Cancer Immunotherapy and Prophylactic Vaccines
The ideal cancer vaccine should activate the adaptive and innate immune system and induce a broad, potent, and long lasting immune response that would include balanced humoral as well as T cell-mediated responses. The direct vaccination with mRNA molecules encoding tumor-associated antigens is an elegant approach to let the patient’s body produce its own vaccine.
It is known that the human immune system recognizes bacterial DNA and viral RNA as "foreign" nucleic acids. Foreign DNA and RNA stimulate the mammalian innate immune system, the nonspecific immune system, through activation of Toll-like receptors (TLRs). Double-stranded RNA (dsRNA), a common viral intermediate, activates TLR3, whereas synthetic single-stranded RNA (ssRNA) and virus-related RNA activate human TLR7 and TLR8.2
A study published more than 10 years ago showed that direct injection of naked, unprotected mRNA induces specific cytotoxic T lymphocytes and antibodies suggesting that mRNAs can provide an attractive alternative to peptide and DNA-based vaccines in cancer immunotherapy. These discoveries later laid the foundation for the first mRNA-based immunotherapy.3
However, the use of naked RNA for vaccination in a clinical setting was not feasible. Additionally, naked mRNA molecules were not efficient in inducing maturation of antigen-presenting cells, but mRNA protected against RNase-mediated degradation by association with a cationic peptide or through a phosphorothioate backbone are very potent immunostimulating molecules.4 Conversely, the complexation of the mRNA, required for strong immune-stimulating activity, can inhibit the antigen translation. A two-component mRNA immunotherapeutic that contains free and protamine-complexed mRNA induces balanced adaptive immune responses and provides humoral and T cell mediated immunity; it supports both antigen expression and TLR7-mediated immune stimulation that is entirely HLA independent and is designed to be self-adjuvanting, a property which peptide- and protein-based vaccines lack.5
Early clinical studies in patients with castration-resistant prostate cancer and lung cancer have shown the favorable safety profile of this approach. It is noteworthy that mRNA-based vaccines don’t require any vehicle and are injected intradermally. Data presented earlier have shown that the specific mRNA-based immunotherapies in both trials were doing what they were supposed to do: Antigen-specific T-cells were detected in the majority of patients, independent of their HLA-background. Additionally, the frequency of antigen-unspecific B-cells was also increased in the majority of patients.6
The concept of mRNA-based vaccines is also under investigation for potential use as prophylactic vaccination for infectious diseases, and a recent proof-of-concept study in animal models for influenza was published in Nature Biotechnology.7