Abstract
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. 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. 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. 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.
Highlights
Cancer is a serious and life-threatening disease with increasing incidence in today’s world [1,2,3,4,5]
Until a few years ago, nucleic acid-based immunotherapeutics have proven successful in preclinical studies, but largely fell short of expectations when evaluated for therapeutic efficacy in clinical trials [57,61]
One major limit has been the lack of appropriate delivery systems required to prevent degradation of pDNA/mRNA, and to enable cell type-specific delivery [125,126]
Summary
Cancer is a serious and life-threatening disease with increasing incidence in today’s world [1,2,3,4,5]. Depending on the tumor type, stage, and location, cancer therapy can be very challenging. 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 [25,26,27,28,29]. 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. In this regard, nucleic acid-based immunotherapeutic approaches have received growing interest [24,30,31]. It is worth mentioning that the first clinical trial ever using in vivo gene transfer was conducted by Nabel et al in 1993 with an intratumorally applied liposomal formulation of immunotherapeutic DNA encoding for HLA (human leukocyte antigen)-B7 [32]
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