Applications of Anti-Cytomegalovirus T Cells for Cancer (Immuno)Therapy

SIMPLE SUMMARY: Numerous studies have developed strategies to utilize anti-cytomegalovirus (CMV) T cells for cancer treatment, as they have many beneficial characteristics including extraordinarily high numbers and frequent presence in cancer tissues. In this review, we present multiple strategies that exploit anti-CMV T cells for cancer (immuno)therapy in various ways. We aim to advance the understanding of how anti-CMV T cells can be applied best to further improve treatment outcomes for cancer patients. For this purpose, we identify similarities and discuss benefits, disadvantages, and challenges of each strategy. Finally, we comment on the future directions of this new promising field of cancer (immuno)therapy. ABSTRACT: Infection with cytomegalovirus (CMV) is highly prevalent in the general population and largely controlled by CD8(pos) T cells. Intriguingly, anti-CMV T cells accumulate over time to extraordinarily high numbers, are frequently present as tumor-resident ‘bystander’ T cells, and remain functional in cancer patients. Consequently, various strategies for redirecting anti-CMV CD8(pos) T cells to eliminate cancer cells are currently being developed. Here, we provide an overview of these strategies including immunogenic CMV peptide-loading onto endogenous HLA complexes on cancer cells and the use of tumor-directed fusion proteins containing a preassembled CMV peptide/HLA-I complex. Additionally, we discuss conveying the advantageous characteristics of anti-CMV T cells in adoptive cell therapy. Utilization of anti-CMV CD8(pos) T cells to generate CAR T cells promotes their in vivo persistence and expansion due to appropriate co-stimulation through the endogenous (CMV-)TCR signaling complex. Designing TCR-engineered T cells is more challenging, as the artificial and endogenous TCR compete for expression. Moreover, the use of expanded/reactivated anti-CMV T cells to target CMV peptide-expressing glioblastomas is discussed. This review highlights the most important findings and compares the benefits, disadvantages, and challenges of each strategy. Finally, we discuss how anti-CMV T cell therapies can be further improved to enhance treatment efficacy.