Rejection resistant CD30.CAR-modified Epstein-Barr virus-specific T cells as an off-the-shelf platform for CD30+ lymphoma

Abstract

Off-the-shelf (OTS) adoptive T-cell therapies have many benefits such as immediate availability, improved access and reduced cost, but face the major challenges of graft-vs-host disease (GVHD) and graft rejection, mediated by alloreactive T-cells present in the graft and host, respectively. We have developed a platform for OTS T-cell therapies by using Epstein-Bar virus (EBV)-specific T-cells (EBVSTs) expressing a chimeric antigen receptor (CAR) targeting CD30. Allogeneic EBVSTs have not caused GVHD in several clinical trials, while the CD30.CAR, that is effective for the treatment of lymphoma, can also target alloreactive T-cells that upregulate CD30 on activation. Although EBVSTs express high levels of CD30, they were protected from fratricide in cis, by the CD30.CAR. Hence, they could proliferate extensively and maintained function both through their native EBV-specific T-cell receptor (TCR) and the CD30.CAR. The CD30.CAR enabled EBVSTs to persist in co-cultures with naïve and primed alloreactive T-cells and eliminate activated NK cells that can also be alloreactive. In conclusion, we show that CD30.CAR EBVSTs have the potential to be an effective OTS therapy against CD30+ tumors and if successful could then be used as a platform to target other tumor antigens.