Antigens in Cancer

Dear Colleagues,

The surface antigens which are restricted or more abundant in cancer cells can be exploited to deliver cytotoxic drugs, biologics, and immune cells to tumor cells. Tumor antigens can be either unique to tumor cells (tumor-specific antigens, TSAs) or relatively more abundant (tumor associated antigens, TAAs). TSAs can be created by the presence of new genetic material of viral origin (e.g., human papillomavirus) or by neoantigens generated by the inherent genetic instability of cancer cells. TAAs are present in normal cells but become abnormally overexpressed in tumor cells (e.g., PSMA, mesothelin, ICAM-1 or Her2) or those that are expressed primarily during embryonic development or are otherwise tissue-restricted (such as cancer testis antigens). TSAs have been more commonly identified as peptide epitopes in complex with MHC, although some neoantigens in common surface molecules have also been identified (e.g., EGFRvIII). All of these can be exploited for targeted therapies.

The types of drugs that are designed to be specific to tumor antigens are quite diverse. For example, drugs based on the radioisotope ¹⁷⁷Lutetium chelated to peptides specific to SSTR2 and PSMA have been approved as cancer therapy against SSTR2-positive gastroenteropancreatic/neuroendocrine cancers and metastatic castration-resistant prostate cancer, respectively. Antibodies are a natural choice to target tumor surface antigens, as these can kill tumor cells via various mechanisms involving natural killer cells, macrophages, complement activation or by directly blocking cell signaling. To further enhance antibody mediated killing, cytotoxic drugs conjugated to antibodies have been developed and proven efficacious, (e.g., T-DM1 (trastuzumab emtansine)).

Recently, T-cell immunotherapy has emerged as a powerful tool for personalized medicine, where autologous or allogeneic T cells are genetically modified to target tumor antigens by the expression of TCRs specific to tumor peptide/MHC complexes or by chimeric antigen receptors (CARs). However, the success of targeting a TAA for one drug type does not guarantee that it can be used for other types of drugs. For example, PSMA-specific radiotherapy (¹⁷⁷Lu-PSMA-617) has proven to be a highly effective drug with limited side effects. In contrast, recent trials with CAR T cells targeting PSMA reported multiple patient deaths, implying that the threshold of antigen density eliciting toxicity can be quite different depending on the type of treatment.

In this special issue, we are particularly interested in papers that report on the identification and/or characterization of novel antigens in cancer and different agents that target these novel antigens. Moreover, papers leading to the development of specific methodologies aiming at the better screening/identification/quantification of cancer antigens would be of great interest. Reviews that summarize current knowledge gained from the preclinical and clinical studies of TCR- and CAR-T cells against cancer would be particularly useful. Potential topics include, but are not limited to:

• Identification or prioritization of novel cancer antigens
• Methodologies for the detection of cancer antigens
• Next-generation or fine-tuning of TCR or CAR constructs to overcome immune suppression or avoid toxicity
• Novel cancer-antigen-specific small molecules or peptides as carriers of cytotoxic drugs or radioisotopes
• Novel antibody designs and formats for improved pharmacokinetics or conjugation with cytotoxic drugs or radioisotopes.

Prof. Dr. Moonsoo Jin
Guest Editor

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• tumor antigens
• immunotherapy
• chimeric antigen receptor (CAR)
• antibody conjugates
• drug carriers