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Simple Summary: Therapies with monoclonal antibodies (mAbs) targeting tumor-associated antigens (TAAs) or immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Nevertheless, the inevitable development of resistance and the failure to respond are among this approach's disadvantages, limiting the duration of disease- or progression-free and overall survival. As an alternative to therapeutically efficacious monoclonal antibodies, the concept of active immunization with vaccines has been repeatedly discussed. In particular, mimotopes, representing the B cell epitope of therapeutic mAbs, have been shown to induce immunological memory and effectively produce antibodies with similar functionality to the respective mAbs/ICIs. This review focuses on a new frontier of vaccinations directed against two cancer-relevant targets, addresses concerns about the safety of active immunization targeting PD-1 and discusses limitations and outlooks. The application of monoclonal antibodies (mAbs), targeting tumor-associated (TAAs) or tumor-specific antigens or immune checkpoints (ICs), has shown tremendous success in cancer therapy. However, the application of mAbs suffers from a series of limitations, including the necessity of frequent administration, the limited duration of clinical response and the emergence of frequently pronounced immune-related adverse events. However, the introduction of mAbs has also resulted in a multitude of novel developments for the treatment of cancers, including vaccinations against various tumor cell-associated epitopes. Here, we reviewed recent clinical trials involving combination therapies with mAbs targeting the PD-1/PD-L1 axis and Her-2/neu, which was chosen as a paradigm for a clinically highly relevant TAA. Our recent findings from murine immunizations against the PD-1 pathway and Her-2/neu with peptides representing the mimotopes/B cell peptides of therapeutic antibodies targeting these molecules are an important focus of the present review. Moreover, concerns regarding the safety of vaccination approaches targeting PD-1, in the context of the continuing immune response, as a result of induced immunological memory, are also addressed. Hence, we describe a new frontier of cancer treatment by active immunization using combined mimotopes/B cell peptides aimed at various targets relevant to cancer biology. [ABSTRACT FROM AUTHOR]

Therapeutic antibodies that block PD‐1‐mediated inhibition of T cells have revolutionized cancer therapy. Murine cancer models are an essential tool for testing the efficacy of PD‐1 blockers alone or in combination with other treatments. Depending on the isotype of the antibody and the host species, blocking antibodies can also exert cytotoxic activity towards cells expressing the target molecule. In the current issue of the European Journal of Immunology [Eur. J. Immunol. 2021. 51: 1473–1481], Polesso et al. demonstrate that depletion of PD‐1+ T cells by "blocking" PD‐1 antibodies can greatly impact the outcome of preclinical immunotherapy experiments. Whereas some PD‐1 antibodies promoted activation and proliferation of PD‐1‐expressing murine T cells, the authors report that administration of a particular PD‐1 antibody can result in a significant loss of antigen‐specific CD8 T cells in different in vivo models. These findings once more highlight that a comprehensive characterization of antibodies is warranted to avoid misinterpretation of immunotherapy studies. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors, which target coinhibitory T cell molecules to promote anticancer immune responses, are on the rise to become a new pillar of cancer therapy. However, current immune checkpoint-based therapies are successful only in a subset of patients and acquired resistances pose additional challenges. Finding new targets and combining checkpoint inhibitors might help to overcome these limitations. In this study, human T cells stimulated with allogeneic dendritic cells (DCs) were used to compare immune checkpoint inhibitors targeting TIM-3, BTLA, LAG-3, CTLA-4, and TIGIT alone or in combination with a PD-1 antibody. We found that PD-1 blockade bears a unique potency to enhance T cell proliferation and cytokine production. Other checkpoint inhibitors failed to significantly augment T cell responses when used alone. However, antibodies to TIM-3, BTLA, LAG-3, and CTLA-4 enhanced T cell proliferation in presence of a PD-1 antibody. Upregulation of coinhibitory T cell receptors upon PD-1 blockade was identified as a potential mechanism for synergistic effects between checkpoint inhibitors. Donor-specific variation in response to immune checkpoint inhibitors was attributed to the T cells rather than DCs. Additionally, we analyzed the regulation of checkpoint molecules and their ligands on T cells and allogeneic DCs in coculture, which suggested a PD-1 blockade-dependent crosstalk between T cells and APC. Our results indicate that several immune checkpoint inhibitors have the capacity to enhance T cell responses when combined with PD-1 blockade. Additional in vitro studies on human T cells will be useful to identify antibody combinations with the potential to augment T cell responses in cancer patients. [ABSTRACT FROM AUTHOR]

