Cancer Vaccines Research Articles

Abstract A116: Cervical cancer awareness, knowledge, and attitudes in young adult students on a Northern California college campus

Abstract Cervical cancer is the fourth most common gynecological malignancy in women worldwide. Human papillomavirus (HPV) is the primary cause of cervical cancer, with increased risk associated with select serotypes HPV 16 and 18. This study assesses cervical cancer awareness, knowledge of HPV, and attitudes towards vaccination among a convenience sample of San Francisco State University (SFSU) students. Despite the availability of effective HPV vaccines and associated cervical cancer prevention, vaccine uptake remains relatively low which may be due to various factors, including lack of awareness and vaccine knowledge. A convenience sample survey assessing cervical cancer awareness, behaviors and attitudes about HPV vaccine was administered to students on the San Francisco State University campus. The data was collected anonymously, via QR code. Participants received a $10 Target gift card. At completion of the survey, a 5x7 information card about Cervical Cancer and HPV vaccines, developed by and for college students, was distributed to participants. A total of 100 students completed the survey. Participants average age was 23-24 years old; 60% of participants identified as female; 34% as male. The vast majority of participants were aware of cervical cancer. Among 60 female respondents, 25 (42%) reported having had a pap smear, but a larger proportion had not. Of the female participants over age 21 years old, 12 out of 62 had never had a pap smear. 39% of respondents were not aware of the HPV vaccine and its relationship to cervical cancer prevention. There was a large difference in HPV vaccine awareness by gender and age. Of the 60 female respondents, 20 had reported being unaware of the HPV vaccine, while 17 of the 34 male respondents also reported being unaware. At completion of the survey, two-thirds of respondents reported a plan to receive a pap smear as recommended. 16% said they will not, and 21% were unsure. Our survey set out to understand the distribution of knowledge, awareness, attitudes and behaviors about cervical cancer and HPV vaccination on the SF State college campus. We found that most students on our campus are aware of cervical cancer. However, a small proportion of participants eligible for pap smears have yet to undergo the procedure. Our research also revealed that there is a lack of understanding regarding the importance of HPV vaccination, with significant differences in awareness by gender and age. This study underscores the need for targeted educational initiatives on cervical cancer awareness, knowledge, and attitudes towards HPV and its vaccine. To improve awareness and preventive actions, we can; increase the efforts to educate the public about the importance of HPV vaccinations and regular Pap smears and improve access to vaccination and screening services. Addressing gaps in knowledge and negative impressions of HPV vaccine can lead to the ultimate eradication of CC as we know it. Citation Format: Elissa I. Sanders, Kim F. Rhoads, Suzana Beyene. Cervical cancer awareness, knowledge, and attitudes in young adult students on a Northern California college campus [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A116.

Abstract B113: Cervical cancer stigma in the Caribbean: Implications for prevention

