Design, development and optimization of novel CAR T cells using Globo H as a target for solid tumors cell therapy

CARs are synthetic molecules that can combine the effector functions of T cells with the specificity of antibody binding domains, consisting of the TCR grafted to extracellular variable region of an antibody. They are composed by an extracellular antigen-recognition domain linked to an intracellular signaling domain. 

The extracellular antigen-recognition domain consists of an antibody single-chain variable (scFv) fragment which allows the CAR to recognize surface tumor-associated antigens; through the covalent link to CD3z, it is possible to activate T cell signaling. 

The presence of costimulatory cytoplasmic domains such as CD28, 4-1BB (CD137), ICOS and OX40 either individually or in combination allows and enhances CAR T cells proliferation and function. The choice of an antigen suitable for solid tumors represents a critical point in the development of new CAR T cells therapy, indeed it is fundamental that the antigen is expressed only by cancer cells to avoid the toxicity caused by on target-off tumor effects. To this extent, we produced a CAR construct engineered to express the variable heavy (VH) and the variable light (VL) chains from the scFv of the monoclonal antibody MBr1 directed against the tumor restricted antigen GloboH. It is overexpressed in several epithelial cancers, such as breast, prostate, lung, colon, liver, ovary and uterus. A complete phenotypic characterization is currently ongoing with the aim to define it role as a novel therapeutic candidate.