Intravenous heterologous prime-boost vaccination activates innate and adaptive immunity to promote tumor regression.

Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 T cells and tumor regression. ChAdOx1 administered intravenously (i.v.) had 4-fold higher antigen-specific CD8 T cell responses than mice boosted by the intramuscular (i.m.) route. In the therapeutic MC38 tumor model, i.v. heterologous prime-boost vaccination enhances regression compared with ChAdOx1 alone. Remarkably, i.v. boosting with a ChAdOx1 vector encoding an irrelevant antigen also mediates tumor regression, which is dependent on type I IFN signaling. Single-cell RNA sequencing of the tumor myeloid compartment shows that i.v. ChAdOx1 reduces the frequency of immunosuppressive Chil3 monocytes and activates cross-presenting type 1 conventional dendritic cells (cDC1s). The dual effect of i.v. ChAdOx1 vaccination enhancing CD8 T cells and modulating the TME represents a translatable paradigm for enhancing anti-tumor immunity in humans.

Overview on Mrna Vaccines Beyond Covid-19

COVID-19 mRNA vaccines: COVID-19 pandemic has made an extraordinary impact on global vaccine technology platform developments. Never in human history have there at least 6 vaccine platforms including: inactivated, protein subunit, VLP and other 3 new platforms i.e., mRNA, viral vector, and DNA, with more than 160 vaccine candidates being developed and tested in clinical trials. Nonetheless, among these several vaccine platforms, mRNA vaccine has been proven to be one of the most effective vaccines against COVID-19. There are two mRNA vaccines authorized for emergency use within a year and currently more than 20 mRNA vaccines are in clinical trials. The main advantages of mRNA vaccines are that they are speedily to design and develop, induce strong antibody and T-cell responses, manufacturing faster and at a lower cost. However, one of the major limitations is that it must be stored in cold temperatures. Currently more than billion doses of COVID-19 mRNA vaccines have been given globally. mRNA vaccines will be a key platform for next pandemics preparedness, it is therefore establishing this platform in various regions and LMICs is critical. Beyond COVID-19: A number of viral and cancer mRNA vaccines have been developing even before COVID-19. At least 12 mRNA vaccines against various infectious diseases are now in clinical evaluation, including Chikungunya virus, Cytomegalovirus, Epstein-Barr virus, Human metapneumovirus and parainfluenza virus type3, HIV, Influenza, Nipah, Rabies, Lasa, RSV, Zika, Varicella-zoster virus. Only few are entering phase 3 such as a CMV vaccine, RSV, seasonal influenza. Current mRNA cancer vaccines development, including brain, breast, melanoma, esophagus, lung, ovarian, prostate and solid tumors. Most are aimed for personalized therapy. By 2023, at least 1 viral mRNA vaccine may get approval, whereas a cancer vaccine might take much longer time. Nevertheless, the remaining challenge at the global level is how to truly overcome the vaccine inequity issues in a sustainable way.Copyright © 2023

mRNA vaccination in breast cancer: current progress and future direction.

Messenger RNA (mRNA) vaccination has proven to be highly successful in combating Coronavirus disease 2019 (COVID-19) and has recently sparked tremendous interest. This technology has been a popular topic of research over the past decade and is viewed as a promising treatment strategy for cancer immunotherapy. However, despite being the most prevalent malignant disease for women worldwide, breast cancer patients have limited access to immunotherapy benefits. mRNA vaccination has the potential to convert cold breast cancer into hot and expand the responders. Effective mRNA vaccine design for in vivo function requires consideration of vaccine targets, mRNA structures, transport vectors, and injection routes. This review provides an overview of pre-clinical and clinical data on various mRNA vaccination platforms used for breast cancer treatment and discusses potential approaches to combine appropriate vaccination platforms or other immunotherapies to improve mRNA vaccine therapy efficacy for breast cancer.

mRNA anti-cancer vaccine research gains momentum

Ongoing research into the use of messenger RNA (mRNA) vaccines for the treatment of cancer has been expediated by the coronavirus pandemic because similar technology was used in the development of mRNA COVID-19 vaccines. So how close are we now to the widespread clinical use of mRNA anti-cancer vaccines?.Copyright © 2023 Wiley Interface Ltd.

mRNA-From COVID-19 Treatment to Cancer Immunotherapy.