Abstract Background: Cervical cancer is still a major threat in the Caribbean region. Stigma may be a contributor to low screening and HPV vaccination practices, but it has been understudied in the region. The study aims to assess stigma among a Caribbean non- patient population in Jamaica, Grenada and Trinidad and Tobago. Methods: A cross-sectional study involving 1207 participants was conducted using a trans-created Cancer Stigma Scale for the Caribbean context and additional measures on cervical cancer and HPV vaccine knowledge and beliefs were added. Cancer stigma was assessed across six sub-domains Severity, Personal Responsibility, Awkwardness, Avoidance, Policy Opposition and Financial Discrimination. The data were collected online between October 2022 and March 2023. Descriptive statistics for characteristics of socio- demographic and variables associated with cancer stigma were run. ANOVA tests compared factor scores with multi categorised variables using SPSS. Results: Levels of cancer stigma were low but varied across the six domains with the severity domain showing high scores (40.1%-77.4%). The majority of the participants disagreed with banks refusing to give loans to people with cancer (85.1%). Under policy opposition (93.0%) agreed that more government funding should be spent on cancer care and treatment. Social rejection was significantly higher in Grenada when compared to both Jamaica and Trinidad and Tobago. More than a third of the participants (35.6%) agreed that the fear of family reaction and rejection may discourage women from getting a further diagnosis after an abnormal Pap smear. Younger participants showed less stigma than older participants. Those aged 18-25 also differed from those aged 26-35 and 56-65 for the factors of Policy Opposition and Severity respectively. In all cases the older age group had higher mean scores. Social impact factors of shame and social rejection are predictors of cancer stigma with p < 0.001 and p = 0.050 respectively. Married/cohabiting individuals had more negative responses than divorced persons across all three factors of Shame, Social Rejection and Social Isolation. The majority of our participants were female 81.4% and fell between the ages of 18-35 years (56.8%). Discussion: Cancer stigma is understudied in the Americas. Our results show that cancer stigma varies by several important factors including stigma domain, and participant demographics e.g. age and gender. The findings indicate that interventions and educational efforts targeting cancer stigma ought to be included in cancer prevention and control efforts. Targeted evidenced-based strategies for reducing stigma include featuring cancer survivors especially prominent survivors like celebrities, and employing mass media public health campaigns. A reduction in cancer stigma may lead to increased prevention, screening, and treatment of cervical cancer. Citation Format: Diadrey-Anne Sealy, Kamilah Thomas- Purcell, Althea Bailey, Gaole Song, Kimlin Ashing. Cervical cancer stigma in the Caribbean: Implications for prevention [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B113.

RNA modifications in cancer immune therapy: regulators of immune cells and immune checkpoints.

RNA modifications are epigenetic changes that alter the structure and function of RNA molecules, playing a crucial role in the onset, progression, and treatment of cancer. Immune checkpoint inhibitor (ICI) therapies, particularly PD-1 blockade and anti-CTLA-4 treatments, have changed the treatment landscape of virous cancers, showing great potential in the treatment of different cancer patients, but sensitivity to these therapies is limited to certain individuals. This review offers a comprehensive survey of the functions and therapeutic implications of the four principal RNA modifications, particularly highlighting the significance of m6A in the realms of immune cells in tumor and immunotherapy. This review starts by providing a foundational summary of the roles RNA modifications assume within the immune cell community, focusing on T cells, NK cells, macrophages, and dendritic cells. We then discuss how RNA modifications influence the intricate regulatory mechanisms governing immune checkpoint expression, modulation of ICI efficacy, and prediction of ICI treatment outcomes, and review drug therapies targeting genes regulated by RNA modifications. Finally, we explore the role of RNA modifications in gene editing, cancer vaccines, and adoptive T cell therapies, offering valuable insights into the use of RNA modifications in cancer immunotherapy.

Fully Synthetic TF-Based Self-Adjuvanting Vaccine Simultaneously Triggers iNKT Cells and Mincle and Protects Mice against Tumor Development.

The Thomsen-Friedenreich (TF) antigen has proven to be a promising target for developing novel therapeutic cancer vaccines. Here, a new strategy that TF antigen covalently coupled with KRN7000 and vizantin was developed. The resulting three-component vaccine KRN7000-TF-vizantin simultaneously triggers invariant natural killer T (iNKT) cells and macrophage-inducible C-type lectin (Mincle) signaling pathways, eliciting much stronger TF-specific immune responses than glycoprotein vaccine TF-KLH/alum and the corresponding two-component conjugate vaccines TF-KRN7000 and TF-vizantin. The analysis of IgG isotypes and the secretion of cytokines revealed that KRN7000-TF-vizantin induced Th1/Th2 mixed immune responses, where Th1 was dominant. In vivo experiments demonstrated that KRN7000-TF-vizantin increased the survival rate and survival time of tumor-challenged mice, and surviving mice rejected further tumor attacks without any additional treatment. This work demonstrates that covalently coupled KRN7000 and vizantin could serve as a promising TF-based vaccine carrier for antitumor immune therapy, and KRN7000-TF-vizantin features great potential to be a vaccine candidate.

