Immunogenicity of CD19 chimeric antigen receptor (CAR) T cells (ARI-0001) in relapsed/refractory CD19-positive B-cell malignancies recruited into the CART-BE-01 clinical trial
[eng] INTRODUCTION: Hematopoiesis is the process of formation, development, and specialization of various immune and blood cells. It begins around the fifth or sixth week of fetal growth in the liver and then migrates to the spleen, thymus, and finally to the bone marrow. All cells originate from a...
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| Format: | doctoral thesis |
| Status: | Published version |
| Publication Date: | 2024 |
| Country: | España |
| Institution: | Universidad de Barcelona |
| Repository: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/215604 |
| Online Access: | https://hdl.handle.net/2445/215604 http://hdl.handle.net/10803/692287 |
| Access Level: | Open access |
| Keyword: | Immunologia clínica Immunoteràpia Hematopoesi Clinical immunology Immunotheraphy Hematopoiesis |
| Summary: | [eng] INTRODUCTION: Hematopoiesis is the process of formation, development, and specialization of various immune and blood cells. It begins around the fifth or sixth week of fetal growth in the liver and then migrates to the spleen, thymus, and finally to the bone marrow. All cells originate from a common progenitor cell, the hematopoietic stem cell (HSC), which has the capacity to self-renew and differentiate into two progenitor cells of the two lineages: lymphoid and myeloid, which give rise to all hematological cell types. The myeloid progenitor produces most blood cells and contributes to the formation of the immune system: erythrocytes, neutrophils, eosinophils, megakaryocytes, basophils, and monocytes. The common lymphoid progenitor (CLP) gives rise to lymphocytes, which differentiate into B-cells, T-cells, and natural killer (NK) cells. Hematologic cancers occur when the uncontrolled growth of abnormal cells disrupts the development of normal hematopoietic function. Based on the stage of B-cell differentiation, it is possible to distinguish between leukemias, non-Hodgkin’s lymphoma (NHL), and multiple myeloma (MM). The main difference between leukemias and lymphomas lies in their origin: leukemias, which arise from blood cell precursors, primarily affect the bone marrow and blood, whereas lymphomas develop from mature lymphocytes and affect the lymph nodes or other organs. HYPOTHESIS AND OBJECTIVES B-cell hematological malignancies are incurable diseases or have poor prognosis after the first relapse. This highlights the need for investing in new therapies to offer more treatment options for patients. Immunotherapy has been developing exponentially in recent years, leading to the emergence of new treatments for various diseases. Specifically, CAR therapy has established itself as a promising new treatment for hematological malignancies, especially anti-CD19 CAR therapy for ALL. However, one of the primary challenges of this therapy is the early loss of CAR, leading to disease relapse, which may result from the immune response against murine regions of CARs and the fusion domains of CAR construct. T-cell compartment could contribute to induce immunological responses and consequently loss the therapy efficacy. Therefore, we hypothesize that murine structures and new antigenic domains of ARI-0001 cells trigger the cellular and humoral immune responses. Altogether, the main aim of the present research is to evaluate the cellular and humoral immune response induced by the ARI-0001 cells in the 47 patients treated in the phase I CART19-BE-01 clinical trial. Specifically, the objectives of humoral and cellular immune responses are: 1. Measure HAMA in patients’ sera or plasma at different timepoints and evaluate whether these antibodies have an impact on the cytotoxic effect on ARI-0001 cells. 2. Assess the clinical impact on persistence of ARI-0001 cells and B-cell aplasia in peripheral blood according to the appearance of HAMA. 3. Determine the presence of CAR-specific T-cells, either CD8+ and CD4+, through activation induce markers. 4. Characterize CAR-specific CD4+ T-cells compared to non-specific CD4+ T-cells. 5. Humanize the scFv of ARI-0001 cells and compare the activity and efficacy of murine scFv (ARI1m) with humanized scFv (ARI1h). 6. Study the differences between HAMA detected through murine scFv (ARI1m) and humanized scFv (ARI1h) from patients treated with ARI-0001 cells. |
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