Cellectis shared how its novel immune-evasive universal CAR T cells may potentially deploy large amounts of T-cell product candidates to target multiple malignancies.
Cellectis has introduced what could be a new engineering approach to enable large-scale T cell product deployment in allogeneic therapy settings.
In a paper published in Nature Communications, Cellectis shared how its novel immune-evasive universal CAR T cells may potentially deploy large amounts of T-cell product candidates to target multiple malignancies.
While the concept of using universal CAR T cells against tumor cells is not new, the full potential of this method in allogeneic environments has yet to be seen. Success means having CAR T cells that can kill tumor targets while avoiding host immune system depletion through the host versus graft (HvG) reaction and proliferating without attacking host tissues through the graft versus host (GvH) reaction. Preventing GvH is possible with an inactive T cell receptor T αβ (TCRαβ) expression in a CAR T cell. However, ensuring that HvG does not happen is still challenging.
For its research, Cellectis scientists engineered CAR T cells to be low in Class 1 major histocompatibility complex (MHC-1) and to express the natural killer (NK) inhibitor HLA-E to endow them with immune-evasive properties toward alloreactive NK cells and T cells.
“This engineering approach is very promising and could enable the universal CAR T cells to become transiently invisible to NK and alloreactive T-cells, allowing them to eradicate tumor cells before being rejected by the patient’s immune system. This could enable the broad use of universal CAR T cells in allogeneic settings, for the benefit of a wider population of patients,” Julien Valton, Ph.D., vice president for gene therapy at Cellectis, said in a statement.
In its paper, Cellectis shared that using TALEN-mediated gene editing and adeno-associated virus-dependent gene insertion to endow CAR T-cells with immune-evasive properties is efficient. It is also adaptable to conventional CAR T cell manufacturing processes and transferable to various CAR constructs.
“We believe this next generation of universal CAR T cell has the potential to improve the therapeutic outcome of off-the-shelf therapeutic T cell products and to allow their large-scale utilization against multiple malignancies for the benefit of a broader range of patients,” the researchers wrote in their summary.
Researchers also observed that even with highly active NK cells, immune-evasive universal CAR T cells overcame alloresponsive T cell and NK cell attacks. In addition, immune-evasive properties versus NK cells from acute myeloid leukemia patients and most healthy donors were similar in terms of the transportability and robustness of the approach to persistence. Researchers recommend further exploration of this process in preclinical and clinical settings.
“One potential advantage of this approach is to spare endogenous immune effectors and allow them to work in concert with CAR T-cells in the fight against hard-to-treat cancers, including solid tumors,” Laurent Poirot, Ph.D., senior vice president for immuno-oncology at Cellectis commented.