Caregiver acceptance of human papillomavirus vaccine for their female children in Chileka, Blantyre, Malawi

IntroductionMalawi is one of the countries enduring an enormous burden of cervical cancer. Human Papillomavirus (HPV) vaccination offers a feasible and effective tool for reducing the burden. Such a prospect however, is being impeded by low uptake rates of the HPV vaccine in the country. This study, therefore, sought to identify barriers to caregiver acceptance of the HPV vaccine for their female children in Chileka, Blantyre, Malawi and to establish the consequential willingness to vaccinate their children. MethodologyA cross-sectional study was conducted using qualitative methods. We conducted 6 Focus Group Discussions (FGDs) with 4 groups of women and 2 groups of men in 4 villages located in a semi-urban area, Chileka, Blantyre. The guiding questionnaire was designed to draw out two main outcomes: barriers to caregiver acceptance of the HPV vaccine and willingness to vaccinate children. The data was analysed by thematic analysis by an inductive approach using NVivo software version 11. ResultsLack of knowledge on cervical cancer and HPV vaccination coupled with numerous misconceptions are the main barriers discouraging the population from accepting the HPV vaccine. Consequently, there was little desire to get their children vaccinated against HPV. Though responsibility to get the children vaccinated was mainly attributed to women, men argued that they need to have a final say in their children’s vaccination. ConclusionIn the wake of the revealed barriers and low acceptance of the HPV vaccine, it is imperative to organize effective and sustainable awareness programmes for the improvement of the HPV vaccine’s uptake.

Emerging immunologic approaches as cancer anti-angiogenic therapies.

Targeting tumor angiogenesis, the formation of new blood vessels supporting cancer growth and spread, has been an intense focus for therapy development. However, benefits from anti-angiogenic drugs like bevacizumab have been limited by resistance stemming from activation of compensatory pathways. Recent immunotherapy advances have sparked interest in novel immunologic approaches that can induce more durable vascular pruning and overcome limitations of existing angiogenesis inhibitors. This review comprehensively examines these emerging strategies, including modulating tumor-associated macrophages, therapeutic cancer vaccines, engineered nanobodies and T cells, anti-angiogenic cytokines/chemokines, and immunomodulatory drugs like thalidomide analogs. For each approach, the molecular mechanisms, preclinical/clinical data, and potential advantages over conventional drugs are discussed. Innovative therapeutic platforms like nanoparticle delivery systems are explored. Moreover, the importance of combining agents with distinct mechanisms to prevent resistance is evaluated. As tumors hijack angiogenesis for growth, harnessing the immune system's specificity to disrupt this process represents a promising anti-cancer strategy covered by this review.

Penyuluhan Pentingnya Vaksin HPV untuk Mencegah Kanker Serviks Sedini mungkin di Kabupaten Takalar

Cervical cancer is one of the most common types of cancer in the female genital organs caused by human papillomavirus (HPV), and preventive measures are highly recommended rather than curative measures. Prevention efforts are still poorly understood, so education is needed to increase vaccination coverage. The aim of this service is to increase participants' understanding of cancer vaccines. This method was used to discuss with partners at SDN Pusat No. 1 Patalasang District. Takalar, and students and teachers participate. Participants' knowledge was assessed through pre-test and post-test. The test result in front of 6 teachers and 15 students was 71.4, increasing to 98.2 at the time of the test. All service participants were satisfied with the implementation of the service because they felt the information was very useful and they needed it. All participants feel the benefits of using the services. Participants hope to continue this service in the future with free pap smears and vaccinations. It can be concluded that advice on cancer prevention and vaccination increased participants' understanding from 71.4 to 98.2 and was highly appreciated by the participants.

