Download Full Text (1.4 MB)

Publication Date



A key hallmark of cancer cells is their ability to evade the immune system through a number of mechanisms including the down regulation of antigen presenting major histocompatibility complexes (MHC). Chimeric antigen receptor (CAR) technology addresses this problem by allowing for a patients’ T cells to be redirected toward different tumor antigens in an MHC independent manor. Although CAR therapy has been successful in the treatment of pediatric B cell malignancies, clinical outcomes have been disappointing for the treatment of most pediatric cancers. Some of these clinical limitations may be attributed to the unregulated surface expression of CARs, which leads to tonic signaling and T cell exhaustion. Moreover, CARs currently used clinically often induce cytokine release syndrome and can damage healthy tissues through on-target/off-tumor effects. While first and second generation (Gen1 and Gen2) CARs contain signaling elements from the T cell receptor (TCR) and costimulatory receptors, they lack key regulatory components necessary for proper T cell activation. To address these limitations, we designed a CAR which incorporates a single chain antibody (scFv) into the endogenous TCR complex. We hypothesize that incorporation of our CAR into the TCR complex will mimic endogenous T cell activation and regulation by including contributions from all CD3 members (CD3δ, CD3ε, CD3γ, and CD3ζ). Furthermore, we propose that endogenous regulation of CAR signaling will prevent the tonic signaling observed with Gen1 and Gen2 CAR constructs and allow for the formation of memory T cells. In contrast to the unregulated expression of Gen1 and Gen2 CARs, surface expression of our novel CAR was limited by the availability of the endogenous CD3 proteins. TCR-based CARs also induced the production of more physiologic levels of cytokines than Gen1 and Gen2 CARs, indicating that the risk of cytokine release syndrome may be lower with TCR-based CARs. Finally, using a xenograft model of B cell lymphoma, we have demonstrated the ability of TCR-based CARs to target and control tumor burden in vivo. Currently, we are examining the effector potential of our TCR-based CAR against pediatric solid tumors. Additionally, we are developing TCR-based CARs capable of signaling not only through the TCR complex but also through endogenous co-stimulatory receptors. In summary, we present a novel platform for CAR therapy that is likely to be less toxic and more broadly applicable than other CARs.

Document Type


Eliminating MHC Restriction From The T Cell Receptor As A Strategy For Immunotherapy