Stimulation and expansion of antigen-specific CD8 + T cell populations are often not sufficient to mediate a persistent response and, even in the presence of antigen-specific CD8 + T cells, tumors can persist and grow.
It is worth noting that a significant limitation of functional immunotherapy is the absence of an effective and durable CD8 + T cell-mediated cytotoxic response. Utilizing cancer vaccine strategies is an alternative type of cancer immunotherapy Sipuleucel-T is an example of a dendritic cell (DC)-based vaccine that has been approved for the treatment of prostate cancer. In particular, there is significant interest in understanding how the concurrent stimulation of both the innate and adaptive immune responses can generate effective cytotoxic T cell responses to eliminate tumor cells. The use of immune stimulants as adjuvants for cancer treatment has also been reported, with the use of Bacillus Calmette-Guérin (BCG) for bladder cancer treatment and interleukins for melanoma as examples. Our findings indicate that C16-R848 adjuvant pulsation to mRNA vaccine NP is a rational design strategy to increase the effectiveness of synthetic mRNA vaccines for cancer immunotherapy.Īdjuvant addition has been widely used for various prophylactic vaccines, such as the use of alum in the vaccine formulations for immunization against hepatitis A and B, diphtheria and tetanus, Haemophilus influenzae B, and others. control) and suppression of tumor growth when given post engraftment (60% reduction vs. The approach led to an effective anti-tumor immunity against OVA expressing syngeneic allograft mouse models of lymphoma and prostate cancer, resulting in a significant prevention of tumor growth when the vaccine was given before tumor engraftment (84% reduction vs. The C16-R848 adjuvant-pulsed mRNA vaccine NP approach induced an effective adaptive immune response by significantly improving the expansion of OVA-specific CD8 + T cells and infiltration of these cells into the tumor bed in vivo, relative to the mRNA vaccine NP without adjuvant. This mRNA vaccine NP formulation retained the adjuvant activity of encapsulated C16-R848 and markedly improved the transfection efficacy of the mRNA (>95%) and subsequent MHC class I presentation of OVA mRNA derived antigen in antigen-presenting cells. Here, we demonstrate a proof-of-concept adjuvant-pulsed mRNA vaccine nanoparticle (NP) that is composed of an ovalbumin-coded mRNA and a palmitic acid-modified TLR7/8 agonist R848 (C16-R848), coated with a lipid-polyethylene glycol (lipid-PEG) shell.
However, inefficient in vivo mRNA delivery along with a requirement for immune co-stimulation present major hurdles to achieving anti-tumor therapeutic efficacy. Synthetic mRNA represents an exciting cancer vaccine technology for the implementation of effective cancer immunotherapy.
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