This review provides an overview covering mRNA from its use in the COVID-19 pandemic to cancer immunotherapy, starting from the selection of appropriate antigens, tumor-associated and tumor-specific antigens, neoantigens, the basics of optimizing the mRNA molecule in terms of stability, efficacy, and tolerability, choosing the best formulation and the optimal route of administration, to summarizing current clinical trials of mRNA vaccines in tumor therapy.

mRNA cancer vaccines: Advances, trends and challenges.

Patients exhibit good tolerance to messenger ribonucleic acid (mRNA) vaccines, and the choice of encoded molecules is flexible and diverse. These vaccines can be engineered to express full-length antigens containing multiple epitopes without major histocompatibility complex (MHC) restriction, are relatively easy to control and can be rapidly mass produced. In 2021, the U.S. Food and Drug Administration (FDA) approved the first mRNA-based coronavirus disease 2019 (COVID-19) vaccine produced by Pfizer and BioNTech, which has generated enthusiasm for mRNA vaccine research and development. Based on the above characteristics and the development of mRNA vaccines, mRNA cancer vaccines have become a research hotspot and have undergone rapid development, especially in the last five years. This review analyzes the advances in mRNA cancer vaccines from various perspectives, including the selection and expression of antigens/targets, the application of vectors and adjuvants, different administration routes, and preclinical evaluation, to reflect the trends and challenges associated with these vaccines.

Fluoroalkane modified cationic polymers for personalized mRNA cancer vaccines.

Messenger RNA (mRNA) vaccines, while demonstrating great successes in the fight against COVID-19, have been extensively studied in other areas such as personalized cancer immunotherapy based on tumor neoantigens. In addition to the design of mRNA sequences and modifications, the delivery carriers are also critical in the development of mRNA vaccines. In this work, we synthesized fluoroalkane-grafted polyethylenimine (F-PEI) for mRNA delivery. Such F-PEI could promote intracellular delivery of mRNA and activate the Toll-like receptor 4 (TLR4)-mediated signaling pathway. The nanovaccine formed by self-assembly of F-PEI and the tumor antigen-encoding mRNA, without additional adjuvants, could induce the maturation of dendritic cells (DCs) and trigger efficient antigen presentation, thereby eliciting anti-tumor immune responses. Using the mRNA encoding the model antigen ovalbumin (mRNAOVA), our F-PEI-based mRNAOVA cancer vaccine could delay the growth of established B16-OVA melanoma. When combined with immune checkpoint blockade therapy, the F-PEI-based MC38 neoantigen mRNA cancer vaccine was able to suppress established MC38 colon cancer and prevent tumor reoccurrence. Our work presents a new tool for mRNA delivery, promising not only for personalized cancer vaccines but also for other mRNA-based immunotherapies.

Stimulation of the immune system by a tumor antigen-bearing adenovirus-inspired VLP allows control of melanoma growth.

Virus-like particles (VLPs) are versatile protein-based platforms that can be used as a vaccine platform mainly in infectiology. In the present work, we compared a previously designed, non-infectious, adenovirus-inspired 60-mer dodecahedric VLP to display short epitopes or a large tumor model antigen. To validate these two kinds of platforms as a potential immuno-stimulating approach, we evaluated their ability to control melanoma B16-ovalbumin (OVA) growth in mice. A set of adjuvants was screened, showing that polyinosinic-polycytidylic acid (poly(I:C)) was well suited to generate a homogeneous cellular and humoral response against the desired epitopes. In a prophylactic setting, vaccination with the VLP displaying these epitopes resulted in total inhibition of tumor growth 1 month after vaccination. A therapeutic vaccination strategy showed a delay in grafted tumor growth or its total rejection. If the "simple" epitope display on the VLP is sufficient to prevent tumor growth, then an improved engineered platform enabling display of a large antigen is a tool to overcome the barrier of immune allele restriction, broadening the immune response, and paving the way for its potential utilization in humans as an off-the-shelf vaccine.

Protein-based nanocages for vaccine development.

