Connecting the dots: adapting innovative antibody technology to improve cancer immunotherapy

Turns out there are times when it’s important to improve on mother nature, especially when confronting a life-threatening disease.

This is what we were trying to do when we developed a new approach to cancer immunotherapy using a recombinant antibody platform that allows recognition of multiple targets by one protein. 

Normally, antibodies recognize one target. Trispecific antibodies have been created in the laboratory that allow three targets to interact with one protein and were described previously our lab (Xu et al. Trispecific broadly neutralizing HIV antibodies mediate potent HIV protection in macaques, Science 358: 85-90,2017).   We took advantage of this technology and its multi-functionality to develop an experimental treatment that targets tumor cells while also stimulating optimal immune function.  Together, it leads to more effective tumor recognition and rejection lysis in a humanized mouse cancer model. 

Our findings published today in the first issue of Nature Cancer were performed by a Sanofi research team who evaluated a novel trispecific antibody in human myelomas in cell culture and in animals. It represents an attempt to improve the efficacy of cancer immunotherapy by targeting multiple antigen sites in order to stimulate, strengthen and direct the body’s natural defenses against a cancer.

The power of T cell co-stimulation in the immune system became apparent to the immunology community from basic studies on T cell activation and T cell receptor function dating back to the 1980’s and 1990’s.  As a professor at the University of Michigan and investigator at its Howard Hughes Medical Institute in the 1990’s, I became aware of this pathway through collaborations with Carl June and Craig Thompson in the 1990s.  At the time, my lab was working on gene therapy for HIV. We were engineering T cells to become resistant to HIV infection by expressing an anti-viral gene (Rev M10).  To test this concept, we genetically modified T cells and returned them to patients and showed that the anti-viral protein prolonged T cell survival in the body (Woffendin C, Yang Z, Udaykumar, Xu L, Yang NS, Sheehy MJ, Nabel GJ.  Non-viral and viral delivery of a human immunodeficiency virus protective gene into primary human T cells.  Proc. Natl. Acad. Sci. USA 91(24):11581-11585, 1994).  To do this, it was necessary to expand those gene-modified T cells in the lab.  When we stimulated T cells by engaging CD3 (a T cell receptor activation signal e.g. signal 1) and CD28 (a survival signal e.g. signal 2), the results were like nothing we had ever seen before…. The co-stimulatory effect led to exceptional T cell proliferation!

This synergy stimulated by dual engagement was striking and stayed with me over the years. Carl and Craig continued to work on this mechanism and later used it to grow CAR T cells and improve immune-based cancer therapy. After our Sanofi team developed the trispecific antibody technology, we realized that it might be possible to engage CD3 and CD28 while targeting T cells to tumors with a third arm, CD38, which is highly expressed on myelomas, all interactions mediated by this one protein.  We demonstrated that administration of this trispecific antibody suppressed myeloma growth in a humanized mouse model and also stimulated memory/effector T cell proliferation in non-human primates.

We still have much work to do to determine whether this multi-specific targeted approach stimulate tumor regression in people with cancer. But, suffice to say, this outcome is encouraging and is opening research avenues to help us achieve our goal to bring new immuno-therapies that help to harness the full potential of our body’s immune system to defeat cancer.