In 2017, the FDA approved two immunotherapies based on a patient’s own genetically modified T-cells — Kymriah to treat B-cell acute lymphoblastic leukemia and Yescarta to treat B-cell lymphoma. These therapies rely on chimeric antigen receptor (CAR) T-cells which consist of collecting a patient’s own immune cells, engineering them to target a specific marker, and reinfusing the cells back into the patient. Because, these immunotherapies rely on T cells to distinguish friend from foe, they cannot be used against T-cell malignancies. The engineered T-cells could indeed kill cancerous T cells, but would also target and destroy themselves because of the close resemblance in target antigens.
To address this challenge, researchers at the Washington University School of Medicine in St. Louis led a study that uses the CRISPR gene editing technology to generate T-cells that can attack malignant T-cells without succumbing to friendly fire.
Many T-cell cancers express CD7, providing an attractive immunotherapy target. However, CD7 is also expressed by normal T-cells. Thus, CD7-targeted CAR T-cells induce T-cell fratricide, limiting therapeutic potential. To create a “fratricide-resistant” CAR T therapy, the authors used CRISPR-Cas9 to delete CD7 from primary T-cells. Next, the authors transduced the edited T-cells with a third-generation CAR backbone directed against CD7. In mice injected with T-cell acute lymphoblastic leukemia (T-ALL) cells, the mice treated with the CD7ΔCART7 cells has significantly prolonged survival over the controls. The CD7ΔCART7 cells prevented self-targeting and destroyed T-ALL cells both in vitro and in vivo.
Next, the authors aimed to reduce the risk of graft-versus-host disease (GvHD) by deleting the T cell receptor alpha chain (TRAC), also using CRISPR-Cas9. The TRAC deletion blocks TCR-mediated signaling, overcoming the reactive barriers that limit the use of non-self, allogeneic T-cells for therapy. Autologous therapies in use today have enormous sourcing, expansion, and storage challenges, and the use of allogeneic T-cells may alleviate those burdens. The double deletion of TRAC and CD7 in CART7 successfully prevented both self-targeting and GvHD, while maintaining robust CD7-directed T-ALL killing. This CD7ΔTRACΔCART7 cell line was termed universal CART7 or UCART7.
Altogether, this study presents an “off-the-shelf” CAR-T therapy that successfully targets CD7+ T-cell acute lymphoblastic
leukemia, offering great promise for allogeneic adoptive cell therapies geared towards T-cell malignancies. The study, titled “An ‘off-the-shelf’ fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies,” was published in Leukemia.