Protein nanocages have attracted considerable attention in various fields of nanomedicine due to their intrinsic properties, including biocompatibility, biodegradability, high structural stability, and ease of modification of their surfaces and inner cavities. In vaccine development, these protein nanocages are suited for efficient targeting to and retention in the lymph nodes and can enhance immunogenicity through various mechanisms, including excellent uptake by antigen-presenting cells and crosslinking with multiple B cell receptors. This review highlights the superiority of protein nanocages as antigen delivery carriers based on their physiological and immunological properties such as biodistribution, immunogenicity, stability, and multifunctionality. With a focus on design, we discuss the utilization and efficacy of protein nanocages such as virus-like particles, caged proteins, and artificial caged proteins against cancer and infectious diseases such as coronavirus disease 2019 (COVID-19). In addition, we summarize available knowledge on the protein nanocages that are currently used in clinical trials and provide a general outlook on conventional distribution techniques and hurdles faced, particularly for therapeutic cancer vaccines.

An OX40L mRNA vaccine inhibits the growth of hepatocellular carcinoma.

mRNA cancer vaccines show therapeutic potential for malignant tumors, including hepatocellular carcinoma (HCC). We optimized and synthesized stable mRNA encoding costimulator Oxford 40 ligand (OX40L). For systemic delivery, OX40L mRNAs were loaded into lipid nanoparticles (LNPs). The expression and costimulatory effects of OX40L were investigated in vitro. OX40L was expressed on the cell surface and costimulated T cells. In vivo, intratumoral injection of LNPs encapsulating OX40L mRNAs significantly reduced tumor growth and increased the survival of mice bearing H22 tumors. Importantly, CD4+ and CD8+ T cells were significantly increased in the OX40L mRNA group in vivo. Taken together, our findings provide a promising clinical strategy for immunotherapy for HCC using mRNA vaccines.

Potential of mRNA vaccines to become versatile cancer vaccines.

For centuries, therapeutic cancer vaccines have been developed and tried clinically. Way back in the late 19th century, the Father of Immunotherapy, William Coley had discovered that bacterial toxins were effective for inoperable sarcomas. In the 1970s, the Bacillus Calmette-Guérin (BCG) vaccine was repurposed, e.g., for advanced melanomas. Then, therapeutic cancer vaccines based on tumor-associated antigens (found on the surfaces of cancer cells) were tried clinically but apparently have not made a really significant clinical impact. For repurposed pathogen vaccines, only the BCG vaccine was approved in 1989 for local application to treat nonmuscle-invading bladder cancers. Although the mildly toxic vaccine adjuvants deliberately added to conventional pathogen vaccines are appropriate for seasonal applications, when repurposed for continual oncology usage, toxicity may be problematic. In 2010, even with the approval of sipuleucel-T as the very first cancer vaccine (dendritic cell) developed for designated prostate cancers, it has also not made a really significant clinical impact. Perhaps more "user friendly" cancer vaccines should be explored. As from approximately 30 years ago, the safety and effectiveness of mRNA vaccination for oncology had already been studied, the current coronavirus disease 2019 pandemic, though disastrous, has given such progressively advancing technology a kickstart. For oncology, other virtues of mRNA vaccines seem advantageous, e.g., rapid and versatile development, convenient modular design, and entirely cell-free synthesis, are being progressively recognized. Moreover, mRNAs encoding various oncology antigens for vaccination may also be tested with the combi-nation of relatively non-toxic modalities of oncology treatments, e.g., metformin or metronomic (low-dose, prolonged administration) chemotherapy. Admittedly, robust clinical data obtained through good quality clinical trials are mandatory.

Advances in mRNA vaccines.

mRNA vaccines have been increasingly recognized as a powerful vaccine platform since the FDA approval of two COVID-19 mRNA vaccines, which demonstrated outstanding prevention efficacy as well as great safety profile. Notably, nucleoside modification and lipid nanoparticle-facilitated delivery has greatly improved the immunogenicity, stability, and translation efficiency of mRNA molecule. Here we review the recent progress in mRNA vaccine development, including nucleoside modification, in vitro synthesis and product purification, and lipid nanoparticle vectors for in vivo delivery and efficient translation. We also briefly introduce the clinical application of mRNA vaccine in preventing infectious diseases and treating inflammatory diseases including cancer.

