Researchers at the University of Pennsylvania were pioneers in the development of CAR-T cells—immune cells that are taken from patients and engineered to be able to recognize and fight some forms of blood cancer. Now, another Penn team is reporting progress in the effort to advance a related technology that’s designed to tackle solid tumors, which have proven difficult to address with CAR-Ts.
The new technology is called human chimeric antigen receptor macrophages, or CAR-Ms. The therapy is designed to address several major shortcomings of CARs that are attached to T cells, including their limited ability to reach solid tumors and their susceptibility to becoming crippled by the immunosuppressive microenvironment that typically surrounds the tumors. Macrophages, another type of immune cell, are naturally drawn to solid tumors and better equipped to survive in a hostile tumor environment, the Penn researchers believe.
The researchers engineered macrophages to express an anti-HER2 CAR and tested it in mouse models of human solid tumors. A single infusion of the therapy shrank tumors and prolonged survival in the animals, the team reported in Nature Biotechnology. The technology is now being developed by Carisma Therapeutics, a Penn spinout that raised $53 million in a series A financing led by AbbVie and HealthCap in 2018. (It then extended the funding round, picking up an additional $6 million.)
Carisma’s technology involves attaching CARs to macrophages using an adenovirus vector. The researchers believe the CAR-Ms upregulate genes that activate patients’ innate immune cells, including T cells, to further boost the anti-cancer response.
For the new study, Carisma researchers tested the HER2-directed CAR-Ms in two separate mouse model of metastatic ovarian cancer. In addition to prolonging survival, they reported, the therapy changed the tumor microenvironment in ways that allowed it to beat back the cancer, even in the presence of immunosuppressive cells.
There are several different approaches under investigation for translating CAR-T technology to solid tumors. A Massachusetts Institute of Technology team reported last year that after they used a vaccine to stimulate CAR-Ts at the lymph nodes in animal models of solid tumors, the cells were better able to withstand the hostile tumor microenvironment. A team at the University of North Carolina at Chapel Hill is targeting glioblastoma using CAR-Ts that are enhanced with two proteins to improve their targeting and activation.
The Penn researchers who founded Carisma believe their new study provides evidence that engineering CARs with macrophages could be the key to combating solid tumors. They’re now planning a phase 1 human trial of the HER2-targeted CAR-M, called CT-0508.
“Our findings also leave open the possibility for combination therapy in the future with other agents that play a role in cell death pathways or T-cell-based immunity,” said co-author Michael Klichinsky, Ph.D., co-founder and vice president of discovery for Carisma, in a statement.