Engineered B Cells as an Approach to Cancer Therapy
Engineered T cells are the dominant form of cell therapy for cancer at the present time, an approach that has achieved considerable success, and remains actively under further development. T cells can attack cancer cells directly, given the right tools to recognize those cells and overcome the various immunosuppressive mechanisms deployed by cancerous tissue. There are other approaches to rousing the immune system to action, however, such as focusing on B cells. B cells carry out a variety of roles that are important in the coordination of the immune response, in providing targets for other cells to attack, and rousing those cells to action. Thus it should be possible to engineer B cells to be much more effective in the context of cancer, improving the overall immune response.
Nowadays, cancers still represent a significant health burden, accounting for around 10 million deaths per year, due to ageing populations and inefficient treatments for some refractory cancers. Immunotherapy strategies that modulate the patient's immune system have emerged as good treatment options. Among them, the adoptive transfer of B cells selected ex vivo showed promising results, with a reduction in tumor growth in several cancer mouse models, often associated with antitumoral immune responses. Aside from the benefits of their intrinsic properties, including antigen presentation, antibody secretion, homing, and long-term persistence, B cells can be modified prior to reinfusion to increase their therapeutic role.
For instance, B cells have been modified mainly to boost their immuno-stimulatory activation potential by forcing the expression of costimulatory ligands using defined culture conditions or gene insertion. Moreover, tumor-specific antigen presentation by infused B cells has been increased by ex vivo antigen loading (peptides, RNA, DNA, virus) or by the sorting/ engineering of B cells with a B cell receptor specific to tumor antigens. Editing of the B cell receptor also rewires B cell specificity toward tumor antigens, and may trigger, upon antigen recognition, the secretion of antitumor antibodies by differentiated plasma cells that can then be recognized by other immune components or cells involved in tumor clearance by antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity for example.
With the expansion of gene editing methodologies, new strategies to reprogram immune cells with whole synthetic circuits are being explored: modified B cells can sense disease-specific biomarkers and, in response, trigger the expression of therapeutic molecules, such as molecules that counteract the tumoral immunosuppressive microenvironment. Such strategies remain in their infancy for implementation in B cells, but are likely to expand in the coming years.