Highly potent mRNA based cancer vaccines represent an attractive platform for combination therapies supporting an improved therapeutic effect

Abstract

Direct vaccination with mRNA encoding tumor antigens is a novel and promising approach in cancer immunotherapy. CureVac's mRNA vaccines contain free and protamine-complexed mRNA. Such two-component mRNA vaccines support both antigen expression and immune stimulation. These self-adjuvanting RNA vaccines, administered intradermally without any additional adjuvant, induce a comprehensive balanced immune response, comprising antigen specific CD4+ T cells, CD8+ T cells and B cells. The balanced immune response results in a strong anti-tumor effect and complete protection against antigen positive tumor cells. This tumor inhibition elicited by mRNA vaccines is a result of the concerted action of different players. After just two intradermal vaccinations, we observe multiple changes at the tumor site, including the up-regulation of many genes connected to T and natural killer cell activation, as well as genes responsible for improved infiltration of immune cells into the tumor via chemotaxis. The two-component mRNA vaccines induce a very fast and boostable immune response. Therefore, the vaccination schedules can be adjusted to suit the clinical situation. Moreover, by combining the mRNA vaccines with therapies in clinical use (chemotherapy or anti-CTLA-4 antibody therapy), an even more effective anti-tumor response can be elicited. The first clinical data obtained from two separate Phase I/IIa trials conducted in PCA (prostate cancer) and NSCLC (non-small cell lung carcinoma) patients have shown that the twocomponent mRNA vaccines are safe, well tolerated and highly immunogenic in humans.

mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer

“…Interestingly, an analysis of changes within the tumor showed a higher frequency and persistence of CD8C T cells after as few as two vaccinations. 41 Close to 70 genes were upregulated in the tumors of vaccinated mice, among these NK-cell related genes, markers of activated, cytolytic T cells as well as those encoding chemokines, IFN-g and IFN-g-related genes. 41 Furthermore, synergistic effects by the co-administration of anti-CTLA-4 antibodies were reported, which is of special interest regarding possible combinatory therapy regimens.…”

“…40 Despite these improvements of antigen expression, "naked" RNA was observed to be insufficient for immunostimulation. 41 To address this drawback, RNActive Ò derived mRNA is combined with protamine, which helps to arise Th1 T cell responses against antigens with the possible involvement of TLR7/TLR8. 27,42 As the protamine/mRNA complexes are very tight, the adjuvant effect comes at the cost of a weak antigen expression and depends strongly on the ratio between protamine and mRNA.…”

“…41 Furthermore, synergistic effects by the co-administration of anti-CTLA-4 antibodies were reported, which is of special interest regarding possible combinatory therapy regimens. 41 …”

A Self-Assembled Non-Viral vector as Potential Platform for mRNA-Based Vaccines

“…With the purpose to demonstrate that the proposed systems represent an important advancement of the current state-ofthe-art in the area of mRNA-base vaccine implementation, we decided to compare our vaccine formulation against protamine sulfate/mRNA polyplex (PS/mRNA), a non-viral vector widely employed for antigen-mRNA delivery and currently under study in several clinical trials for anti-cancer immunotherapy [40][41][42]. The detection of OVA-specific IFN-γ secreting cells in the spleen and lymph nodes of vaccinated mice, revealed a significantly higher number of primed T-cell in the mice treated with OVAmRNA loaded PEG-Polyplex than mice vaccinated with PS/OVAmRNA polyplex.…”

A personalized view on cancer immunotherapy

“…In this regard, it has been shown in preclinical and clinical studies that direct administration of mRNA as an anti-cancer vaccination strategy is feasible, safe and elicits potent T cell responses with therapeutic efficacy [92][93][94][95]. It is fair to state that mRNA became the focus of research in molecular medicine at the beginning of the millennium.…”