- One of the biggest challenges in the engineering of cells inside the patients' body is the specific delivery of the engineering machinery and the genes to the right cells in the body. In fact, viral vectors used in the state-of-the-art therapies can enter many different tissues and types of cells in the body, thus potentially leading to undesired side effects.
We tackled this problem by incorporating to the viral vector a specific molecule that targets them exclusively to B cells and not to other cells in the body. In this way we minimize the risks and make the engineering-based therapy more precise and effective.
- Besides their role in producing antibodies, B cells have an important function as activators of other immune cells by capturing, processing, and presenting antigen fragments to those cells. We demonstrated that in the presence of the antigen, T cells were robustly activated by B cells engineered to express a specific antibody to that antigen, but not by non-engineered B cells. These results show that engineered B cells are potent at presentation of processed internalized antigens and therefore could play a role in enhancing the antitumor immune response by facilitating the activation of T cells which orchestrate the tumor killing.
- Chimeric Antigen Receptor T-cell (CAR T-cell) therapy is an innovative and promising treatment for certain types of cancers, particularly specific types of blood cancers, which consists on genetic modification of the patients' T cells for the specific recognition and targeting of cancer cells.
Multiple clinical trials based on donor-derived cells employ a T-cell engineering step to prevent the donor's T cells from recognizing and attacking the patient’s own body or to improve their persistence and efficacy. This gene-editing methods are very efficient but might cause a variety of undesired outcomes such as DNA alterations and mutations which might cause potential malignancies.
By using an unbiased novel approach based on sequencing single cells, further corroborated by other technologies we observed that a fraction of engineered cells displayed chromosomal alterations such as loss of chromosome 14. This discovery highlights potential risks of tumorigenicity and underscores the need for mitigation strategies to allow the safe application of gene editing methods -taking place both outside or inside the patient's body- in immunotherapy and beyond.