Vaccine Therapy in Non-Small Cell Lung Cancer.

Immunotherapy using immune checkpoint modulators has revolutionized the oncology field, emerging as a new standard of care for multiple indications, including non-small cell lung cancer (NSCLC). However, prognosis for patients with lung cancer is still poor. Although immunotherapy is highly effective in some cases, not all patients experience significant or durable responses, and further strategies are needed to improve outcomes. Therapeutic cancer vaccines are designed to exploit the body's immune system to activate long-lasting memory against tumor cells that ensure tumor regression, with minimal toxicity. A unique feature of cancer vaccines lies in their complementary approach to boost antitumor immunity that could potentially act synergistically with immune checkpoint inhibitors (ICIs). However, single-line immunization against tumor epitopes with vaccine-based therapeutics has been disappointingly unsuccessful, to date, in lung cancer. The high level of success of several recent vaccines against SARS-CoV-2 has highlighted the evolving advances in science and technology in the vaccines field, raising hope that this strategy can be successfully applied to cancer treatments. In this review, we describe the biology behind the cancer vaccines, and discuss current evidence for the different types of therapeutic cancer vaccines in NSCLC, including their mechanisms of action, current clinical development, and future strategies.

The paradigm shift in treatment from Covid-19 to oncology with mRNA vaccines.

mRNA vaccines have gained popularity over the last decade as a versatile tool for developing novel therapeutics. The recent success of coronavirus disease (COVID-19) mRNA vaccine has unlocked the potential of mRNA technology as a powerful therapeutic platform. In this review, we apprise the literature on the various types of cancer vaccines, the novel platforms available for delivery of the vaccines, the recent progress in the RNA-based therapies and the evolving role of mRNA vaccines for various cancer indications, along with a future strategy to treat the patients. Literature reveals that despite multifaceted challenges in the development of mRNA vaccines, the promising and durable efficacy of the RNA in pre-clinical and clinical studies deserves consideration. The introduction of mRNA-transfected DC vaccine is an approach that has gained interest for cancer vaccine development due to its ability to circumvent the necessity of DC isolation, ex vivo cultivation and re-infusion. The selection of appropriate antigen of interest remains one of the major challenges for cancer vaccine development. The rapid development and large-scale production of mRNA platform has enabled for the development of both personalized vaccines (mRNA 4157, mRNA 4650 and RO7198457) and tetravalent vaccines (BNT111 and mRNA-5671). In addition, mRNA vaccines combined with checkpoint modulators and other novel medications that reverse immunosuppression show promise, however further research is needed to discover which combinations are most successful and the best dosing schedule for each component. Each delivery route (intradermal, subcutaneous, intra tumoral, intranodal, intranasal, intravenous) has its own set of challenges to overcome, and these challenges will decide the best delivery method. In other words, while developing a vaccine design, the underlying motivation should be a reasonable combination of delivery route and format. Exploring various administration routes and delivery route systems has boosted the development of mRNA vaccines.

Synergistic immunotherapy effects of antiCOVID-19 and anti-cancer vaccines in preventing tumors and infections

To assure efficacy, safety and security of medicines and products including those of cancer and infection prevention ones, the concepts of immunology and immunotherapy, treatments, therapeutics, research, reviews, approvals and according agency, nation and world-wide managements are highly important. Often rationally planned combinations of U.S. Food and Drug Administration (USFDA) approved medicines in preventing or treating the same or similar or multiple diseases are realized to be pharmacologically and biologically effective in mechanisms and toxicologically safe in applications. Because, multiple mechanisms are simultaneously combined in enhancing systemic immunities within the permissible limits of the doses. In this work, the immunology and immunotherapy aspects of both anticancer vaccines and anti-COVID-19 vaccines are taken into account to prevent current and future occurrences of cancer and infectious diseases. Though the intended mechanisms of actions are only disease specific and are primarily different between anti-cancer and anti-COVID-19 vaccines, their combinations are worthwhile in providing synergistic effects against carcinogenesis, metastasis and infections. Based on the chemical, biological and pharmacological input and output information for both kinetics and dynamics of vaccines including mRNA-1273, BNT162b2, and JNJ-78436735 to prevent covid-19 are explored in combinations with anti-cancer vaccines including Human Papillomavirus (HPV) Vaccine and Hepatitis B Vaccine (HBV). In addition to safety and efficacy, mRNA, viral-vector, protein and antigen mechanisms, pH, vaccine-vaccine interactions, independent and combined dose regimens, toxicities, solubilities, intrinsic and extrinsic covariates were taken into account for careful planning of combinations. Simultaneous dual combinations from both groups were improved to three to five levels of combinations. It was realized that these combinations qualify for pre-clinical followed by clinical-investigations further. Also, these conclusions promised us to explore additional new and approved vaccines of these indications.

