Constantine MitsiadesPhD, MD
Dana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2026
Although they represent a major therapeutic progress for blood cancers, CAR-T cells and other T-cell based therapies are subject to eventual development of resistance to many patients. Natural killer (NK) cell-based therapies are highly active against many types of blood cancer cells which are resistant to T cells, but in our CRISPR studies death receptor signaling defects emerge as a common downstream mechanism of resistance to both T- and NK-cell therapies. Building on extensive pharmacological and genomic screens, this project will specifically examine the role of SMAC mimetics and JAK/STAT inhibitors in enhancing the response of blood cancer cells (e.g., multiple myeloma, leukemias) to CAR-T or NK cell therapies. We will place emphasis of studies with patient-derived samples in vitro (Integrated Functional Immune Profiling Platform) and in vivo, including humanized bone marrow-like scaffolds, to provide a translationally-relevant simulation of the potential of these compounds to enhance the clinical activity of cell-based immunotherapies in blood cancers.
Chimeric antigen receptor T (CAR-T) cells and other immunotherapies leveraging the activity of T-cells have had major impact in blood cancers, but many patients eventually relapse, highlighting the need for new approaches to overcome this resistance. Our collaborating groups recently documented that most blood cancer cells which are resistant to T cells remain highly responsive to natural killer (NK) cells, suggesting that NK cells can be promising therapies to overcome resistance to CAR-T or other T-cell therapies. However, we also observed that resistance to both CAR-T and NK cells can emerge in tumor cells with defects of the so called “death receptor signaling” cascade, a molecular system which helps immune cells to clear normal tissues from virally infected or damaged cells. “Death receptor signaling” is often at least partly active in malignant cells, but its defects can allow blood cancer cells in our studies the key advantage of escaping both T and NK cells. To identify therapeutic agents that can overcome this advantage, we conducted extensive screens among substances that are approved for clinical use for various conditions or have been administered in clinical trials: we identified that SMAC mimetics can bypass the advantage of blood cancer cells with “death receptor signaling” defects and render them highly sensitive to either T- or NK cells. We also identified that JAK/STAT inhibitors can augment the activity of NK cells against blood cancer cells. This project seeks to examine the ability of these 2 classes of compounds to improve the activity of CAR-T or NK cells against patient-derived blood cancer cells. To better simulate the clinical setting our studies will include testing of these patient cells in mice implanted with specialized ceramic scaffolds engineered to contain human bone marrow (BM) mesenchymal stromal cells (BMSCs): these latter nonmalignant cells are critical supporters of normal blood cell protection, but are often “highjacked” by blood cancer cells to protect themselves from drug treatments and immune effector cells. Mouse BMSCs cannot fully protect human blood cancer cells from these treatments, hence the significance of studying these patient-derived blood cancer cells within engineered “humanized” BM scaffolds in mice. We will also apply the Integrated Functional Immune Profiling Platform (IFIP), a preclinical laboratory system to assess how the behavior of tumor vs. nonmalignant cells in patient-derived blood cancer sample can be altered upon exposure to immunotherapies and/or drug treatments. We expect that this project to directly inform how these 2 classes of compounds can enhance the clinical efficacy of CAR-T or NK cells, e.g., if these compounds should be given at the same time as these immunotherapies or in sequence, and also identify subgroups of blood cancer patients that may be better candidates for participation in upcoming clinical trials of these inhibitors together with immune cell therapies