Designing universal T cell therapies: strategies to evade natural killer cells

Cell therapies such as chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cells marked transformative advances in the treatment of hematologic and solid malignancies, respectively. Thus, adoptive T cell therapy (ACT), in which autologous T cells sourced from the patient constitute the starting immune population, represents a contemporary modality for the treatment of cancers. The need of an autologous cell product poses scientific and logistical challenges that need to be overcome to develop efficacious, scalable and cost-effective ACT. Peripheral blood lymphocytes procured from healthy donors can serve as a starting population for manufacturing a universal allogeneic T cell product offering solutions to both challenges. Recent advances in gene-engineering and -editing technologies have facilitated progress in the development and large-scale manufacturing of allogeneic T cell products. A strategy in development of allogenic ACT is ablation of the TCRαβ/CD3 complex to avoid graft versus host disease mediated by unrelated donor T cells. Mitigating host allogeneic T cells recognition is a complex endeavor that may begin with HLA-I/-II ablation, avoiding recognition and rejection of "non-self" HLA molecules. However, HLA-deficient T cells are susceptible to host NK cell recognition via the "missing-self" response. Here, we discuss immune evasive strategies taken to reduce NK cell mediated rejection of HLA-deficient T cells with particular emphasis on exploitation of HLA-E, a non-classical HLA-I, with regulatory function on NK cell activity. Current progress suggests that off-the-shelf universal T cell products may evolve to become a standard of care treatment options for certain disease indications.