Macrophage-targeted CAR T cells: Rethinking cancer immunotherapy

Immunotherapy represents a recent and promising new approach to cancer treatment. The use of novel genetic engineering techniques allows development of T cells tailored for specific attack of tumor cells. Such modified immune cells, referred to as chimeric antigen receptor T cells (CAR T), have shown impressive effects in the management of certain types of cancer that were previously refractory to treatment. Despite the promise of this form of therapy, there are still major challenges that need to be overcome in order for such therapy to become a viable treatment option for the vast majority of cancer patients. Refinement of current CAR T treatment strategies is therefore needed for widespread utility of this form of immunotherapy. In particular, launching a successful immune attack against solid tumors, including major classes of cancer such as breast, colon and lung, has proved difficult. This is largely due to the highly immunosuppressive nature of such tumors, allowing only short-lived immune responser against the cancer cells. Our project has involved the development and preclinical evaluation of a new approach to CAR T cell therapy focused on active modulation of tumor-infiltrating macrophages. Our results show that strong anti-tumor immune responses can be achieved by this approach in a number of animal models of solid tumors, and in in vitro models using human macrophages and tumor cells. The project has allowed in-depth understanding of the underlying mechanisms of action of this form of cancer treatment, and has identified factors critical to the success of such intervention. This knowledge will be instrumental for further preclinical/clinical development of this new form of CAR T therapy.

Prosjektet har gitt ny kunnskap om virkningsmekanismer for CAR T-basert immunterapi. Dette vil ha direkte relevans for videre preklinisk/klinisk utvikling av en slik behandlingsmodalitet for fremtidig kreftbehandling. Kunnskapen er også av bredere relevans for forståelsen av hvordan CD4+ T-celler interagerer med makrofager, og vi har utviklet modellsystemer som kan gi grobunn for fremtidig nasjonalt og internasjonalt forskningssamarbeid.

CAR T cell therapy uses genetically engineered immune cells to attack cancer cells, and represents one of the most significant breakthroughs in oncology. Despite radically improving the prognosis in some types of cancer, it remains ineffective in treatment of most solid tumors, including breast, colon and lung cancer. This is largely explained by the presence of a strongly immunosuppressive environment surrounding the cancer cells in solid tumors, which rapidly shuts down immune attacks. As a result, CAR T cells show no or only short-lived effects. To unleash the full potential of cellular immunotherapy, and make CAR T cell therapy a feasible treatment option for large groups of patients, there is therefore a need for new and more efficient treatment strategies. To address this issue, we have developed a novel form of immunotherapy that takes a new, radically different approach to fighting cancer. Our strategy involves attacking tumor-infiltrating macrophages, a cell type present in most types of cancer. Our engineered T cells target these cells, initiates a broad immunological attack of tumor cells, and actively counteracts immunosuppression. Since the cancer cells themselves are not the direct targets of the therapy, this provides a universal strategy to fight cancer using the immune system. Ongoing studies in mouse models have shown impressive responses against several types of advanced-stage cancer. This project involves optimisation and thorough preclinical evaluation our novel treatment concept in treatment of different types of cancer, using mouse models and patient-derived xenografted cancer cells. We aim to develop a high precision therapy that allows efficient and complete elimination of advanced-stage cancer, and pave the way for clinical evaluation of this new for of cancer immunotherapy. Our findings challenge current dogmas in immunotherapy, and will provide a deeper understanding of how efficient immune attacks against tumors can be achieved.