GD2/CD56 Bi-specific CAR-T Cell Therapy

Study Overview
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Brief Summary
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The purpose of this clinical trial is to assess the feasibility, safety and efficacy of anti-GD2/CD56 bi-specific CAR-T cell therapy in patients with GD2 and/or CD56 positive cancer. Another goal of the study is to learn more about the function of the anti-GD2/CD56 bi-specific CAR-T cells and their persistency in patients.

Detailed Description
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Patients with refractory and/or recurrent malignancies have poor prognosis despite complex multimodal therapy; therefore, novel curative approaches are needed. The investigators attempt to use T cells genetically modified to express a 4th generation lentiviral GD2/CD56 bi-specific chimeric antigen receptor (bi-4SCAR-GD2/CD56). The chimeric antigen receptor (CAR) molecules enable the T cells to recognize and kill tumor cells through the recognition of a surface antigen, GD2 or CD56, which is expressed at high levels on tumor cells but not at significant levels on normal tissues. Disialoganglioside (GD2) is a well-studied tumor associated antigen which is expressed uniformly in nervous system-related tumors but at low levels in normal tissues. Over the past few years, CAR-T therapy against GD2 in tumor has achieved encouraging but modest outcomes. Only a fraction of patients achieved measurable responses. In solid tumors, GD2 CAR-T therapy alone may not be as effective as CAR-T cell therapy in hematological malignancies. Similar to GD2, the CD56 antigen (NCAM-1) is highly expressed on malignancies with neuronal or neuroendocrine differentiation, including small-cell lung cancer, glioblastoma and neuroblastoma, tumor types for which new therapeutic options are needed. CD56-CAR-T cell therapy has potential for treating patients with aggressive malignancies that are nonresponsive to conventional radiotherapy and chemotherapy, or are unsuitable for hematopoietic stem cell transplantation. To overcome tumor escape of single target antigen and enhance in vivo CAR-T efficacy, a novel bi-specific GD2/CD56 CAR-T therapy regimen is developed to include booster and consolidation CAR-T applications to target highly-refractory cancer. The aim is to evaluate safety and long term efficacy of the bi-CAR-T therapy strategy in GD2 and/or CD56 positive cancer patients.

Official Title
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GD2/CD56 Bi-specific CAR-T Cells for Cancer Treatment

Conditions
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Malignant Disease

Intervention / Treatment
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* Biological: bi-4SCAR GD2/CD56 T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with tumors received standard first-line therapy and have been judged to be non-resectable, metastatic, progressive or recurrent. The expression status of GD2 or CD56 antigens in the tumor tissue will be determined for eligibility. Positive expression is defined by GD2 and CD56 antibody staining results based on immunohistochemistry or flow cytometry analyses. Body weight greater than or equal to 10 kg. Age: ≥1 year and ≤ 75 years of age at the time of enrollment. Life expectancy: at least 8 weeks. Prior Therapy: There is no limit to the number of prior treatment regimens. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must be resolved to grade 2 or less. Participant must not have received hematopoietic growth factors for at least 1 week prior to mononuclear cells collection. At least 7 days must have elapsed since the completion of therapy with a biologic agent, selected targeted agent or a metronomic non-myelosuppressive regimen. At least 4 weeks must have elapsed since prior therapy that included a monoclonal antibody. At least 1 week since any radiation therapy at the time of study entry. Karnofsky/jansky score of 60% or greater. Cardiac function: Left ventricular ejection fraction greater than or equal to 40/55 percent. Pulse Ox greater than or equal to 90% on room air. Liver function: defined as alanine transaminase (ALT) <3x upper limit of normal (ULN), aspartate aminotransferase (AST) <3x ULN; serum bilirubin and alkaline phosphatase <2x ULN. Renal function: Patients must have serum creatinine less than 3 times upper limit of normal. Marrow function: White blood cell count ≥1000/ul, Absolute neutrophil count ≥500/ul, Absolute lymphocyte count ≥500/ul, Platelet count ≥25,000/ul (not achieved by transfusion). Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria, and the marrow disease does not have hematologic toxicity. For all patients enrolled in this study, themselves or their parents or legal guardians must sign an informed consent and assent. Exclusion Criteria: Existing severe illness (e.g. significant cardiac, pulmonary, hepatic diseases, etc.) or major organ dysfunction, or greater than grade 2 hematologic toxicity. Untreatable central nervous system (CNS) metastasis: Patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible. Previous treatment with other genetically engineered GD2 or CD56-specific CAR T cells. Active HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) infection or uncontrolled infection. Patients who require systemic corticosteroid or other immunosuppressive therapy. Evidence of tumor potentially causing airway obstruction. Inability to comply with protocol requirements. Insufficient CAR T cells availability.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 75 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: bi-4SCAR-GD2/CD56 T Cell Therapy for GD2 and/or CD56 positive tumor<br> | Biological: bi-4SCAR GD2/CD56 T cells<br>* Infusion of bi-4SCAR GD2/CD56 T cells at 10^6 cells/kg body weight via IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events. | Determine the toxicity profile the bi-4SCAR GD2/CD56 cells with Common Toxicity Criteria for Adverse Effects version 4.0 | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor effects | Objective complete response (CR) are assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. | 1 year | 
| Anti-tumor effects | Objective partial response (PR) are assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. | 1 year | 
| The expansion of bi-4SCAR GD2/CD56 T cells | Scale of CAR copies | 1 year | 
| The persistence of bi-4SCAR GD2/CD56 T cells | Scale of tumor burden (for efficacy) | 1 year | 
| Survival time of the patients | The progression free survival (PFS) time of the patients treated with the bi-4SCAR GD2/CD56 T cells will be evaluated | 3 years | 
| Survival time of the patients | The overall survival (OS) time of the patients treated with the bi-4SCAR GD2/CD56 T cells will be evaluated | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR-T, cancer, CD56, GD2