piSTING: A Pocket-Independent Agonist Based on Multivalency-Driven STING Oligomerization.

The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket-dependent small-molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket-independent STING-activating agonists (piSTINGs), which act through multivalency-driven oligomerization to activate STING. Additionally, a piSTING-adjuvanted vaccine elicited a significant antibody response and inhibited tumour growth in therapeutic models. Moreover, a piSTING-based vaccine combination with aPD-1 showed remarkable potential to enhance the effectiveness of immune checkpoint blockade (ICB) immunotherapy. In particular, piSTING can strengthen the impact of STING pathway in immunotherapy and accelerate the clinical translation of STING agonists.

Myeloid Cell-Triggered In Situ Cell Engineering for Robust Vaccine-Based Cancer Treatment.

Following the success of the dendritic cell (DC) vaccine, the cell-based tumor vaccine shows its promise as a vaccination strategy. Except for DC cells, targeting other immune cells, especially myeloid cells, is expected to address currently unmet clinical needs (e.g., tumor types, safety issues such as cytokine storms, and therapeutic benefits). Here, it is shown that an in situ injected macroporous myeloid cell adoptive scaffold (MAS) not only actively delivers antigens (Ags) that are triggered by scaffold-infiltrating cell surface thiol groups but also releases granulocyte-macrophage colony-stimulating factor and other adjuvant combos. Consequently, this promotes cell differentiation, activation, and migration from the produced monocyte and DC vaccines (MASVax) to stimulate antitumor T-cell immunity. Neoantigen-based MASVax combined with immune checkpoint blockade induces rejection of established tumors and long-term immune protection. The combined depletion of immunosuppressive myeloid cells further enhances the efficacy of MASVax, indicating the potential of myeloid cell-based therapies for immune enhancement and normalization treatment of cancer.

Identification of a Self-Assembling Small-Molecule Cancer Vaccine Adjuvant with an Improved Toxicity Profile.

Protein or peptide cancer vaccines usually include immune potentiators, so-called adjuvants. However, it remains challenging to identify structurally simple, chemically accessible synthetic molecules that are effective and safe as vaccine adjuvant. Here, we present cholicamideß (6), a self-assembling small-molecule vaccine adjuvant with an improved toxicity profile and proven efficacy in vivo. We demonstrate that cholicamideß (6), which is less cytotoxic than its parent compound, forms virus-like particles to potently activate dendritic cells with the concomitant secretion of cytokines. When combined with a peptide antigen, cholicamideß (6) potentiated the antigen presentation on dendritic cells to induce antigen-specific T cells. As a therapeutic cancer vaccine adjuvant in mice, a mixture of cholicamideß (6) and a peptide antigen protected mice from the challenges of malignant cancer cells without overt toxicity. Cholicamideß (6) may offer a translational opportunity as an unprecedented class of small-molecule cancer vaccine adjuvants.

Self-assembling small-molecule adjuvants as antigen nano-carriers.

The effective co-delivery of antigens and immune potentiators (adjuvants) and the high degree of antigen presentation have been two major challenges in the development of subunit vaccines. Here, we address these issues by conjugating peptide antigens with cholicamide, a self-assembling small molecule adjuvant. Co-assemblies of the conjugates and cholicamide achieved high levels of both cytokine induction and MHC class II peptide presentation.

A chitosan-mediated inhalable nanovaccine against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with several antigenic variants, has grown into a global challenge, and the rapid establishment of an immune barrier is crucial to achieving long-term control of the virus. This has led to a great demand for easy preparation and scalable vaccines, especially in low-income countries. Here, we present an inhalable nanovaccine comprising chitosan and SARS-CoV-2 spike protein. The chitosan-mediated nanovaccine enabled a strong spike-specific antibody immune response and augmented local mucosal immunity in bronchoalveolar lavage and lungs, which might be capable of protecting the host from infection without systemic toxicity. In addition, the enhanced adaptive immunity stimulated by chitosan showed potential protection against SARS-CoV-2. Furthermore, inhalation of the nanovaccine induced a comparable antibody response compared to intramuscular injection. This inhalable nanovaccine against SARS-CoV-2 offers a convenient and compliant strategy to reduce the use of needles and the need for medical staff. Electronic Supplementary Material: Supplementary material (the immune activation of CS-mediated nanovacccine on BMDCs, cell viability, immune responses in lungs and BALF, serum chemistry and H&E histopathological analysis.) is available in the online version of this article at 10.1007/s12274-021-4012-9.