Ashley Goland ’23
Immunotherapy is a form of cancer treatment that utilizes the body’s own immune system to destroy cancerous tumors and has shown promise in past animal and clinical human trials. For all of its dazzling successes to date, however, immunotherapy is not completely effective for treating the full range of cancer types and patients— yet. Scientists working in Sanofi Research and Development believe that antibodies that can send three signals at once could be key to future success of anticancer immunotherapy. These trispecific antibodies have the ability to find a tumor, activate the immune system’s T-cells, and prevent T-cell death in order to prolong its response.
The team of Sanofi researchers obtained multiple myeloma cells, or cancerous plasma cells, to test with from two organizations (the American Type Culture Collection and the Deutsche Sammlung von Mikroorganismen und Zellkulturen) and T-cells from healthy, consenting donors. They then designed numerous different trispecific antibodies, combined them with T-cells on cell culture plates, and tested them in humanized mice and monkey models. Although the three specificities (CD3, CD28, and CD38) of the antibody were not equally effective in activating T-cells, an antibody with all three specificities produced greater T-cell activation compared to an antibody with only one or two specificities. In-vivo trials showed far slower tumor growth in mice treated with the trispecific antibody than in untreated mice. Not only was the antibody very effective at stimulating T-cells, but also successful in promoting helper T-cell function and immune system memory, suggesting that if used to treat humans, it could allow the body to better sustain tumor immunity.
However, in a clinical trial conducted by other researchers, a large dose of anti-CD28 antibody was observed to have caused extreme toxicity in their subjects. Subsequent investigation by Sanofi scientists indicated that these toxic effects could be avoided by using safe dosages of the antibody. To find out which dosages would work optimally while minimizing toxicity, the researchers tested on monkeys. By administering the drug via injection under the skin (as opposed to intravenous injection) or by giving numerous doses of the drug in gradually increasing amounts, it was observed that the toxic effects of the antibody treatment could be minimized.
Trispecific antibodies have demonstrated the potential to increase immunotherapy efficacy and possibly even successfully treat some of the difficult cancer cases and types that are still resistant or unresponsive to current treatments. As this technology advances, different types of trispecific antibodies could be used to treat a wider range of cancers and other infectious diseases as well.
 L. Wu, et al., Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nature Cancer 1, 86-98 (2019). Doi: https://doi.org/10.1038/s43018-019-0004-z
 Image retrieved from: https://search.creativecommons.org/photos/dc6123e2-f86e-4e35-88bd-7365298b5981