Banking on virus-specific T-cells (VSTS) to fulfill the need for "off the shelf" cell therapies

Adoptively transferred virus-specific T-cells (VSTs) have shown remarkable safety and efficacy for the treatment of virus-associated diseases and malignancies in hematopoietic stem cell transplant (HSCT) recipients, for whom VSTs are derived from the HSCT donor (DD-VSTs). Autologous VSTs have also shown promise for the treatment of virus-driven malignancies outside the HSCT setting. In both cases VSTs are manufactured as patient-specific products and the time required for procurement, manufacture, and release testing precludes their use in acutely ill patients. Further, good manufacturing practices (GMP)-compliant products are expensive, and failures are common in virus naive HSCT donors and in patient-derived VSTs rendered anergic by immunosuppressive tumors. Hence, highly characterized, banked VSTs (B-VSTs) that can be used for multiple unrelated recipients are highly desirable. The major challenges facing B-VSTs result from the inevitable mismatches in the highly polymorphic and immunogenic human leukocyte antigens (HLA) that presents internally processed antigens to the T-cell receptor leading to the requirement for partial HLA matching between B-VST and recipient. HLA mismatches lead to rapid rejection of allogenic T-cell products, and graft versus host disease induced by alloreactive T-cells in the infusion product. Here we summarize clinical outcomes to date of trials of B-VSTs used for the treatment of viral infections and malignancies, and their potential as a platform for chimeric antigen receptors targeting non-viral tumors. We will highlight the properties of VSTs that make them attractive off-the-shelf cell therapies, as well as the challenges that must be overcome before they can become mainstream.