Factors influencing HPV vaccine hesitancy among university students in China: A cross-sectional survey utilizing the 3Cs model

ABSTRACT The HPV vaccine, which has been demonstrated to be an effective method of reducing the risk of developing cervical cancer, is still being underutilized among college students in China. To assess the current status of HPV vaccine hesitancy among college students in Guangdong Province after the COVID-19 outbreak, and to systematically analyze the influencing factors of HPV vaccine hesitancy and construct a prediction model based on the WHO 3Cs model. A cross-sectional web-based survey was conducted in June 2023 among female college students in four cities in Guangdong Province. The data were analyzed using binary logistic regression with a focus on the 3Cs model: Complacency, Convenience, and Confidence. LASSO regression was employed to analyze the variables deemed to be of significance and to construct predictive models. Out of 1399 participants, 86.5% expressed no hesitancy toward HPV vaccination. However, 11.9% exhibited hesitancy, and 1.6% refused vaccination altogether. Factors such as trust in vaccine efficacy, perception of HPV infection risk, price considerations, and constraints like distance or time were significant contributors to hesitancy. Knowledge of the HPV vaccine, socio-demographic characteristics, and the educational level of participants’ mothers also played a role in vaccine hesitancy. It is recommended that targeted interventions be implemented within educational institutions with the aim of raising awareness of cervical cancer and HPV vaccines, simplifying the scheduling of vaccination appointments, and increasing affordability through the implementation of strategic purchasing measures or subsidy schemes.

Carbohydrate-Lectin Interactions Reprogram Dendritic Cells to Promote Type 1 Anti-Tumor Immunity.

Cancer vaccine development is inhibited by a lack of strategies for directing dendritic cell (DC) induction of effective tumor-specific cellular immunity. Pathogen engagement of DC lectins and toll-like receptors (TLRs) is thought to shape immunity by directing T cell function. Controlling downstream responses, however, remains a major challenge. A critical goal in advancing vaccine development involves the identification of receptors that drive type 1 cellular immunity. The immune system monitors cells for aberrant glycosylation (a sign of a foreign entity), but potent activation occurs when a second signal, such as single-stranded RNA or lipopolysaccharide, is present to activate TLR signaling. To exploit dual signaling, we engineered a glycan-costumed virus-like particle (VLP) vaccine that displays a DC-SIGN-selective aryl mannose ligand and encapsulates TLR7 agonists. These VLPs deliver programmable peptide antigens to induce robust DC activation and type 1 cellular immunity. In contrast, VLPs lacking this critical DC-SIGN ligand promoted DC-mediated humoral immunity, offering limited tumor control. Vaccination with glycan-costumed VLPs generated tumor antigen-specific Th1 CD4+ and CD8+ T cells that infiltrated solid tumors, significantly inhibiting tumor growth in a murine melanoma model. The tailored VLPs also afforded protection against the reintroduction of tumor cells. Thus, DC lectin-driven immune reprogramming, combined with the modular programmability of VLP platforms, provides a promising framework for directing cellular immunity to advance cancer immunotherapies and vaccines.

Fighting Pancreatic Cancer with a Vaccine-Based Winning Combination: Hope or Reality?

Pancreatic adenocarcinoma (PDA) represents the fourth leading cause of cancer-related mortality in the USA. Only 20% of patients present surgically resectable and potentially curable tumors at diagnosis, while 80% are destined for poor survival and palliative chemotherapy. Accordingly, the advancement of innovative and effective therapeutic strategies represents a pivotal medical imperative. It has been demonstrated that targeting the immune system represents an effective approach against several solid tumors. The immunotherapy approach encompasses a range of strategies, including the administration of antibodies targeting checkpoint molecules (immune checkpoint inhibitors, ICIs) to disrupt tumor suppression mechanisms and active immunization approaches that aim to stimulate the host's immune system. While vaccines have proved effective against infectious agents, vaccines for cancer remain an unfulfilled promise. Vaccine-based therapy targeting tumor antigens has the potential to be a highly effective strategy for initiating and maintaining T cell recognition, enhancing the immune response, and ultimately promoting cancer treatment success. In this review, we examined the most recent clinical trials that employed diverse vaccine types to stimulate PDA patients' immune systems, either independently or in combination with chemotherapy, radiotherapy, ICIs, and monoclonal antibodies with the aim of ameliorating PDA patients' quality of life and extend their survival.

