For over a century, harnessing the power of the immune system to treat cancer has been hypothesized as an effective strategy to eliminate tumor cells and provide protection against tumor recurrence. In the last decade, this hypothesis has been proven correct and unprecedented clinical results have been achieved in hematological malignancies treated with genetically modified autologous T cells and in solid tumors with high mutation burden using checkpoint inhibitors. Adoptive T cell therapy describes the use of autologous T cells that are in most cases genetically modified to express either a T cell receptor that is specific for a tumor peptide:MHC complex (TCR-Tg T cells) or a chimeric antigen receptor (CAR) specific for a tumor-associated cell surface antigen. Chimeric antigen receptors consist of an antibody-based antigen-binding domain known as a single chain variable fragment (scFv) that is linked to a hinge, (that allows the receptor to move freely on the surface of the cell), a transmembrane domain (to anchor the receptor in the cell membrane) and intracellular signaling domains that initiate T cell activation upon scFv-ligand engagement. CAR-T cells genetically re-directed against CD19, a molecule expressed on B cells from the pro-B to late plasmablast stage, have received FDA approval for the treatment of human patients with refractory or second relapse acute lymphoblastic leukemia and B-non Hodgkin Lymphoma. Despite success in hematological malignancies, the use of adoptive T cell transfer using CAR-T cells and TCR-Tg T cells in solid malignancies has been less effective. This is in part due to the hostile, immunosuppressive tumor microenvironment frequently associated with solid tumors, which inhibits the effector function of adoptively transferred T cells and their survival within the tumor. Tumor stromal elements including regulatory T cells, myeloid derived suppressor cells, IDO and checkpoint molecules contribute to this hostile environment and must be overcome to enable ACT to attain the same success as seen with hematological malignancies. Another major challenge for the advancement of ACT is the ability to generate allogeneic ACT products that can be used in an off-the-shelf manner without concern for GVHD or immune rejection. Advanced gene-editing technologies are now addressing this need. Finally, the use of ACT for the treatment of autoimmunity, allergy and infectious disease is now being explored. The current state and future prospects of ACT using genetically modified T cells and its application in veterinary medicine will be discussed in this lecture.
Learning Objectives:
Upon completion, participants will be able to define adoptive cell therapy (ACT) and describe the different types of ACT
Upon completion, participants will be able to describe how a chimeric antigen receptor T cell works and key clinical results that have been achieved using CART in the human clinic.
Upon completion, participants will be able to describe the major obstacles to effective CAR T cell therapy and potential solutions to further increase the effectiveness of therapy
