Chimeric Antigen Receptors (CARs)-redirected T lymphocytes are a promising novel immunotherapeutic approach, nowadays object of accurate preclinical evaluation also for the treatment of Acute Myeloid Leukemia (AML). In this context, we recently developed a CAR against CD123, over-expressed on AML blasts and leukemic stem cells. However, the potential recognition of low CD123-positive healthy tissues, through the "on-target-off-organ" effect, limits the safe clinical employment of CAR-redirected T cells. Therefore, in search for a CAR design optimization, we here evaluated the effect of variables capable to modulate CAR T-cell functional profiles in a context-dependent manner, such as CAR binding affinity for the target antigen, CAR expression and target antigen density. To study these variables in the absence of other interfering elements we exploited computational structural biology tools to design rational mutations in the anti-CD123 CAR antigen binding domain that altered CAR expression and CAR binding affinity, without affecting the overall CAR design. We were able to define both “lytic” and “activation” antigen thresholds, showing that whereas the early T-cell cytotoxic activity is not affected either by CAR expression or CAR affinity tuning, later effector functions are impaired by low CAR expression. Moreover, a promising balance in the efficacy and safety profiles of CAR T cells was observed in the lowest affinity mutant in response to targets with different antigen densities. Overall, the full dissection of all these variables offers additional knowledge for the proper design of a suitable anti-CD123 CAR for the treatment of AML.
(2016). Optimization of Chimeric Antigen Receptor (CAR) design strategy for a specific anti-CD123 targeted therapy in pediatric Acute Myeloid Leukemia (AML). (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2016).
Autori: | |
Tutore: | BIAGI, ETTORE |
Data di pubblicazione: | 30-giu-2016 |
Co-tutore: | TETTAMANTI, SARAH |
Titolo: | Optimization of Chimeric Antigen Receptor (CAR) design strategy for a specific anti-CD123 targeted therapy in pediatric Acute Myeloid Leukemia (AML) |
Settore Scientifico Disciplinare: | MED/06 - ONCOLOGIA MEDICA |
Lingua: | English |
Scuola di dottorato: | Scuola di Dottorato in Medicina Traslazionale e Molecolare |
Corso di dottorato: | SCUOLA DI DOTTORATO IN MEDICINA TRASLAZIONALE E MOLECOLARE (DIMET) - 72R |
Ciclo: | 28 |
Anno Accademico: | 2014/2015 |
Citazione: | (2016). Optimization of Chimeric Antigen Receptor (CAR) design strategy for a specific anti-CD123 targeted therapy in pediatric Acute Myeloid Leukemia (AML). (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2016). |
Parole Chiave (Inglese): | AML, CAR, Cell Immunotherapy, CD123, CAR design |
Appare nelle tipologie: | 07 - Tesi di dottorato Bicocca post 2009 |
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phd_unimib_701403.pdf | Tesi dottorato | Doctoral thesis | Open Access Visualizza/Apri |