Abstract A085: Engineered novel bioactive Nectin-4 dimer protein significantly enhances the binding of TIGIT

Abstract The goals of this study are to: (a) create a novel soluble bioactive Nectin-4 dimer molecule mimicking its native dimer quaternary structure on the cell surface and (b) evaluate the recombinant Nectin-4 dimer binding potency to its receptor vs the monomer form, so that the dimer can be used as an immunogen and an antigen to increase the potential of cancer therapeutic antibody and vaccine discovery when targeting quaternary structural epitopes. Nectin-4 is a cell adhesion molecule belonging to the nectin family. It's involved in cell-cell junctions and plays a role in cancer progression by influencing cell adhesion, migration, and proliferation. Nectin-4 is overexpressed on various types of tumor cells including breast, lung, ovarian and pancreatic cancers. Nectin-4 has been recently identified as a novel ligand of T cell immunoglobulin and ITIM domain (TIGIT) and interaction between Nectin-4 and TIGIT inhibits NK cell cytotoxicity thus suppressing immune responses, allowing cancer cells to evade immune surveillance. Nectin-4 and Nectin-1 interact in a heterophilic manner, however in the context of cancer, altered expression of Nectin-4 and Nectin-1 can contribute to tumor progression. Nectin-4 is a type 1 single transmembrane protein, and can form homodimers on the cell surface. While therapeutics such as Enfortumab Vedotin, an antibody-drug conjugate, binds Nectin-4 on the surface of cancer cells, mimicking the Nectin-4 dimer quaternary structure can present many more critical opportunities for therapeutic antibody and vaccine discovery. To better mimic the native dimer conformation and quaternary structure, we designed a novel soluble Nectin-4 dimer with 3 extracellular domains fused to a dimer motif at the C-terminus. The Nectin-4 dimer protein was expressed and purified from HEK293 cells and confirmed by SDS-PAGE and Western blot analyses. We characterized the Nectin-4 dimer protein binding potency to TIGIT and Nectin-1 by ELISA. Very interestingly, the results demonstrated that the Nectin-4 dimer binding potency to TIGIT increased dramatically as measured by ELISA, compared to the Nectin-4 monomer protein. Conversely, the Nectin-4 dimer binding to Nectin-1 monomer was significantly decreased, compared to Nectin-4 monomer, as expected. We also studied Nectin-4 dimer immunogenicity using a Nectin-4 dimer DNA immunization to induce potent antibody responses in mice. In summary, these findings imply that the Nectin-4 dimer protein is bioactive and in the desirable conformation, resulting in an increased binding potency to its receptor TIGIT, reduced binding to Nectin-1 (as expected), and eliciting strong antibody responses in mice. This novel Nectin-4 dimer protein can be a very useful molecule for cancer research, therapeutic antibody and vaccine discovery. The Nectin-4 dimer protein can be used to: (i) elicit antibody responses against the dimer quaternary structure, (ii) screen antibodies targeting more conformational epitopes, and (iii) study the Nectin-4 and TIGIT ligand/receptor interactions. Citation Format: Christofer Walsh, Timothy Smith, Mikhail Rashkovskii, Richard Parent, Jean Qiu, Shixia Wang. Engineered novel bioactive Nectin-4 dimer protein significantly enhances the binding of TIGIT [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A085.

