Editorial on “Cell Therapy, Bispecific Antibodies and Other Immunotherapies against Cancer”

This Special Issue in Cancers, "Cell Therapy, Bispecific Antibodies and other Immunotherapies Against Cancer", includes interesting reports and reviews on cell therapies and bispecific antibodies [...].

This year, the FDA granted accelerated approval for glofitamab, a CD20-CD3 bispecific antibody [32], against relapsed or diffuse large B-cell lymphomas (DLBCL).Many different designs of bispecific antibodies are developed with one domain binding to T/NK cells and another domain binding to cancer cell antigens: BITEs, Fc-containing, CrossMab, knob-hole, uni-, bi-valent and others [33,34].There are several advantages of bi-and tri-specific T cell engagers versus cell therapy, such as off-the-shelf availability, easier logistics of administration and more economical manufacturing [35].Several challenges exist for this approach, such as toxicity or repressive tumor microenvironment, that will be addressed in future pre-clinical and clinical studies.The improved engineering of antibodies and combination with inhibitors of tumor microenvironment can be applied to design these therapies.
Cancer vaccines (cell-based, peptide/protein-based, or gene-based) are another promising approach developed by several groups [36][37][38][39].The goal of cancer vaccines is to target cancer cells via antigen-specific effector T cells.Activated T cells recognize MHC (major histocompatibility complex) I-peptide complexes, effector T cells target tumor cells and memory T cells prevent tumor relapse.The dendritic vaccine is a promising approach that stimulates T cells against tumor antigens [40].The pulsing of DC with tumor cell lysate, tumor antigen or mRNA is a widely used approach for antigen delivery and the stimulation of an immune response.Dendritic cells are antigen-presenting cells and can be divided into several groups: conventional dendritic cells (cDC), plasmocytoid (pDC) and monocyte-derived DC (MoDC) [40].The benefit of cancer vaccines is that they can target intracellular antigens versus CAR-T cells or bispecific antibodies, which target extracellular tumor-specific antigens [40].Although conventional dendritic vaccines encounter limitations due to the low immunogenicity of cold tumors, the induction of immunogenic cell death (ICD) can convert cold tumors into hot tumors and improve DC vaccine potential.Immunogenic cell death can be achieved via chemotherapy, radiotherapy, photodynamic or photothermal therapy [40].The local delivery of immunostimulants can increase the effect of immunogenic cell death of tumors and lead to the activation of DC and effector T cells.
The combination of cell therapy, bi-, tri-specific antibodies, CAR-NK, immunomodulators, checkpoint inhibitors and vaccines will be developed in future pre-clinical and clinical studies [41][42][43].In addition, a personalized medicine approach will be used when patient tumors are sequenced to detect neoantigens that can be used for dendritic vaccine, bispecific antibody, and cell therapy development [35].The combination therapy targeting several tumor antigens will be used to better target heterogeneous solid tumors.All discussed linked approaches are presented in Figure 1.For example, bispecific antibody (EpCAM-CD3 Ab is shown in Figure 1) can be delivered into tumors using mRNA [44], embedded into LNP [45] and attract T cells to kill tumor cells.The lysed tumor cells can release tumor neoantigens, serve as a cancer vaccine for attracting dendritic cells and, in combination with co-stimulants (cytokines, chemokines, receptor ligands and other immuno-stimulants), can target distant circulating tumor cells [37,46,47].While EpCAM-CD3 mRNA-LNP was delivered intratumorally, future studies will expand the tumor-specific delivery of mRNA-LNP and the intravenous delivery of mRNA with tumor-specific expression of proteins.The proteins and antibodies can be produced inside tumors representing factories of proteins or antibodies, and secreted proteins will attract immune cells in the case of bispecific immune-engaging antibodies.Combination therapy with immunomodulators and checkpoint inhibitors will increase the efficacy of bispecific antibody and cell therapy to target distant metastatic tumor cells [48][49][50].

Conclusions
Novel immunotherapy approaches, including bispecific antibodies, cell therapies, checkpoint inhibitors, vaccines and immunomodulators or their combination, must be developed and tested in future pre-clinical and clinical studies.The mRNA-LNP is a novel approach to deliver bispecific antibodies locally by enhancing immunomodulators to target distant tumor cells.The personalized medicine approach with a high-throughput sequencing of tumor antigens, detecting novel antigens and targets for immunotherapy, will be developed for more effective anticancer therapies.Dendritic, peptide and protein vaccines will be improved via novel tumor targets.The reports from this Special Issue in Cancers provide a basis to further develop novel immunotherapies.

2 Figure 1 .
Figure 1.Bispecific antibody, immune T cell, immunostimulant and vaccine approaches.mRNA-LNP is shown for intratumoral delivery of bispecific antibodies.Secreted bispecific antibody attracts T cells to tumor and kills tumor cells.Tumor is lysed and serves as a tumor vaccine for stimulating further immune response in combination with immunostimulants.