The present invention relates to compositions and methods of generating modified hematopoietic stem or progenitor cells. One aspect of the invention includes a modified hematopoietic stem or progenitor cell comprising a nucleic acid capable of decreasing expression of an endogenous gene or a portion thereof, wherein the endogenous gene encodes a polypeptide comprising an antigen domain targeted by a chimeric antigen receptor (CAR). Another aspect of the invention includes a method for generating a modified hematopoietic stem or progenitor cell. Also included are methods and pharmaceutical compositions comprising the modified cell for adoptive therapy and treating a condition, such as an autoimmune disease or cancer. In certain embodiments, the invention includes a modified hematopoietic stem or progenitor cell comprising a nucleic acid capable of decreasing expression of CD33. In certain embodiments, the invention includes compositions and methods for treating cancer comprising administering CD33 CAR-T cells and modified hematopoietic stem or progenitor cells that are resistant to CD33-targeted therapy.