Non‐natural MUC1 Glycopeptide Homogeneous Cancer Vaccine with Enhanced Immunogenicity and Therapeutic Activity

Glycopeptides derived from the glycoprotein mucin‐1 (MUC1) have shown potential as tumor‐associated antigens for cancer vaccine development. However, their low immunogenicity and non‐selective conjugation to carriers present significant challenges for the clinical efficacy of MUC1‐based vaccines. Here, we introduce a novel vaccine candidate based on a structure‐guided design of an artificial antigen derived from MUC1 glycopeptide. This engineered antigen contains two non‐natural amino acids and has an α‐S‐glycosidic bond, where sulfur replaces the conventional oxygen atom linking the peptide backbone to the sugar N‐acetylgalactosamine. The glycopeptide is then specifically conjugated to the immunogenic protein carrier CRM197 (Cross‐Reactive Material 197), a protein approved for human use. Conjugation involves selective reduction and re‐bridging of a disulfide in CRM197, allowing the attachment of a single copy of MUC1. This strategy results in a chemically defined vaccine while maintaining both the structural integrity and immunogenicity of the protein carrier. The vaccine elicits a robust Th1‐like immune response in mice and generates antibodies capable of recognizing human cancer cells expressing tumor‐associated MUC1. When tested in mouse models of colon adenocarcinoma and pancreatic cancer, the vaccine is effective both as a prophylactic and therapeutic use, significantly delaying tumor growth. In therapeutic applications, improved outcomes were….

Engineering PEG10assembled endogenous virus-like particles with genetically encoded neoantigen peptides for cancer vaccination.

Tumor neoantigen peptide vaccines hold potential for boosting cancer immunotherapy, yet efficiently co-delivering peptides and adjuvants to antigen-presenting cells in vivo remains challenging. Virus-like particle (VLP), which is a kind of multiprotein structure organized as virus, can deliver therapeutic substances into cells and stimulate immune response. However, the weak targeted delivery of VLP in vivo and its susceptibility to neutralization by antibodies hinder their clinical applications. Here, we first designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous VLP (eVLP) with high protein loading and transfection efficiency. Then, an engineered tumor vaccine, named ePAC, was developed by packaging genetically encoded neoantigen into eVLP with further modification of CpG-ODN on its surface to serve as an adjuvant and targeting unit to dendritic cells (DCs). Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells. Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy. Overall, these results support that ePAC could be safely utilized as cancer vaccines for antitumor therapy, showing significant potential for clinical translation.

Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B.

Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease's pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which-upon effective drug delivery to their target cells-allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease.

Extracellular Silica Nanomatrices Promote In Vitro Maturation of Anti-tumor Dendritic Cells via Activation of Focal Adhesion Kinase.

The efficacy of dendritic cell (DC)-based cancer vaccines is critically determined by the functionalities of in vitro maturated DCs. The maturation of DCs typically relies on chemicals that are cytotoxic or hinder the ability of DCs to efficiently activate the antigen-specific cytotoxic T-lymphocytes (CTLs) against tumors. Herein, the maturation chemicals are replaced with extracellular silica nanomatrices, fabricated by glancing angle deposition, to promote in vitro maturation of murine bone marrow-derived DCs (mBMDCs). The extracellular nanomatrices composed of silica nanozigzags (NZs) enable the generation of mature mBMDCs with upregulated levels of co-stimulatory molecules, C-C chemokine receptor type-7, X-C motif chemokine recetpor-1, DC-specific ICAM-3 grabbing nonintegrin, and enhanced endocytic capacity. The in vitro maturation is partially governed by focal adhesion kinase (FAK) that is mechanically activated in the curved cell adhesions formed at the DC-NZ interfaces. The NZ-maturated mBMDCs can prime the antigen-specific CTLs into programmed cell death protein-1 (PD-1)lowCD44high memory phenotypes in vitro and suppress the growth of tumors in vivo. Meanwhile, the NZ-mediated beneficial effects are also observed in human monocyte-derived DCs. This work demonstrates that the silica NZs promote the anti-tumor capacity of in vitro maturated DCs via the mechanoactivation of FAK, supporting the potential of silica NZs being a promising biomaterial for cancer immunotherapy.

