Cancer vaccines aim at eliciting tumor-specific responses for the immune system to identify and eradicate malignant tumor cells while sparing the normal tissues. Furthermore, cancer vaccines can potentially induce long-term immunological memory for antitumor responses, preventing metastasis and cancer recurrence, thus presenting an attractive treatment option in cancer immunotherapy. However, clinical efficacy of cancer vaccines has remained low due to longstanding challenges, such as poor immunogenicity, immunosuppressive tumor microenvironment, tumor heterogeneity, inappropriate immune tolerance, and systemic toxicity. Recently, bioinspired materials and biomimetic technologies have emerged to play a part in reshaping the field of cancer nanomedicine. By mimicking desirable chemical and biological properties in nature, bioinspired engineering of cancer vaccine delivery platforms can effectively transport therapeutic cargos to tumor sites, amplify antigen and adjuvant bioactivities, and enable spatiotemporal control and on-demand immunoactivation. As such, integration of biomimetic designs into delivery platforms for cancer vaccines can enhance efficacy while retaining good safety profiles, which contributes to expediting the clinical translation of cancer vaccines. Recent advances in bioinspired delivery platforms for cancer vaccines, existing obstacles faced, as well as insights and future directions for the field are discussed here.

Bioinspired and Biomimetic Delivery Platforms for Cancer Vaccines

MUC1 is a mucinous glycoprotein which is overexpressed and under or aberrantly glycosylated in many human malignancies. MUC1 is associated with cellular transformation and can confer resistance to genotoxic agents. L-BLP25 is a peptide vaccine strategy that targets the exposed core peptide of MUC1. In preclinical studies, L-BLP25 induced a cellular immune response characterized byT-cell proliferation in response to MUC1 and production of IFN-γ. Phase I and II trials have established the dose and schedule of the vaccine as well as its excellent safety profile. A randomized phase II trial of maintenance L-BLP25 versus best supportive care in patients with stage IIIB/ IV non-small cell lung cancer who experienced clinical benefit from initial therapy has been reported. Updated survival analysis of this trial continues to show a strong survival trend in favor of L-BLP25 (median survival, 30.6 versus 13.3 months) in a subgroup of patients with locoregional stage IIIB disease. These promising results will be tested in a phase III trial of L-BLP25 versus placebo in patients with stage III non-small cell lung cancer after response to primary chemoradiotherapy.

L-BLP25 : A peptide vaccine strategy in non-small cell lung cancer. Discussion

Here we present a protocol for the construction and use of two types of nanocarrier based on bacterial membrane materials for cancer vaccine delivery. Cancer vaccines induce tumor regression through triggering the specific T-cell responses against tumor neoantigens, a process that can be enhanced by nanocarrier delivery. Inspired by the body's natural immune defenses against bacterial invasion, we have developed two different types of nanocarrier based on bacterial membrane materials, which employ genetically engineered outer-membrane vesicles (OMVs), or hybrid membrane vesicles containing bacterial cytoplasmic membrane, respectively. The OMV-based nanocarriers can rapidly display different tumor antigens through the surface modified Plug-and-Display system, suitable for customized cancer vaccines when the tumor neoantigens can be identified. The hybrid membrane-based nanocarriers are prepared through fusion of the bacterial cytoplasmic membrane and the primary tumor cell membrane from surgically removed tumor tissues, possessing unique advantages as personalized cancer vaccines when the neoantigens are not readily available. Compared with chemically synthesized nanocarriers such as liposomes and polymer without intrinsic adjuvant properties, owing to the large amounts of pathogen-associated molecular patterns, the two nanocarriers can activate the antigen-presenting cells while delivering multiple antigens, thus inducing effective antigen presentation and robust adaptive immune activation. Excluding bacterial culture and tumor tissue collection, the preparation of OMV- and hybrid membrane-based nanocarriers takes ~8 h and 10 h for tumor vaccine construction, respectively. We also detail how to use these nanocarriers to create cancer nanovaccines and evaluate their immunostimulatory and antitumor effects. 

/pdf/nanocarriers-based-on-bacterial-membrane-materials-for-3u9jta10.pdf

Nanocarriers based on bacterial membrane materials for cancer vaccine delivery

Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable clinical success in eradicating hematologic malignancies. However, hostile microenvironment in solid tumors severely prevents CAR-T cells migrating, infiltrating, and killing. Herein, a nanoengineered CAR-T strategy is reported for enhancing solid tumor therapy through bioorthogonal conjugation with a nano-photosensitizer (indocyanine green nanoparticles, INPs) as a microenvironment modulator. INPs engineered CAR-T biohybrids (CT-INPs) not only retain the original activities and functions of CAR-T cells, but it is further armed with fluorescent tracing and microenvironment remodeling abilities. Irradiated with laser, CT-INPs demonstrate that mild photothermal intervention destroys the extracellular matrix, expanded blood vessels, loosened compact tissue, and stimulated chemokine secretion without damping CAR-T cell activities. Those regulations induce an immune-favorable tumor microenvironment for recruitment and infiltration of CT-INPs. CT-INPs triggered photothermal effects collapse the physical and immunological barriers of solid tumor, and robustly boosted CAR-T immunotherapy. Therefore, CAR-T biohybrids provide reliable treatment strategy for solid tumor immunotherapy via microenvironment reconstruction.

Nanoengineered CAR-T Biohybrids for Solid Tumor Immunotherapy with Microenvironment Photothermal-Remodeling Strategy.

Combining mannose receptor mediated nanovaccines and gene regulated PD-L1 blockade for boosting cancer immunotherapy.

Therapeutic cancer vaccines that harness the immune system to reject cancer cells have shown great promise for cancer treatment. Although a wave of efforts have spurred to improve the therapeutic effect, unfavorable immunization microenvironment along with a complicated preparation process and frequent vaccinations substantially compromise the performance. Here, we report a novel microcapsule-based formulation for high-performance cancer vaccinations. The special self-healing feature provides a mild and efficient paradigm for antigen microencapsulation. After vaccination, these microcapsules create a favorable immunization microenvironment in situ, wherein antigen release kinetics, recruited cell behavior, and acid surrounding work in a synergetic manner. In this case, we can effectively increase the antigen utilization, improve the antigen presentation, and activate antigen presenting cells. As a result, effective T cell response, potent tumor inhibition, antimetastatic effects, and prevention of postsurgical recurrence are achieved with various types of antigens, while neoantigen was encapsuled and evaluated in different tumor models.

Self-healing microcapsules synergetically modulate immunization microenvironments for potent cancer vaccination

The invention relates to a vaccine comprising an antigen and a biodegradable polymer blend matrix. The polymer blend contains a hydrophobic polymer and an amphiphilic block copolymer. The vaccine exists in a microcapsule mode; a multi-cavity structure is contained in the microcapsule; and the average particle size of the microcapsule is preferably 10 to 100 micrometers, preferably 30 to 60 micrometers. The microcapsule is prepared by the following method: preparing open-pore microspheres from a polymer blend; mixing the open-pore microspheres with an antigen-containing solution; and then sealing the open-pore microspheres loaded with an antigen solution to form the sealed microcapsule loaded with the antigen.

Microcapsule-based vaccine

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Self-healing microcapsules synergetically modulate immunization microenvironments for potent cancer vaccination

Microcapsule-based vaccine