![]() in 1993 with an intratumorally applied liposomal formulation of immunotherapeutic DNA encoding for HLA (human leukocyte antigen)-B7. It is worth mentioning that the first clinical trial ever using in vivo gene transfer was conducted by Nabel et al. As depicted in Figure 1, such strategies aim (i) to deliver tumor-related antigen plus adjuvant to antigen presenting cells (APC) like dendritic cells (DC) that induce tumor-specific immune responses, (ii) to either deplete or reprogram tumor-induced/expanded immunoregulatory cell types, especially regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), which collectively inhibit the induction of adaptive immune reactions in the periphery, (iii) to generate tumor-specific T cells and natural killer (NK) cells by genetic introduction of synthetic antigen receptors, termed CARs (chimeric antigen receptors), and (iv) at the tumor site itself to yield direct tumor cell killing, and to inhibit the tumor-promoting function of the tumor microenvironment (TEM). This review aims to present a comprehensive overview of the current state of nucleic acid-based anti-tumor therapeutics, and associated optimization strategies. In this regard, nucleic acid-based immunotherapeutic approaches have received growing interest. Nanotechnology-based strategies, and in particular therapeutic nucleic acids, as well as combined immunotherapies may improve the therapeutic outcome in more patients for a broad range of tumors, even in late stage. However, still only a limited number of patients respond to the already approved immunotherapies, and toxicity as well as induction of resistance towards treatment are often a problem. As a consequence of a better understanding of the tumor as a heterogeneous tissue with different types of cells, new strategies for cancer therapy have been developed, which are also applicable in combination with classical therapies. In the last 20–30 years, however, cancer treatment regimens have changed remarkably, based on the gained knowledge about molecular biology as well as tumor pathobiology and pathophysiology. Moreover, the patients often suffer from severe side-effects. The main reasons for therapy failure are chemoresistance as well as metastasis. Conventional treatments (surgery, chemotherapy, and irradiation) are often inefficient, resulting in recurrence and even death. ![]() ![]() ![]() Depending on the tumor type, stage, and location, cancer therapy can be very challenging. Aside from further improvements of individual nucleic acid-based drugs, the major perspective for successful cancer therapy will be combination treatments employing conventional regimens as well as immunotherapeutics like checkpoint inhibitors and nucleic acid-based drugs, each acting on several levels to adequately counter-act tumor immune evasion.Ĭancer is a serious and life-threatening disease with increasing incidence in today’s world. This review intends to provide a comprehensive overview of the current state of the therapeutic use of nucleic acids for cancer treatment on various levels, comprising (i) mRNA and DNA-based vaccines to be expressed by antigen presenting cells evoking sustained anti-tumor T cell responses, (ii) molecular adjuvants, (iii) strategies to inhibit/reprogram tumor-induced regulatory immune cells e.g., by RNA interference (RNAi), (iv) genetically tailored T cells and natural killer cells to directly recognize tumor antigens, and (v) killing of tumor cells, and reprograming of constituents of the tumor microenvironment by gene transfer and RNAi. Furthermore, especially in the context of the development of biocompatible, cell type targeting nano-carriers, nucleic acid-based drugs aimed to initiate and to enhance anti-tumor responses have come of age. Within the last decade, the introduction of checkpoint inhibitors proposed to boost the patients’ anti-tumor immune response has proven the efficacy of immunotherapeutic approaches for tumor therapy.
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