the study period. History or concomitant presence of any other malignancy, except for any other effectively treated malignancy that has been in remission for >5 years or that is highly likely to be cured at the time of enrollment. Patients with a second invasive malignancy requiring treatment within the last 2 years are not eligible. Patients with any form of systemic immunodeficiency, including AIDS or primary immunodeficiency such as Severe Combined Immunodeficiency Disease, are ineligible. The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the treatment. Active hepatitis B, C infection Patients on immunosuppressive drugs including corticosteroids. Patients with autoimmune diseases such as Crohn s disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis, autoimmune pancreatitis, or systemic lupus erythematosus. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations at the time of treatment that would limit compliance with study requirements. Allergic to human albumin or IL-2. History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study. Pregnant or breast-feeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DC vaccine<br>Vaccination with autologous or HLA-matched donors' WT1/TERT/survivin loaded DCs plus follow-up care. | Biological: DC vaccine<br>* Autologous/or HLA-matched donors' DCs loaded with WT1/TERT/survivin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the Incidence of Treatment Adverse Events | To determine the safety of autologous/or HLA-matched DCs loaded with WT1/TERT/Survivin. The primary objective of this single-arm phase I clinical study is to determine the safety and feasibility of WT1/TERT/survivin-targeted DC vaccination in adult AML patients with MRD at very high risk of relapse. | through study completion,an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | Overall survival | through study completion,an average of 3 years | 
| Complete MRD response rate | To determine the Complete MRD response rate | through study completion,an average of 3 years | 
| Relapse rate | (time frame: at study completion, an average of 5 year) | through study completion,an average of 3 years | 
| Relapse-free survival | (time frame: at study completion, an average of 5 year) | through study completion,an average of 3 years | 
| Change in WT1 mRNA levels from peripheral blood samples and/or bone marrow biopsy samples. | Efficacy assessment will also be performed on a molecular level. Bone marrow biopsy samples obtained from participants will be examined, and part of samples will be analyzed by qRT-PCR for WT1 expression. | through study completion,an average of 3 years |