Transforming Cancer Care by Transitioning from Traditional Chemotherapy to Advanced CAR-T Cell Immunotherapy

The treatment for cancer has undergone a paradigm shift in recent years due to the introduction of cellular-based targeted therapies and immunotherapy, particularly Chimeric Antigen Receptor (CAR)-T Cell Therapy. This narrative review examines the biology of how CARs function, along with the advances made in the development of CAR construct design over the last 3 decades. These advances include the addition of co-stimulatory signals such as CD28 and 4-1BB in the new generation CARs that improved T Cell proliferation and longevity. There have been multiple different Cancer types that have demonstrated a high degree of effectiveness using CAR-T Cell therapy, and the US FDA has approved the use of CAR-T Cell therapies for treatment of certain hematological malignancies, specifically B Cell Acute Lymphoblastic Leukemia and Diffuse Large B Cell Lymphoma. However, there remains a significant limitation for the use of CAR-T Cell therapies for solid tumor therapies. Three major limitations preventing CAR-T Cell therapies from being used as an effective treatment for solid tumors include the existence of an immune suppressive tumor microenvironment (TME), the physical barriers preventing T Cells from migrating to tumor sites, as well as tumor antigen heterogeneity preventing treatment efficacy. This review discusses potential emerging modalities for overcoming some of these limitations, including the development of "armored" CAR-T Cells, the use of multi-antigen targeting strategies to prevent antigen escape, and the development of combinatorial approaches to modulate the TME. Lastly, this review discusses future opportunities in the development of CAR-T Cell therapies, including the development of "off-the-shelf" allogeneic CAR-T Cells, in vivo gene delivery systems to create CAR-T Cells, and gene editing via CRISPR/Cas9 systems to increase the safety profile of CAR-T Cells and expand their therapeutic application beyond blood cancers.