Biology subjects

Ishizuka, A. S.

Publications and source records attributed to Ishizuka, A. S..

3 recordsLinked to original sources

bioRxiv2026

Spatiotemporal dynamics of adoptively transferred stem-like CD8+ T cells in the tumor microenvironment following vaccination

Adoptive cell therapy (ACT) of tumor-specific T cells can improve survival in a subset of cancer patients. Current ACT approaches may be limited by using highly differentiated T cells which can be inhibited by an immunosuppressive tumor microenvironment (TME). Here, we developed an approach to optimize ACT and used spatial transcriptomics to show how stem-like and effector CD8+ T cells differentially mediate tumor control following vaccination. Spatial transcriptomic profiling of the TME showed that ACT with stem-like T cells followed by intravenous vaccination prevented immune exclusion, increased infiltration of pro-inflammatory macrophages, and reprogrammed tumor cells to upregulate Type I and Type II IFN signaling and apoptotic gene programs. The protective transcriptomic signature of the TME in this ACT model contained overlapping biomarkers with patients who responded to ACT therapy. This approach demonstrates synergy between transferred stem-like T cells and intravenous vaccination to transcriptionally remodel the TME and enhance tumor control.

immunology↗

bioRxiv2026

Improving peptide vaccine manufacturability without sacrificing immunogenicity: substitution of methionine and cysteine with oxidation-resistant isosteres

AO_SCPLOWBSTRACTC_SCPLOWVaccines comprising peptide antigens for inducing T cell immunity are being developed for a broad range of therapeutic applications including prevention and treatment of cancer, autoimmunity, and infectious diseases. However, many peptide antigens contain cysteine and/or methionine, which are prone to form oxidation products that can present challenges to manufacturing and reduce biological activity. To address this challenge, we introduced oxidation resistant (OXR) antigens wherein the cysteine and methionine residues of naturally occurring, wild type (WT) peptide antigens are substituted with isosteric residues that are structurally related but omit the oxidation-prone sulfur atom. Our results showed that vaccination with OXR antigens substituting cysteine and methionine with isosteres alpha-aminobutyric acid and norleucine, respectively, induced immune responses to the WT antigen that were equivalent or higher than those induced by vaccination with WT antigens. T cell responses were not affected by the position of the amino acid substitutions indicating that the isosteres do not negatively impact major histocompatibility complex (MHC) binding or T cell recognition. The T cells induced were high quality and associated with anti-tumor efficacy in vivo. Interestingly, substitution of cysteine with serine, which replaces the sulfur for an oxygen, did not yield cross-reactive T cell responses, highlighting the high degree of molecular discernment of peptide-MHC processing and presentation. In sum, OXR antigens provide a generalizable strategy for eliminating sulfur oxidation products and improving the manufacturability and shelf-life of peptide-based vaccines without affecting desired biologic activity.

immunology↗

bioRxiv2024

Preclinical Development of a Stabilized RH5 Virus-Like Particle Vaccine that Induces Improved Anti-Malarial Antibodies

The development of a highly effective vaccine against the pathogenic blood-stage infection of human malaria will require a delivery platform that can induce an antibody response of both maximal quantity and functional quality. One strategy to achieve this includes presenting antigens to the immune system on virus-like particles (VLPs). Here we sought to improve the design and delivery of the blood-stage Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) antigen, which is currently in a Phase 2 clinical trial as a full-length soluble protein-in-adjuvant vaccine candidate called RH5.1/Matrix-M. We identify disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees, and a re-engineered and stabilized immunogen that includes just the alpha-helical core of RH5 induces a qualitatively superior growth-inhibitory antibody response in rats vaccinated with this protein formulated in Matrix-M adjuvant. In parallel, bioconjugation of this new immunogen, termed "RH5.2", to hepatitis B surface antigen VLPs using the "plug-and-display" SpyTag-SpyCatcher platform technology also enabled superior quantitative antibody immunogenicity over soluble antigen/adjuvant in vaccinated mice and rats. These studies identify a new blood-stage malaria vaccine candidate that may improve upon the current leading soluble protein vaccine candidate RH5.1/Matrix-M. The RH5.2-VLP/Matrix-M vaccine candidate is now under evaluation in Phase 1a/b clinical trials.

immunology↗