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.

Cellular immunotherapies are revolutionizing cancer treatment but suffer from serious limitations. Drawing inspiration from a surprising discovery we made working on fruit flies, we propose to revolutionize and democratize an emerging cellular immunotherapy called CAR-M. We further propose to generalize the approach to remove any unwanted cell or substance from the body – from cancer to drug resistant microbes to amyloid plaques.