Anti-CD7 CAR-Engineered T Cells for T Lymphoid Malignancies Malignancies

Study Overview
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Brief Summary
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This is a single-center, open-label, single-arm study to evaluate the primary safety and efficacy of anti-CD7 chimeric antigen receptor(CAR)-modified T cells(CAR7-Ts) in patients with relapsed or refractory T lymphoid malignancies.

Detailed Description
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Chimeric antigen receptor-T cells (CAR-T) have made breakthroughs in the treatment of B-cell tumors, especially refractory/relapsed acute B lymphocytes. CD7 is a transmembrane glycoprotein expressed by T cells and natural killer cells and their precursors; it is also expressed in >95% of lymphoblastic T-cell leukemias and lymphomas . CD7 was previously evaluated as a target for immunotoxin-loaded antibodies in patients with T-cell malignancies, but tumor responses were limited. Enhancing the potency of CD7-directed cytotoxicity by substituting donor-derived CAR-T cells for a monoclonal antibody would augment the efficacy of CD7-targeted therapy in patients with T-cell malignancies. To prepare CAR7-T cells, CD7 expression is suppressed on donor-derived T cells by unique blocking technique, and CD7-negative T cells are transduced with a humanized anti-CD7-41BB-CD3ζ lentiviral vector. This is an investigational study. The objectives are to evaluate the safety and efficacy of CAR7-T cells in patients with CD7+ T-cell malignancies.

Official Title
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Safety and Efficacy of Anti-CD7 CAR-Engineered T Cells for Relapsed/Refractory T Lymphoid Malignancies: a Single-center, Open-label, Non-randomized, Single-arm Clinical Study

Conditions
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T-Cell Lymphocytic Leukemia, T-Cell Chronic Lymphocytic Leukemia, T Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Fludarabine + Cyclophosphamide + CAR7-T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged from 14 to 70 years; Expected survival over 60 days; Eastern Cooperative Oncology Group score 0-2; Diagnosed as T-cell hematologic malignancies (including leukemia and lymphoma) according to WHO2016 criteria; Patients must relapse or be refractory after at least two lines of therapy. CD7 were positive in bone marrow or cerebrospinal fluid by immunohistochemistry or flow cytometry at screening, and one of the following conditions is satisfied: A. No remission was achieved after at least 2 lines of standard therapy; B. Relapse or progression after standard treatment; C. Relapse after autologous or allogeneic hematopoietic stem cell transplantation; Have no fertility requirements or plans for one year since enrollment in this clinical trial; Patient or his or her legal guardian voluntarily participates in and signs an informed consent form. Exclusion Criteria: Complicated with central system leukemia/lymphoma with active intracranial lesions; Existing or preexisting CNS conditions, such as epileptic seizures, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any CNS related autoimmune disease; Symptomatic heart failure or severe arrhythmias; Symptoms of severe respiratory failure; Complicated with other types of malignant tumors; Serum creatinine and/or urea nitrogen ≥ 1.5 times of normal value; Suffer from sepsis or other uncontrollable infections; Intracranial hypertension or brain consciousness disorder; Severe mental disorders; Have received organ transplantation (excluding bone marrow transplantation); Female patients (fertile patients) had positive blood HCG test; Hepatitis (including hepatitis B and C), AIDS and syphilis were screened positive; Patients with graft-versus-host disease (GVHD) or who require immunosuppressant treatment; The absolute value of lymphocytes was too low to manufacture CART cells; Other conditions considered inappropriate by the researcher.

Ages Eligible for Study
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Minimum Age: 14 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: Fludarabine + Cyclophosphamide + anti-CD7 CAR-T Cells<br>Patients will received lymphodepletion with fludarabine (30 mg/kg) and cyclophosphamide (250 mg/kg) on day -5, -4, and -3, followed by the infusion of CAR7-T cells with the dose of 1×10^6/kg and 2×10^6/kg (with an allowance of ±20%). If no dose-limited toxicity (DLT) emerges in the group, then the subsequent higher dose will be used in the next group. If DLT emerges in a single subject in any dose level, 3 more subjects will be enrolled to the same dose level. The maximum dose could be extended. | Drug: Fludarabine + Cyclophosphamide + CAR7-T Cells<br>* fludarabine 30 mg/kg on day -5, -4, and -3; cyclophosphamide 250 mg/kg on day -5, -4, and -3; CAR7-T Cells on day 0.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-related Adverse Events | Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0). | within 2 years after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate(ORR) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-cell hematological malignancies. | ORR will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Complete response rate(CRR) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-cell hematological malignancies. | CRR will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Progress-free survival(PFS) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-cell hematological malignancies. | PFS will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Duration of Response(DOR) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-cell hematological malignancies. | DOR will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Overall survival(OS) of administering CAR7-T cells in Relapsed/Refractory CD7+ T-cell hematological malignancies. | OS will be assessed from CAR T cell infusion to death or last follow-up (censored). | within 2 years after infusion |