A new study published in Nature Communications cites using Cellero human primary isolated T cells to test a new strategy that uses red blood cells (RBCs) as antigen-presenting cells. 
The research team who published the study last month hail from the renowned biotech hub in Cambridge, Massachusetts. They came up with their novel strategy as a way to bypass some of the key limitations of T cell therapy, namely the risk of serious and even fatal adverse effects, as well as the potential for developing treatment resistance. The research group’s primary goal was to use engineered RBCs as artificial antigen-presenting cells (aAPCS) in place of conventional APCs in a cancer immunotherapy model.
RBCs from O-negative donors are nearly universally bio-compatible and have been safely used for transfusion for many years. This makes the cells an attractive target for allogeneic cell therapy development. RBCs are associated with various “immune privilege” mechanisms that can protect them from being attacked by the host’s immune system, and they can easily be expanded in culture as part of normal progenitor cell differentiation. Genetically engineered RBCs have already been successfully used to carry therapeutic proteins .
The immune system requires 3 distinct signals to successfully target invading cells:
- engagement of the T-cell receptor (TCR) complex by a major histocompatibility complex (MHC) molecule
- a co-stimulatory signal to promote T cell function
- a cytokine signal to promote immune cell expansion, differentiation, and memory cell formation
The scientists therefore designed their RBC-derived aAPCs to incorporate all 3 signals. Engineered RBCs contained a tumor-specific peptide bound to MHC, a co-stimulatory ligand called 4-1BBL, and IL-12 to provide for cytokine signaling.
The group carried out extensive testing in 2 separate in-vivo mouse models to determine whether their engineered RBCs performed as predicted. They were pleased to find that the cells were everything they had hoped for. The aAPCs worked as well or better in the mouse models than current treatment modalities such as CAR-T cells. They were able to stimulate appropriate T cell function and generate significant anti-tumor response. Moreover, the aAPCs generated a long-term protective antigen-specific memory response which provided protection against tumor re-challenge.
The overwhelming success in mouse in vivo models prompted the researchers to continue their work, this time using human primary cells for an in-vitro cancer immunotherapy model. A human version of the RBC-derived aAPCs (RTX-321) was designed using human papilloma virus (HPV) E7 peptide as the tumor-specific signal. Human primary CD8+ T cells were sourced from Cellero and co-cultured with RTX-321 to test TCR signal transduction with the new aAPC complex.
Cellero primary human T cell products include primary T cell subsets, as well as an exclusive collection of antigen-specific T cells that respond to peptides derived from viruses, bacteria, tumor cells, and normal tissues. You can learn more about these products below:
- CD3+ T Cells: CD3 is a protein complex and T cell co-receptor involved in activating both CD4 helper T cells and CD8 cytotoxic T cells.
- CD4+ T Cells: CD4+ helper T cells facilitate the body’s immune response by interacting with antigen-presenting cells.
- CD8+ T Cells: Upon activation, cytotoxic T cells can directly bind to and destroy invading cells.
- Induced T Regulatory Cells: These cells are essential to the balance between pro- and anti-inflammatory responses. Induced regulatory T cells arise from CD4+ T cells and can be generated in vitro.
- Natural T Regulatory Cells: These regulatory T cells develop in the thymus and work by regulating or suppressing other immune cells.
- Antigen-specific T Cells: Cellero provides a number of antigen-specific T cell lines, including T cells specific for SARS-CoV-2, HPV, breast cancer, and tetanus antigens. We can also develop custom antigen-specific T cell lines upon request.
Results of the in-vitro study showed that RTX-321 treatment activated HPV-specific, TCR-transduced primary human CD8+ T cells. CD8+ T cells that expanded in response to RTX-321 treatment were HPV antigen-specific and consisted of both cytotoxic T cells and memory T cells.
The ability to engineer RBCs into fully functional APCs is a game changer. There is a high unmet need for treatment of HPV cancers – recurring HPV in particular has a high mortality rate. Artificial APCs derived from O-negative RBCs could potential be used as a near universal allogeneic cancer treatment with a much lower risk of toxic side effects than currently available treatments. We applaud this research and are proud to see our products supporting ongoing pre-clinical efforts.
Please visit our website to check out Cellero’s wide array of immune cell products!
- Zhang X., et al. Engineered red blood cells as an off-the-shelf allogeneic anti-tumor therapeutic. Nature Communications. 12 (2637). May 2021.
- Shi, J. et al. Engineered red blood cells as carriers for systemic delivery of a wide array of functional probes. Proc. Natl Acad. Sci. USA 111, 10131–10136. 2014.