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Review
. 2023 Jul 25;15(15):3767.
doi: 10.3390/cancers15153767.

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

Isabel Britsch  1 , Anne Paulien van Wijngaarden  1 , Wijnand Helfrich  1
Affiliations
Review

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

Isabel Britsch et al. Cancers (Basel). .

Abstract

Infection with cytomegalovirus (CMV) is highly prevalent in the general population and largely controlled by CD8pos 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 CD8pos 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 CD8pos 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.

Keywords: ACT; CMV; T cells; cancer immunotherapy; memory inflation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Proposed mode of action of TEDbodies (adapted from Jung et al. [39]). TEDbodies deliver HLA-I-restricted CMV peptide epitopes to cancer cells, thereby rendering them susceptible to elimination by pre-existing (inflationary) anti-CMV CD8pos T cells. TEDbodies bind to integrin αvβ5/αvβ3 on the surface of cancer cells, and are internalized and then relocated into the cytosol through endosomal escape. Subsequent cleavage by proteasomes creates precursor CMV peptides that are taken up into the ER and N-terminally trimmed. Mature CMV peptides bind to the cognate HLA-I complex and are transported through the ER–Golgi pathway to the surface of cancer cells. Anti-CMV CD8pos T cells then recognize and eliminate CMV peptide-presenting cancer cells.
Figure 2
Figure 2
Proposed mode of action of APECs (adapted from Millar et al. [41]). APECs deliver HLA-I-restricted CMV peptide epitopes to the surface of cancer cells, thereby rendering them susceptible to elimination by pre-existing (inflationary) anti-CMV CD8pos T cells, as follows: tumor-directed antibodies bind to corresponding target antigens on cancer cells. Cancer-associated matrix metalloproteases (MMPs) cleave the linker used to conjugate the CMV peptide of choice to an antibody moiety. Subsequently, the CMV peptide is released and binds to an ‘empty’ HLA-I molecule present on the surface of cancer cells. Anti-CMV CD8pos T cells can now recognize and eliminate CMV peptide-presenting cancer cells.
Figure 3
Figure 3
Proposed mode of action of intratumoral (i.t) injection of CMV peptide epitopes. I.t. injection delivers MHC-I-restricted and MHC-II-restricted CMV peptide epitopes into the tumor microenvironment. MHC-I-restricted CMV peptide epitopes are taken up by empty MHC-I molecules on the surface of cancer cells. Anti-CMV CD8pos T cells can now recognize and eliminate CMV peptide-presenting cancer cells. MHC-II-restricted CMV peptide epitopes are taken up by empty MHC-II molecules on the surface of antigen-presenting cells (APCs). Anti-CMV CD4pos T cells bind, become activated, and secrete proinflammatory cytokines that promote the induction of an adaptive immune response.
Figure 4
Figure 4
Schematic and proposed mode of action of various tumor-directed fusion proteins comprising CMV peptide–HLA-I complexes. Typically, tumor-directed fusion proteins comprising CMV peptide–HLA-I complexes contain a CMV peptide-equipped HLA-I/β2M complex and a tumor-directed antibody fragment (or whole antibody). These fusion proteins bind to the respective target antigen that is selectively (over)expressed on the surface of cancer cells via their antibody domain and thereby ‘present’ exogenous CMV peptide–HLA-I complexes. Anti-CMV CD8pos T cells can then recognize and eliminate CMV peptide-presenting cancer cells.
Figure 5
Figure 5
Therapeutic procedure and proposed mode of action of CMV-CAR T cells. PBMCs are isolated from cancer patient (or donor) blood using leukapheresis. Anti-CMV CD8pos T cells are expanded by CMV peptide stimulation and subsequent supplementation with cytokines. Subsequently, anti-CMV CD8pos T cells are transduced with CARs, expanded, and cryopreserved until intravenous reinfusion. CMV-CAR T cells expand (and are maintained) in vivo following endogenous TCR interaction with latent virus antigens (cross-)presented by APCs. Simultaneously, CMV-CAR T cells migrate to the tumor site and eliminate cancer cells via their TCR.
Figure 6
Figure 6
Therapeutic procedure and proposed mode of action of expanded/reactivated anti-CMV CD8pos T cells for glioblastoma treatment. PBMCs are isolated from the blood of the patient using leukapheresis. Anti-CMV CD8pos T cells are expanded by CMV peptide stimulation and subsequent supplementation with cytokines. A phenotypic analysis is performed to ensure adequate quality of anti-CMV CD8pos T cells. After sufficient expansion, functional anti-CMV CD8pos T cells are cryopreserved until intravenous reinfusion. Reinfused anti-CMV CD8pos T cells migrate to the tumor site, recognize, and eliminate CMV-positive cancer cells.
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