One of the major current trends in cancer immunotherapy is the blockade of immune checkpoint proteins that negatively regulate the immune response. This has been achieved through antibodies blocking PD-1/PD-L1 and CTLA-4/CD80/CD86 interactions. Such antibodies have revolutionized oncological therapy and shown a new way to fight cancer. Additional (negative) immune checkpoints are also promising targets in cancer therapy and there is a demand for inhibitors for these molecules. Our studies are focused on BTLA/HVEM complex, which inhibits T-cell proliferation and cytokine production and therefore has great potential as a new target for cancer treatment. The goal of the presented studies was the design and synthesis of compounds able to block BTLA/HVEM interactions. For that purpose, the N-terminal fragment of glycoprotein D (gD), which interacts with HVEM, was used. Based on the crystal structure of the gD/HVEM complex and MM/GBSA analysis performed on it, several peptides were designed and synthesized as potential inhibitors of the BTLA/HVEM interaction. Affinity tests, ELISA tests, and cellular-based reporter assays were performed on these compounds to check their ability to bind to HVEM and to inhibit BTLA/HVEM complex formation. For leading peptides candidates, all-atom and subsequent docking simulations with a coarse-grained force field were performed to determine their binding modes. To further evaluate their potential as drug candidates, their stability in plasma and their cytotoxicity effects on PBMCs were assessed. Our data indicate that the peptide gD(1-36)(K10C-T29C) is the best candidate as a future drug. It interacts with HVEM protein, blocks the BTLA/HVEM interaction, and is nontoxic to cells. The present study provides a new perspective on the development of BTLA/HVEM inhibitors that disrupt protein interactions. [ABSTRACT FROM AUTHOR]

Inhibitors of PD-1 signaling have revolutionized cancer therapy. PD-1 and PD-L1 antibodies have been approved for the treatment of cancer. To date, therapeutic PD-1 inhibitors have not been compared in a functional assay. We used an efficient T cell reporter platform to evaluate the efficacy of five clinically used PD-1 inhibitors to block PD-1 signaling. The half maximal effective concentrations (EC50) for nivolumab and pembrolizumab were 76.17 ng/ml (95% CI 64.95–89.34 ng/ml) and 39.90 ng/ml (34.01–46.80 ng/ml), respectively. The EC50 values of the PD-L1 inhibitors were 6.46 ng/ml (5.48–7.61 ng/ml), 6.15 ng/ml (5.24–7.21 ng/ml) and 7.64 ng/ml (6.52–8.96 ng/ml) for atezolizumab, avelumab, and durvalumab, respectively. In conclusion, a functional assay evaluating antibodies targeting PD-1 inhibition in vitro revealed that pembrolizumab is a slightly more effective PD-1 blocker than nivolumab, and that PD-L1 antibodies are superior to PD-1 antibodies in reverting PD-1 signaling. [ABSTRACT FROM AUTHOR]

[Display omitted] • This study was focused on blocking of PD-1/PD-L1 complex formation. • PD-1 derived peptides were used to design PD-1/PD-L1 complex inhibitors. • The interactions of peptides with PD-L1 were confirmed using the SPR technique. • The peptides inhibit PD-1/PD-L1 in cell based blocking bioassay. • The NMR studies confirmed that the inhibitors adopt β-harpin structure. Over the past few years, many molecules such as monoclonal antibodies, affibodies, nanobodies, and small compounds have been designed and tested as inhibitors of PD-1/PD-L1 complex formation. Some of them have been successfully implemented into clinical oncology practice. However, the majority of these compounds have disadvantages and limitations, such as high production price, potential for immunogenicity and/or prolonged clearance. Thus, new inhibitors of the PD-1/PD-L1 immune checkpoints are needed. Recently, peptides emerged as potential novel approach for blocking receptor/ligand interaction. In the presented studies we have designed, synthesised and tested peptides, which are potential inhibitors of the PD-1/PD-L1 axis. The amino acid sequences of the designed peptides were based on the binding sites of PD-1 to PD-L1, as determined by the crystal structure of the protein complex and also based on MM/GBSA analysis. Interactions of the peptides with PD-L1 protein were confirmed using SPR, while their inhibitory properties were studied using cell-based PD-1/PD-L1 immune checkpoint blockade assays. The characterization of the peptides has shown that the peptides PD-1(119–142)T120C-E141C, PD-1(119–142)C123-S137C and PD-1(122–138)C123-S137C strongly bind to PD-L1 protein and disrupt the interaction of the proteins. PD-1(122–138)C123-S137C peptide was shown to have the best inhibitory potential from the panel of peptides. Its 3D NMR structure was determined and the binding site to PD-L1 was established using molecular modelling methods. Our results indicate that the PD-1 derived peptides are able to mimic the PD-1 protein and inhibit PD-1/PD-L1 complex formation. [ABSTRACT FROM AUTHOR]