Scientists from Boston Children’s Hospital and Massachusetts Institute of Technology (MIT) have used alpaca-derived nanobodies to create a novel approach to CAR T cell therapy that addresses the challenge of treating patients with solid tumor cancers. Currently, CAR-T cell immunotherapy has been applied to the treatment of non-solid tumors such as acute lymphoblastic leukemia (ALL). However, for solid tumors, CAR-T therapy has not been effective. This is because researchers have been unable to find effective and safe biological targets in solid tumors. In addition, extracellular matrix (ECM) forms a protective barrier around the tumor, inhibiting the cytotoxic role of T cells.
In an attempt to solve the problem, Hidde Ploegh, a cell and molecular medical immunologist at Boston Children’s Hospital, teamed up with Noo Jalikhani and Richard Hynes of MIT to use nanobody-based retroviral DNA modified T cells to kill cancer cells (nanobody CAR-T). Camelidae nanobodies are similar to human antibodies, except that these nanobodies generally lack the light chain on the Y-shape of the antibody and are therefore relatively small (15kDa). They have many useful properties such as greater binding capacity and improved stability compared to standard antibodies. (Figure 1)
Figure 1. Camelidae (Alpacas, Llamas and Camels) nanobodies have many advantages over mouse models due to their small size and specificity.
Instead of focusing on finding specific antigens on the tumor, these scientists actively aim at the tumor microenvironment. Nanobody CAR-T cells identify proteins in the tumor microenvironment, such as fibronectin EIIIB – which is found in neovascularization – immunosuppressive protein, and PD-L1 which is a known tumor surface marker for immunological checkpoint inhibition. In recent experiments, scientists treated both a melanoma mouse model, and melanoma and colon adenocarcinoma cell lines by using nanobody CAR-T. The results showed that nanobody CAR-T can significantly slow tumor growth and effectively kill tumor cells, improving animal survival without obvious side effects. The authors confirmed that the use of this CAR-T treatment that does not target the tumor itself may reduce the body’s excessive immune response. In addition, attacking the ECM molecule EIIIB fibronectin in the tumor may help other cancer drugs to better access the tumor, providing opportunities for improved combination therapies.
For over a decade, nanobodies have been attracting the attention of the pharmaceutical industry with their unique characteristics. Recently, Sanofi acquired the nanobody developer Ablynx for $4.5 billion. Subsequently, Ablynx’s thrombotic thrombocytopenic plaque drug Caplacizumab (trade name Cablivi) was successfully approved by the FDA. In influenza prevention, nanobodies have the potential to develop universal influenza vaccines. Scientists at Scripps Research Institute have developed nanobody vaccines that neutralize all sixty known influenza strains in mice. In the future, these nanobodies are expected to provide better and safer strategies to cure a variety of diseases. Read more here.