Ubiquitous Virus-Targeted CD8⁺ T Cells Can Be Redirected to Tumors

Although patients with cancer may exhibit dramatic responses to immunotherapies, not all patients respond to these treatments, which may in part be due to a dearth of cytotoxic CD8⁺ T lymphocytes (CTL) that recognize the epitopes displayed by human leukocyte antigen (HLA) on tumor surfaces. In an effort to circumvent this issue, Millar and colleagues developed antibody–peptide epitope conjugates (APEC) that retarget cytomegalovirus (CMV)-specific CTLs—which are potent and ubiquitous in adults—to tumor cells. An APEC consists of an antibody that binds a cell-surface protein connected to an immunogenic CMV epitope via a linker that can be cleaved by a tumor cell–specific protease, thus releasing the CMV epitope in the vicinity of tumor HLA class I molecules that can bind and present the epitope to circulating CMV-directed CTLs. After confirming that patients with cancer (like healthy individuals) have CMV-directed CTLs, tumor cells cultured in vitro were shown to have unoccupied HLA molecules that could be loaded with exogenously provided peptides. Further, tumor cells treated with APECs in which the antibody was conjugated to the CMV peptide epitope via a linker that can be cleaved by a cancer cell–specific protease activated CMV-directed CTLs. Following additional experiments to optimize the choice of peptide epitope and cleavage site, it was demonstrated in experiments using peripheral blood mononuclear cells that APECs activated only CTLs specific to their peptide epitopes, and these CTLs exhibited increased cytotoxicity and proliferative capability after exposure to the APEC-labeled tumor cells. In immunodeficient mice xenografted with human breast, liver, or lung tumors, APEC treatment delayed tumor growth or increased survival. In experiments using an immunocompetent mouse model of liver-metastatic colorectal cancer, APEC treatment alone did not produce a notable response; however, when immunosuppressive myeloid suppressor cells were depleted, APEC therapy substantially improved survival. Together, these experiments provide proof of concept for APECs and demonstrate how they can be rationally designed, paving the way for future work to optimize these therapies.

Millar DG, Ramjiawan RR, Kawaguchi K, Gupta N, Chen J, Zhang S, et al. Antibody-mediated delivery of viral epitopes to tumors harnesses CMV-specific T cells for cancer therapy. Nat Biotechnol 2020 Feb 10 [Epub ahead of print].

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