Clinically Relevant Immune Responses against Cytomegalovirus: Implications for Precision Medicine

Abstract

Immune responses to human cytomegalovirus (CMV) can be used to assess immune fitness in an individual. Further to its clinical significance in posttransplantation settings, emerging clinical and translational studies provide examples of immune correlates of protection pertaining to anti-CMV immune responses in the context of cancer or infectious diseases, e.g., tuberculosis. In this viewpoint, we provide a brief overview about CMV-directed immune reactivity and immune fitness in a clinical context and incorporate some of our own findings obtained from peripheral blood or tumour-infiltrating lymphocytes (TIL) from patients with advanced cancer. Observations in patients with solid cancers whose lesions contain both CMV and tumour antigen-specific T-cell subsets are highlighted, due to a possible CMV-associated “bystander” effect in amplifying local inflammation and subsequent tumour rejection. The role of tumour-associated antibodies recognising diverse CMV-derived epitopes is also discussed in light of anti-cancer immune responses. We discuss here the use of anti-CMV immune responses as a theranostic tool—combining immunodiagnostics with a personalised therapeutic potential—to improve treatment outcomes in oncological indications.

Affinity Maturation of a T-Cell Receptor-Like Antibody Specific for a Cytomegalovirus pp65-Derived Peptide Presented by HLA-A*02:01

“…Another approach is the transfer of donor-derived CMV-specific CTLs, but it remains limited due to the occurrence of graft-versus-host disease (GVHD) in allogeneic recipients [ 25 ]. The high-affinity TCR-like Ab C1-17 can be converted into a bispecific T-cell engager [ 20 ] and a chimeric antigen receptor (CAR) for CAR-T therapy based on the autologous T-cells to overcome allogeneic immunogenicity [ 3 , 26 ]. Moreover, C1-17 can be developed as a therapeutic Ab to eliminate CMV-infected cells through the effecter functions, such as Ab-dependent cellular cytotoxicity [ 27 , 28 ], or via a targeting agent to deliver cytotoxic payloads, such as potent drugs and toxins [ 9 , 29 ].…”

“…Human cytomegalovirus (CMV), a β-herpes virus with a double-stranded DNA, infects a wide variety of cells and establishes latency in the host [ 1 ]. CMV infection is very common in adults (60‒90% of the population), with higher infection rates with age [ 2 ], and is usually asymptomatic in healthy subjects but can cause severe diseases in immunocompromised patients with cellular immunosuppression or immunodeficiency, including transplant recipients and fetuses [ 1 , 3 ].…”

Trained Immunity for Personalized Cancer Immunotherapy: Current Knowledge and Future Opportunities

“…NKG2A + memory-like NK cells may, therefore, be clinically beneficial for cellular therapy of patients with HLA-E hi malignancies (de Kruijf et al, 2010;Benevolo et al, 2011;Gooden et al, 2011;Lin et al, 2011;Bjorklund et al, 2018). CMV may also imprint on anticancer directed immune responses, which may be of clinical relevance, since CMV as well as EBV-reactive T-and B-cells infiltrate into tumor lesions (Meng et al, 2018;Lerias et al, 2019). Reprograming of tumor-associate T-cells by epigenetic targeting of CD8 + tissue resident memory (Trm) cells and tumor infiltrating T-lymphocytes (TIL) may also promote tumor control, in part by increasing "mitochondrial fitness" (Li et al, 2019).…”

Guillain-Barré syndrome after adoptive cell therapy with tumor-infiltrating lymphocytes

“…Given that CMV-specific T cells have been isolated from TILs of patients with melanoma, 5 we assessed the presence of such cells in the TIL product as well as in blood pre-TIL-ACT and post-TIL-ACT. We reasoned that if the patient experienced CMV reactivation post-T-cell infusion, the product would not contain any measurable frequencies of CMV-specific T cells to provide immediate protection during the lymphopenic period, while such cells would eventually reconstitute from endogenous precursors.…”