RaceCAR-M immunotherapy for cancer and beyond - Cellular immunotherapies like Chimeric Antigen Receptor T cells (CAR-T) extend the lives of
cancer patients who are otherwise out of options. These therapies represent a leap forward in
cancer treatment but suffer from severe limitations because 1) the tumor microenvironment
excludes and exhausts T cells including CAR-T cells, 2) some tumor cells escape by
downregulating the target antigen, 3) the therapy incites cytokine storms and autoimmune
reactions, and 4) cellular therapies are currently complex, time-consuming, and exorbitantly
expensive. Here we propose to overcome these limitations and thereby revolutionize,
generalize, and democratize cellular immunotherapies. A promising new cellular immunotherapy
approach is CAR-M (macrophage). Two Phase 1 clinical trials are in progress and it is clear that
the approach is safe though there is substantial room for improvement in efficacy. While CAR-M
has many advantages over CAR-T, it is clear that it would be of great value to enhance the
capacity of CAR macrophages to attack and kill cancer cells while sparing normal tissue. Based
on fundamental cell and developmental biology we have been doing in fruit flies, we discovered
how to greatly increase the ability of human macrophages to attack and kill specific whole target
cells of our choosing. Inspired by our discovery in fruit flies, we have been able to engineer
mouse and human macrophages to avidly and specifically engulf and kill cancer cells. Here we
propose to test this approach against the most prevalent solid tumors like breast, lung, and
colon, and against hard-to-treat cancers like ovarian, pancreatic, and glioblastoma. Another
huge limitation of cellular immunotherapies is their cost and complexity. We propose to
overcome this problem by greatly simplifying the production and delivery of CAR-M. We
propose to transform CAR-M into an affordable, off-the-shelf therapy. This will enable
generalization of the approach to hard-to-treat diseases beyond cancer, such as multidrug
resistant bacteria, viral and fungal infections, autoimmune diseases, and more.
