Phd in IINNOVATION IN IMMUNO-MEDIATED AND HEMATOLOGICAL DISORDERS

Thesis title: Long-term in vivo host immune modulation following CD19-CAR-T cell therapy in diffuse large B-cell lymphoma and B-lineage ALL patients

Chimeric antigen receptor (CAR)-T cells represent a potentially curative strategy for patients with advanced relapsed or refractory (R/R) B-cell malignancies. However, little is known about the in vivo effects of this treatment on the patients' immune lymphocyte populations. In this study, we investigated the effects of Axi-cel and Tisa-cel administration in the control of R/R diffuse large B-cell lymphoma (DLBCL) and B-lineage acute lymphoblastic leukemia (B-ALL), with a primary focus on the immunomodulatory changes induced over time on the host immune system of treated patients. Despite the short in vivo persistence of CAR+ cells, we could document a constant and significant increase over time of CD3+, CD4+, CD8+ and NK cells, associated with an increased capacity of T lymphocytes to produce IFNγ and TNFα. The results obtained also highlight the fact that different co-receptors endow T cells with different functions: the presence of 4-1BB or CD28 domain affects T cells function and fate and our results suggest that infusion with Tisa-cel product induces a bigger expansion of T lymphocytes compartment, which is also found to be functionally more active in producing immunomodulatory cytokines, compared to Axi-cel. We, furthermore, confirmed the prominent role of plasmatic IL-6 in mediating CRS, but we also emphasized the involvement of plasmatic IL-8 in ICANS pathophysiology. IL-8, moreover, emerged as a new early indicator of clinical response, as high IL-8 levels at T3d resulted associated with partial or absent response evaluated at day 30 and month 3. Taken together, these findings show that CAR-T cells are capable to exert a modulation and activation of host immune system, highlighted the differences induced by different product phenotypes and shed light on the role of IL-6 and IL-8 in adverse events.