Cancer Vaccines and Immunotherapy for Tumor Prevention and Treatment.

In this editorial, we highlight articles published in this Special Issue of Vaccines on "Cancer Vaccines and Immunotherapy for Tumor Prevention and Treatment", recent developments in the field of cancer vaccines, and the potential for immunotherapeutic combinations in cancer care. This issue covers important developments and progress being made in the cancer vaccine field and possible future directions for exploring new technologies to produce optimal immune responses against cancer and expand the arena of prophylactic and therapeutic cancer vaccines for the treatment of this deadly disease.

Development of a Virus-Like Particle-Based Anti-HER2 Breast Cancer Vaccine.

To develop a human epidermal growth factor receptor-2 (HER2)-specific cancer vaccine, using a plant virus-like particle (VLP) platform. Copper-free click chemistry and infusion encapsulation protocols were developed to prepare VLPs displaying the HER2-derived CH401 peptide epitope, with and without Toll-like receptor 9 (TLR9) agonists loaded into the interior cavity of the VLPs; Physalis mottle virus (PhMV)-based VLPs were used. After prime-boost immunization of BALB/c mice through subcutaneous administration of the vaccine candidates, sera were collected and analyzed by enzyme-linked immunosorbent assay (ELISA) for the CH401-specific antibodies; Th1 vs. Th2 bias was determined by antibody subtyping and splenocyte assay. Efficacy was assessed by tumor challenge using DDHER2 tumor cells. We successful developed two VLP-based anti-HER2 vaccine candidates-PhMV-CH401 vs. CpG-PhMV-CH401; however, the addition of the CpG adjuvant did not confer additional immune priming. Both VLP-based vaccine candidates elicited a strong immune response, including high titers of HER2-specific immunoglobulins and increased toxicity of antisera to DDHER2 tumor cells. DDHER2 tumor growth was delayed, leading to prolonged survival of the vaccinated vs. naïve BALB/C mice. The PhMV-based anti-HER2 vaccine PhMV-CH401, demonstrated efficacy as an anti-HER2 cancer vaccine. Our studies highlight that VLPs derived from PhMV are a promising platform to develop cancer vaccines.

Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers.

Virus-like particles (VLPs) are virus-derived structures made up of one or more different molecules with the ability to self-assemble, mimicking the form and size of a virus particle but lacking the genetic material so they are not capable of infecting the host cell. Expression and self-assembly of the viral structural proteins can take place in various living or cell-free expression systems after which the viral structures can be assembled and reconstructed. VLPs are gaining in popularity in the field of preventive medicine and to date, a wide range of VLP-based candidate vaccines have been developed for immunization against various infectious agents, the latest of which is the vaccine against SARS-CoV-2, the efficacy of which is being evaluated. VLPs are highly immunogenic and are able to elicit both the antibody- and cell-mediated immune responses by pathways different from those elicited by conventional inactivated viral vaccines. However, there are still many challenges to this surface display system that need to be addressed in the future. VLPs that are classified as subunit vaccines are subdivided into enveloped and non- enveloped subtypes both of which are discussed in this review article. VLPs have also recently received attention for their successful applications in targeted drug delivery and for use in gene therapy. The development of more effective and targeted forms of VLP by modification of the surface of the particles in such a way that they can be introduced into specific cells or tissues or increase their half-life in the host is likely to expand their use in the future. Recent advances in the production and fabrication of VLPs including the exploration of different types of expression systems for their development, as well as their applications as vaccines in the prevention of infectious diseases and cancers resulting from their interaction with, and mechanism of activation of, the humoral and cellular immune systems are discussed in this review.