Scientific Rationale: Why Macrophages?
Exciting results generated using T cells that bear chimeric antigen receptors (CAR-T cells) in leukemia and other hematologic malignancies show that the patient’s immune system can be engineered to eradicate cancer. However, unlike the positive results in hematologic malignancies, response rates in solid cancers have been disappointing. Since T cells penetrate poorly into solid tumors, we postulate that they are not the right immune cell type to use for immunotherapy of solid cancer. In contrast, macrophages are an innate immune cell that is actively recruited into the tumor microenvironment (TME), where they are abundant.
CAR-Macrophage Platform TechnologyTo improve upon current immuno-oncology approaches to the treatment of solid tumors, CARMA Therapeutics has established a novel platform for adoptive cancer immunotherapy by genetically engineering patient macrophages to create chimeric antigen receptor macrophages (CAR-macrophages). CAR-macrophage cells are poised to have better access to the TME because of active recruitment of monocyte/macrophages into the TME by tumor-derived factors called chemokines. In a sense, CAR-macrophages act as a Trojan horse. Once they enter the tumor, macrophages are less prone to the immunosuppression issues that T cells face in the TME, and are able to exert their natural function of phagocytosis, whereby they engulf and break down diseased material (such as cancerous or infected cells). Adoptive transfer of macrophages into cancer patients has already been performed, albeit without tumor-recognition capacity. The CAR Macrophage platform now brings together tumor recognition with the effector functions of macrophages.
Unique Macrophage Gene Engineering Capability
To date, significant gene engineering hurdles have precluded the use of macrophages in adoptive cell therapies. We have now developed a unique gene transfer approach to overcome those hurdles. Our novel macrophage engineering approach furthermore confers on our CAR-macrophages a desirable anti-tumor phenotype along with resistance to tumor-induced subversion that otherwise polarizes non-engineered macrophages to an immunosuppressive, pro-tumor phenotype.
Our therapies are intended to bring the power of cellular immunotherapy to the large number of solid tumor patients in whom other approaches fail. CARMA Therapeutics is building a pipeline with an initial focus on solid tumor indications using next generation cellular products, antibody combination therapy approaches and genetically engineered off-the-shelf products.
Our preliminary data include in vitro and in vivo experiments demonstrating that human macrophages can be endowed with antigen specificity upon genetic engineering with a tumor-specific targeting moiety, that CAR-macrophage cells selectively phagocytose (eat) and kill a variety of tumor cells, and that infusion of human CAR-macrophages into tumor-bearing mice leads to long-term tumor control and enhanced survival.
CARMA Therapeutics proposes to validate the power of the CAR-Macrophage platform through initially testing the safety and biological effect of CAR-macrophage therapeutics in patients with HER2-overexpressing malignancies through a basket trial approach. We project filing our first IND and enrollment of first patient in 2019. We are actively seeking partnerships for the development of complementary therapeutic approaches and we are convening a clinical advisory board to explore a broader set of indications.