Bio-CAR-T BS Study

Study Overview
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Brief Summary
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The aim of this Study is the evaluation of post-infusion CAR-T (Chimeric Antigen Receptor T Cell) expansion and persistence in patients with DLBCL, PMBCL and ALL undergoing CAR-T therapy; and the feasibility and efficacy of the treatment in the real life practice.

Detailed Description
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This Study is characterized by several biological sub-studies, reported as below: Post-infusion CAR-T expansion and persistence analysis by both Flow Cytometry and digital PCR (dPCR): the aim of this point are the evaluation and enumeration of CAR T cells (CD4+ and/or CD8+) during patients follow-up and set up of specific panels for longitudinal evaluation and monitoring of CAR-T subsets. Circulating Extracellular Vesicles quantification and analysis on peripheral blood and CNS (Central Nervous System) liquor: the aim are the identification of alterations in small EVs (Extracellular vesicles) ( number and cargos composition (proteins or miRNA) after CAR-T cell infusion and identification of small EVs markers which may distinguish patients good responders from patients not responders and/or which may predict particular post-infusion complications. Evaluation of neurological markers for ICANS (Immune effector cell-associated neurotoxicity syndrome): the purpose of this substudy are the assessment of previously identified plasma and CSF (Cerebrospinal fluid)biomarkers for inflammation, neuronal damage and glial activation in patients who develop ICANS and the characterize temporal neuronal and glial involvement by assessing plasma and CSF inflammatory, neuronal and glial biomarkers in ICANS and their role on outcome.

Official Title
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Bio-CAR-T Study on Pre and Post-infusion CAR-T Cell Therapy

Conditions
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Diffuse Large B Cell Lymphoma (DLBCL), Primary Mediastinal Large B-cell Lymphoma (PMBCL), Acute Lymphoblastic Leukemia (ALL)

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with B-cell-ALL (≤ 25 years) or patients with DLBCL (18-70 years) or patients with PMBCL (18-70 years) who were relapsed/refractory after two lines of treatments; Adequate performance status (0 or 1); Adequate organ function; No active or uncontrolled infections; No thrombo-embolisms within the last 6 months; Absence of clinically relevant co-morbidities (e.g., select cardiovascular, neurologic, or immune disorders with organ dysfunction or requiring immunosuppressive treatment in the last 24 months); Life expectancy of at least 3 months. Exclusion Criteria: Patients with B-cell-ALL > 25 years Patients with DLBCL <18 or >70 years Patients with PMBCL <18 or >70 years Performance status > 1; Active or uncontrolled infections; Thrombo-embolisms within the last 6 months; Presence of clinically relevant co-morbidities (e.g., select cardiovascular, neurologic, or immune disorders with organ dysfunction or requiring immunosuppressive treatment in the last 24 months); Life expectancy < 3 months.

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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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of change post-infusion CAR-T cell expansion and persistence in patients with DLBCL, PMBCL and ALL undergoing CAR-T therapy evaluated by flow-cytometry and measures by number of cells/mL |  | At day +1; +3; +7; +10; +14; +21; +30; +60; +90; +120; +150; +180; +210; +240; +270; +300; +330; +360 post CAR-T cell infusion or at any time for relapse/CRS-ICANS onset (assessed up to 2 years)) | 
| Change of disease burden after CAR-T Cells treatment | Disease response will be evaluated according to Lugano criteria | At day +30; +90; +180; 270 and + 360 post CAR-T infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v 4.0 and ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells | CTCAE v 4.0 and ASTCT (American Society for Transplantation and Cellular Therapy) Consensus Grading for Cytokine Release Syndrome (CRS) and Neurologic Toxicity Associated with Immune Effector Cells | At day +1; +3; +7; +10; +14; +21; +30; +60; +90; +120; +150; +180; +210; +240; +270; +300; +330; +360 post CAR-T cell infusion or at any time for relapse/CRS-ICANS onset (assessed up to 2 years) | 
| Evaluation of disease persistence and immune recovery and neurological biomarkers after CAR-T infusion | In addiction to cytokine panel (IL-1, IL-2, IL-5, IL-6, IL-7, IL-10, IL-12, IL-15, IL-17A, GM-CSF, TNFα, IFNγ, IL-22, IL-23) as per normal clinical practice the investigators will process interleukin: IL 8, IL 1β and CP-1. Cytokine profiles will be analyzed from blood and CSF samples using Luminex platform and all the measure element will expressed in pg/mL. | Before starting the treatment and at day +1; +3; +7; and +30 after infusion of CAR-T cell and in case of development of neurological symptoms | 
| Evaluation of plasma level of biomarkers for ICANS neural damage and glial activation in patients who develop ICANS. | Evaluation of previously identify plasma and CSF biomarkers for inflammation,neural damage and glial activation in patients who develop ICANS. NfL and GFAP markers of neuronal injury and astroglia will be analyzed by SIMOAQuanterix, while sTREM2 (microglia activation) by Luminex, together with cytokines analysis. The unit of measurement will be pg/mL. | Before starting the treatment and at day +1; +3; +7; and +30 after infusion of CAR-T cell and in case of development of neurological symptoms |