Provided are CAR-T compositions that are directed to HLA-DR. Certain provided HLA-DR CAR compositions exhibit low affinity for a polymorphic region of HLA-DR of a subject. Various in vitro and in vivo methods and reagents related to HLA-DR CAR-T are also provided. Methods described herein can include, for example, characterization of HLA-DR binding, proliferation of T-cells, as well as prevention and/or therapeutic treatment of cancer using a HLA-DR CAR-T composition provided herein.
