NGS-MRD Assessment of Combination Immunotherapies Targeting T-ALL

• ClinicalTrials.gov Identifier: NCT05277753
• Recruitment Status: Recruiting
• First Posted: March 14, 2022
• Last Update Posted: March 15, 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 14, 2022
• Last Update Posted Date: March 15, 2022
• Estimated Study Start Date: March 15, 2022
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 11, 2022)

• Treatment-related adverse events are assessed by NCI CTCAE V4.0 criteria. [ Time Frame: 1 year ]
  Safety of infusion
• Clinical response [ Time Frame: 1 year ]
  Leukemia blast cells are detected by multiparameter flow cytometry
• Evaluate the percentage of minimal leukemia residue in bone marrow [ Time Frame: 1 year ]
  Minimal leukemia residue（MRD）is measured by TCR next generation sequencing（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 T-ALL
• Official Title: NGS-MRD Evaluation of Antigen-specific T Cells and DC Vaccine Combination Targeting T-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 T-cell acute lymphoblastic leukemia (T-ALL): multi-antigen-targeted chimeric antigen receptor T cells (CAR-T) followed by engineered immune effector cytotoxic T cells (CTLs) and immune modified dendritic cell vaccine (DCvac). This approach is aimed to achieve NGS MRD negativity in T-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 T-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. The 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 clonal T cell receptors (TCR) by next-generation sequencing (NGS) can reliably detect blasts at levels ≤10-6 cells. Given the high sensitivity, 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.

Acute lymphoblastic leukemia (ALL) is hematological malignancy with the highest incidence in children and adolescents. After standardized treatment, the survival rate is relatively high. ALL is divided into two types: B cells and T cells, the latter accounting for about 15% of childhood leukemias and about 25% of adult leukemias. Compared with children and adolescents with B-lineage ALL (B-ALL), T-ALL is extremely aggressive, and patients are prone to early disease recurrence, and in the event of recurrence, event-free survival (EFS) and overall survival (OS) are lower, at less than 25%, even with more intensive treatment, which might require further combination therapy to enhance anti-tumor immunity and eradicate all malignant cells. Therefore, this protocol includes multi-target CAR-T cell infusions followed by antigen-specific cytotoxic T lymphocyte (CTL)-based immunotherapy, which is based on T cells reacting with specific T-ALL tumor antigens and immune-modified dendritic cells (DCvac) fused with T leukemic cells as DC vaccines. In addition to the significant success of CAR-T cell therapy, various clinical studies also reported the importance and potential benefits of using tumor-specific T cells in different types of cancer. Moreover, DC-based vaccines as another agent of immunotherapy have proven to prevent or delay relapse in leukemia patients achieving remission. In this study, we combine those strategies to augment anti-tumor immunity in patients and expect undetectable NGS-MRD, a long-lasting remission to prevent disease recurrence.

We propose a novel protocol which combines multi-CAR-T cell therapy, engineered immune effector CTLs and DCvac against T-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: T-Cell Acute Lymphoblastic Leukemia

Intervention

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

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

Study Arms

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

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 11, 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) bone marrow sample for NGS TCR clonal identification and CTL/DC vac preparation is required
3. Expression of CD7, CD5, CD317, CD47, CD99, CD38 or TRBC1/2 is determined in malignant cells by flow cytometry or immuno-histochemical staining.
4. Karnofsky performance status (KPS) score is higher than 80 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 ≤ 2.0 mg/dL.
6. Hgb ≥ 80g/L.
7. No cell separation contraindications.
8. 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. Previous 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: NCT05277753
• Other Study ID Numbers: GIMI-IRB-22002
• 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