Exploration of T-cell dysfunction in CLL and other B-cell malignancies: Implications for therapy

Treatment of B-cell malignancies has transformed over the last few years due to development of various targeted agents. Nevertheless, curation of these diseases can often not be achieved. T-cells form the new frontier in anti-tumor therapy for hematological malignancies. Although successful in acute leukemia, results are rather disappointing in indolent lymphomas including chronic lymphocytic leukemia (CLL). In CLL these disappointing results regarding T-cell therapy have been mainly attributed to acquired T-cell dysfunction that is observed in these patients.
This thesis further elaborates on T-cell dysfunction in CLL and investigates efficacy of T-cell mediated therapy in vitro. We show in a CLL mouse model that antigen-specific T-cell responses are shifted towards a short-lived effector phenotype, resulting in impaired memory T-cell responses. Investigation of human CD8+ T cells shows CLL induces decreased glucose uptake as well as mitochondrial defects, correlating with efficacy of chimeric antigen receptor (CAR) T-cell therapy. In contrast to CLL, T cells of Waldenström’s Macroglobulinemia patients did not display changes in T-cell function or composition.
Although T-cell dysfunction is observed in CLL, we show that application of a bispecific antibody (BsAb) targeting CD3 and CD19, does not result in impaired T-cell activation and leads to effective killing of high-risk CLL. In addition, we investigated targeting B-cell malignancies using BCMA, which was originally described to be highly expressed on multiple myeloma. We were able to target CLL and cell lines of other B-cell malignancies using a BCMAxCD3 BsAb. Furthermore, we show that T-cell mediated killing using CAR T cells and BsAbs contains a necroptotic component.