Receptor-edited cellular therapy of cancer has yet to fulfill its full potential. To increase the fraction of curative responses it will be crucial to increase the therapeutic breadth of cellular... Show moreReceptor-edited cellular therapy of cancer has yet to fulfill its full potential. To increase the fraction of curative responses it will be crucial to increase the therapeutic breadth of cellular therapy products, both in the antigens that are targeted as well as in functionality. The ideal cellular therapeutic will target multiple antigens at a time, both HLA-dependently as well as independently of HLA. Functionally, cellular therapy needs to be efficient enough to induce sufficiently deep responses in diverse microenvironments, lesion sites and patients, while at the same time maintaining a manageable toxicity profile. The results presented within this thesis support the complementary use of TCR-engineered (eTCR) T-cell therapy together with chimeric antigen receptor (CAR) T cells to realize a multi-targeting, multi-functional product. We found that eTCR T cells are functionally different from CAR T cells, performing differently in different contexts. Furthermore, HLA-dependent and HLA-independent targeting could be leveraged to enable a broader coverage of tumor antigens to prevent antigen escape. Multi-antigen-targeting, single T-cell products using TCRs and CARs can be utilized to achieve that, but pose additional caveats. Show less
Most lymphomas and leukemias are neo¬plasms of B cells. Due to the many different B cell development stages from which these neoplasms arise, the resulting diseases are quite heterogeneous, which... Show moreMost lymphomas and leukemias are neo¬plasms of B cells. Due to the many different B cell development stages from which these neoplasms arise, the resulting diseases are quite heterogeneous, which amongst other things is manifested in different tumor growth location, proliferation potential and surface antigen repertoire. Neverthe¬less, some population characteristics are found in almost all B cell malignancies as the cell-of-origin is identical. One of these is the cell surface antigen CD20. Originally used as a marker to distinguishing B cells from other lymphocytes, it quickly became a target for immunotherapy. Immuno-therapy is a treatment that makes use of immune system components to fight cancer, in this case by the injection of a monoclonal antibody specifically targeting one protein: CD20. The addition of CD20-targeting an¬tibodies to an anti-tumor treatment allows your immune system to recognize CD20-ex¬pressing B cells (diseased and healthy), and dispose of them. Overall, after several decades of research and therapeutic experience with antibodies targeting CD20, new functional discoveries as well as therapeutic advances are still being made, and CD20 therefore remains a highly attractive and fruitful target for the therapy of B cell malignancies as well as certain B-cell mediated autoimmune diseases. Show less
