NGS-MRD Assessment of Combination Immunotherapies Targeting B-ALL

• ClinicalTrials.gov Identifier: NCT05262673
• Recruitment Status: Recruiting
• First Posted: March 2, 2022
• Last Update Posted: March 8, 2022
• Sponsor: Shenzhen Geno-Immune Medical Institute
• Information provided by (Responsible Party): Shenzhen Geno-Immune Medical Institute

Tracking Information

• First Submitted Date: February 21, 2022
• First Posted Date: March 2, 2022
• Last Update Posted Date: March 8, 2022
• Estimated Study Start Date: March 1, 2022
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 21, 2022)

• Safety of infusion [ Time Frame: 1 year ]
  Treatment-related adverse events are assessed by NCI CTCAE V4.0 criteria and physiological parameters (for safety, measuring cytokine response, fever, symptoms)
• Clinical response [ Time Frame: 1 year ]
  Leukemia blast cells are detected by multiparameter flow cytometry, and MRD is measured by IgH NGS.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: NGS-MRD Assessment of Combination Immunotherapies Targeting B-ALL
• Official Title: NGS-MRD Evaluation of Antigen-specific T Cells and DC Vaccine Combination Targeting B-cell Acute Lymphoblastic Leukemia
• Brief Summary: The purpose of this study is to determine the feasibility, safety, and efficacy of a combination therapy in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) based on multi-antigen-targeted chimeric antigen receptor T cells (CAR-T) followed by engineered immune effector cytotoxic T lymphocytes (CTLs) and immune-modified dendritic cell vaccine (DCvac). This approach is aimed to achieve NGS MRD negative in B-ALL patients, which can identify a very low risk of relapse and define patients with possible long-term remission without further treatment.

Detailed Description

Minimal residual disease (MRD) monitoring is currently performed in B-ALL patients to evaluate treatment response and define risk stratification. Patients with good prognosis have undetectable MRD levels after treatment, while persistent MRD defines high relapse-risk patients. A standardized flow cytometry assay detects MRD reliably in bone marrow or peripheral blood at levels ≥0.01% mononuclear cells. More sensitive MRD assay detecting specific immunoglobulin heavy (IgH) chain rearrangement by next-generation sequencing (NGS) can approach reliably detectable blast level at ≤10-6 cells. Given the high sensitivity, the NGS-MRD approach improves distinction between deeply negative and very low positive cases. Recent studies also demonstrate that NGS-MRD assessment of the bone marrow with undetectable blast cells is a strong predictive factor, indicating patients with possible long-term response after CAR-T cell therapy.

In the past decade, adoptively transferred T cells modified with chimeric antigen receptors (CARs) have demonstrated high effectiveness and changed the treatment paradigm for B-ALL. More than 80% B-ALL patients achieved complete remission due to CAR-T treatment, but some patients with CR still have MRD that ultimately leads to relapse, which indicates the importance for further combination therapy to enhance anti-tumor immunity and to eradicate all malignant cells. Therefore, this protocol includes multi-target CAR-T cell infusions followed by cytotoxic T lymphocyte (CTL)-based immunotherapy, which react with B-ALL tumor antigens, and then followed by injection of immune-modified dendritic cells fused with leukemic cells (DCvac). In addition to the significant success of CAR-T cell therapy, various clinical studies also reported the importance and potential benefits of using engineered tumor-specific T cells in different types of cancer. Moreover, DC-based vaccine as another agent of immunotherapy has proven to prevent or delay relapse in leukemia patients achieving remission. In this study, we propose to combine those strategies to augment anti-tumor immunity in patients and expect undetectable NGS-MRD remission to prevent disease recurrence.

We propose a novel protocol which combines multiple CAR-T cell therapy, engineered immune effector CTLs and DCvac against B-ALL. The aim of this study is to evaluate the feasibility, safety, and efficacy of the NGS-MRD analysis-based combinational immunotherapy.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: B-Cell Acute Lymphoblastic Leukemia

Intervention

Biological: Antigen-specific T cells CART/CTL and DCvac

Antigen-specific T cells CAR-T/CTL and DCvac cells to treat B-ALL

Study Arms

Experimental: CART/CTL/DCvac cells to treat B-ALL

Intervention: Biological: Antigen-specific T cells CART/CTL and DCvac

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 21, 2022): 10
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age older than 6 months.
2. High-burden (≥30% blast cells) B-ALL tumor specimen for clonal IgH identification and CTL/DC vac preparation is required
3. Expression of CD19, CD22, CD20, CD10 or CD123 is determined in malignant cells by flow cytometry or immuno-histochemical staining.
4. Karnofsky performance status (KPS) score is higher than 60 and life expectancy > 3 months.
5. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements: cardiac ejection fraction ≥ 50%, oxygen saturation ≥ 90%, creatinine ≤ 2.5x upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3x upper limit of normal, total bilirubin ≤ 2.0mg/dL.
6. No cell separation contraindications.
7. Abilities to understand and the willingness to provide written informed consent.

Exclusion Criteria:

1. Sever illness or medical condition, which would not permit the patient to be managed according to the protocol, including active uncontrolled infection.
2. Active bacterial, fungal or viral infection not controlled by adequate treatment.
3. Known HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
4. Pregnant or nursing women may not participate.
5. History of glucocorticoid for systemic therapy within the week prior to entering the test.
6. Previously treatment with any gene therapy products.
7. Patients, in the opinion of investigators, may not be eligible or not able to comply with the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Lung-Ji Chang, Ph.D; 86-0755-86725195; c@szgimi.org

• Listed Location Countries: China

Administrative Information

• NCT Number: NCT05262673
• Other Study ID Numbers: GIMI-IRB-22001
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Shenzhen Geno-Immune Medical Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Shenzhen Geno-Immune Medical Institute
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Shenzhen Geno-Immune Medical Institute
• Verification Date: March 2022