Nucleic Acid-Based Approaches for Tumor Therapy

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.

Recent Advances in Oligonucleotide Therapeutics in Oncology

“…TLR9 subfamilies are mainly expressed in B cells and plasmacytoid dendritic cells (pDCs) and recognize unmethylated CpG-DNA [ 55 ]. CpG motifs interact with TLR9 and activate B cells and pDCs, which boosts the immune response, leading to proliferation and differentiation of these cells and cytokine secretion, and the activation of genes involved in inflammatory responses [ 57 , 58 , 59 ]. In response to chemotherapy, TLR9 acts as a tumor sensor by recognizing tumor released DNA, triggering an immune response and activating tumor-specific cytotoxic T lymphocytes (CTLs) [ 57 ].…”

“…In response to chemotherapy, TLR9 acts as a tumor sensor by recognizing tumor released DNA, triggering an immune response and activating tumor-specific cytotoxic T lymphocytes (CTLs) [ 57 ]. This principle is exploited in the application of synthetic CpG oligonucleotides to enhance TLR9 related immune responses [ 57 , 58 , 59 ]. Currently, there are three types of CpG oligonucleotides being developed and tested in clinical trials, based on the types of immune cells activated: class A, B, and C. Class A CpG oligonucleotides (including ODN-2216) contain a single CpG motif and induce IFN-α secretion from pDCs [ 60 ].…”

Albumin Nanostructures for Nucleic Acid Delivery in Cancer: Current Trend, Emerging Issues, and Possible Solutions

“…Among all, immune checkpoint inhibitors have gained wide success in cancer treatment, however, only a limited number of patients benefit from these therapies, where the induction of resistance and toxicity are still huge problems [ 80 ]. Interestingly, nucleic acid therapeutics are emerging as the potential candidate for cancer immunotherapy, which may improve the therapeutic outcome in a wide range of tumors, and even in the late stages [ 81 ]. These nucleic acids include immunostimulatory DNA/RNA, genome editing nucleic acids, and mRNA/plasmid, which can be further translated to immunotherapeutic proteins [ 82 ].…”

Argonaute Proteins Take Center Stage in Cancers

“…To date, two RNAi-based drugs, ONPATTRO and GIVLAARI, have been approved by the FDA for the treatment of acute hepatic porphyria and peripheral nerve disease, respectively [ 123 ]. Cancer development is driven by overexpression or aberrant activation of proto-oncogenes; therefore, various therapeutics taking advantage of endogenous RNAi machinery, specifically targeting transcripts upregulated in cancer cells, have been developed and are currently undergoing clinical trials [ 124 ]. Given the efforts put into delineation of the detailed mechanisms of RNAi, development of novel RNAi-based approaches and methods of delivery, we are on the verge of broad engagement of RNAi for anti-cancer therapies.…”