Engineering B cells to fight cancer

Project Information

EngineerBcells

Grant agreement ID: 101045763

DOI

10.3030/101045763

EC signature date 5 July 2022

Start date 1 October 2022

End date 30 September 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 996 250,00

EU contribution

€ 1 996 250,00

Coordinated by

TEL AVIV UNIVERSITY
Israel

Periodic Reporting for period 1 - EngineerBcells (Engineering B cells to fight cancer)

Reporting period: 2022-10-01 to 2025-03-31

Summary of the context and overall objectives of the project

B cells have an important role in the immune response against cancer. Tumor-specific B cells in in the tumor surroundings and circulating anti-tumor antibodies are associated with a favorable prognosis and with an improved response to checkpoint inhibition in different types of cancer. Antigen-specific B cells home to tumors and prolong survival in mice, while B cell-based vaccines allow durable anti-tumor activity in cervical cancer patients. We have recently demonstrated successful engineering of B cells both outside of the body or directly inside the mice, for the expression of antibodies against the Human Immunodeficiency Virus (HIV). Here, we propose a novel cancer immunotherapy approach based on engineered B cells. In particular, we use an editing protein and a viral vector to deliver the anti-tumor antibody gene inside the location of the antibody genes in the genome. In diverse tumor models, we plan to demonstrate localized B cell activation upon antigen engagement. The B cells will exert multiple anti-tumor effects such as secretion of antibodies as well as activation of T cells which ultimately kill the tumor. The B cell will be co-engineered to locally secrete factors enhancing the immune response upon activation, including stimulatory proteins and antibodies. Localized secretion is predicted to increase efficacy while reducing systemic toxicities. When targeting self antigens, B cells will be engineered to co-express a receptor which provides them T cell-independent activation allowing them to be transferred to patients from a donor.
We will further demonstrate that engineering B cells directly in the body will consent increased therapy scalability and ensure safety by inducing the specific elimination of the engineered B cells, if adverse outcomes are verified.
B cell engineering is thus a flexible and robust platform technology that may revolutionize cancer immunotherapy.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

- 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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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 the T cell 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.
Our discovery of frequent chromosomal alterations in T cells engineered with state-of-the-art methods 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.