Cell Types Used for CAR Generation

The most common CAR T-cell product generated and infused into patients, today and in the past, is an unsorted, αβ Τ-cell derived directly from the cancer patient. Although this personalized autologous T-cell manufacturing method has many advantages and has resulted in outstanding clinical data in hematologic malignancies, a number of aspects require improvement for cell therapy to impact broader patient populations. The first aspect relates to the poor sustained anti-tumor response of CAR T-cells in solid tumors as well as a significant group of leukemia and lymphoma patients. Utilizing cells that naturally penetrate larger tumor masses better, kill through additional mechanisms, are less prone to antigen escape or intrinsic cytotoxic resistance, or that better establish and maintain an anti-tumor microenvironment, may overcome some of the deficiencies of CAR T-cells in poorly responsive tumors. Further, utilizing other cell types may lessen the tremendous cost of autologous manufacturing, the possibility of manufacturing failure in some patients, the length of time for manufacturing, and the side effect profile. This chapter will discuss alternative cellular sources developed to date, including allogeneic T-cells, Natural Killer (NK) cells, invariant NK T-cells (iNKT), induced pluripotent stem cells (iPSCs), T-cells of a defined CD4/CD8 ratio, T-cells of a defined memory phenotype, and myeloid cells modified with a CAR.