1. Identify the physical site and process by which tumor-reactive T cells are activated:
We have recently sequenced the T cell clones that migrate into the tumor site following treatment with tumor-binding antibodies. Additionally, we have established a photoactivatable mouse model that enables us to monitor the migration patterns of T cells and DC. These experimental tools allow us to determine the anatomical site from which tumor-reactive T cells are recruited and to assess the process through which they were generated.
2. Define the mechanism by which tumor cells escape killing by T cells
To study this process, we established several mouse models in which tumors are drastically regressed following immunotherapy, yet relapse within a few weeks afterward. By characterizing the remaining tumor cells following effective immunotherapy, we encountered cells with unique morphological and metabolic features that have never been described before. These cells can survive the engagement with immune cells despite being recognized as targets by them and are the main cause of cancer relapse after effective immunotherapy. Importantly, we found that this cellular organization is induced specifically by T cells and could recapitulate the in vivo cancer cell morphology in experimental in vitro system.
3. Elucidate the biological basis for the interactions between T cell and antibodies
We have discovered a novel subset of CD4+ T cell, which express the high-affinity Fcg receptor and exert antibody-mediated cell cytotoxicity capabilities. Based on their unique killing machinery, we have engineered a genetic construct that enables the integration of complex signals, which are impossible to transmit using conventional CAR designs. Moreover, since targeting tumor cells is mediated by antibodies, this technology can be applied to treat a wide range of cancers, by the tumor-binding antibody. Indeed, our engineered T cells exerted remarkable killing capabilities of solid tumors in both in vitro and in vivo models and are about ten times more potent compare to conventional CAR T cells.
4. Engineering myeloid cells to express chimeric antigen receptors
While CAR T cells showed remarkable activity in liquid tumors, their efficacy in solid tumors is limited. One major limitation stems mainly from the unique microenvironment in solid tumors. as hypoxic and acidic conditions at tumor sites, along with an immunosuppressive capacity of tumor cells limit T cell infiltration, survival, and cytotoxic capacity. In contrast to T cells, myeloid cells migrate efficiently into tumor sites and are well adapted to survive and function under this harsh environment. However, while myeloid cells have the potential to produce cytotoxic compounds, they lack antigen-specific receptors that identify tumor cells. Nonetheless, we discovered that in contrast to cells of lymphoid lineage which can be induced to express chimeric receptors, myeloid cells prevent its expression through an unknown mechanism.