Engineering PEG10-assembled endogenous virus-like particles with genetically encoded neoantigen peptides for cancer vaccination

Tumor neoantigen peptide vaccines hold potential for boosting cancer immunotherapy, yet efficiently co-delivering peptides and adjuvants to antigen-presenting cells in vivo remains challenging. Virus-like particle (VLP), which is a kind of multiprotein structure organized as virus, can deliver therapeutic substances into cells and stimulate immune response. However, the weak targeted delivery of VLP in vivo and its susceptibility to neutralization by antibodies hinder their clinical applications. Here, we first designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous VLP (eVLP) with high protein loading and transfection efficiency. Then, an engineered tumor vaccine, named ePAC, was developed by packaging genetically encoded neoantigen into eVLP with further modification of CpG-ODN on its surface to serve as an adjuvant and targeting unit to dendritic cells (DCs). Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells. Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy. Overall, these results support that ePAC could be safely utilized as cancer vaccines for antitumor therapy, showing significant potential for clinical translation.

Long-term storage and intradermal vaccination of tumor-derived exosomes via sugar microneedles for improving tumor immunotherapies

Tumor-derived exosomes are gaining recognition as a promising cancer vaccine for immunotherapies due to their abundant tumor antigens and their role as endogenous carriers for antigen delivery. However, challenges including unstable membrane structures and compromised protein integrity during long-term storage, as well as the absence of effective delivery methods, restrict their clinical applications. Herein, we introduce an exosomes-loaded sugar microneedle (EXO-SMN) patch that not only allows for the long-term storage of exosomes but also facilitates intradermal delivery to enhance immunotherapies. By employing a two-casting micro-molding method, the EXO-SMN patch is composed of an array of tips simply made from trehalose, with a polyvinylpyrrolidone backing. The EXO-SMN patch demonstrates the capability to effectively protect the loaded exosomes, maintaining their membrane structure and protein integrity even after being stored at room temperature for at least one month. Additionally, the EXO-SMN patch possesses strong mechanical properties for skin penetration, facilitating the rapid release of exosomes into the skin within 120 s, and prolonging exosome retention in both skin and lymph nodes compared to intravenous (IV) or subcutaneous (SC) injections. Intradermal vaccination of tumor-derived exosomes via the EXO-SMN patch elicited higher antigen-specific immune responses and resulted in slower tumor growth compared to IV or SC injection. Given its easy to use and reliability, the proposed EXO-SMN patch could eventually facilitate the storage and delivery of exosomes in various biomedical applications.

DNA-Engineered Degradable Invisibility Cloaking for Tumor-Targeting Nanoparticles.

Nanoparticle (NP) delivery systems have been actively exploited for cancer therapy and vaccine development. Nevertheless, the major obstacle to targeted delivery lies in the substantial liver sequestration of NPs. Here we report a DNA-engineered approach to circumvent liver phagocytosis for enhanced tumor-targeted delivery of nanoagents in vivo. We find that a monolayer of DNA molecules on the NP can preferentially adsorb a dysopsonin protein in the serum to induce functionally invisibility to livers; whereas the tumor-specific uptake is triggered by the subsequent degradation of the DNA shell in vivo. The degradation rate of DNA shells is readily tunable by the length of coated DNA molecules. This DNA-engineered invisibility cloaking (DEIC) is potentially generic as manifested in both Ag2S quantum dot- and nanoliposome-based tumor-targeted delivery in mice. Near-infrared-II imaging reveals a high tumor-to-liver ratio of up to ∼5.1, approximately 18-fold higher than those with conventional nanomaterials. This approach may provide a universal strategy for high-efficiency targeted delivery of theranostic agents in vivo.

The expanding universe of type I regulatory Tcell biology: a new role in cancer immunotherapy.

In this article, we discuss new findings which suggest that type I regulatory T (Tr1) cells can interfere with cancer vaccine efficacy in mice by exerting strong regulatory control over antitumor immune responses.

Galloyl-boosted gold nanorods: Unleashing personalized cancer immunotherapy potential

Cancer immunotherapy has emerged as a potent treatment strategy by harnessing the host immune system to target cancer cells. However, challenges including low tumor vaccine immunogenicity and tumor heterogeneity hinder its clinical efficacy. To address these issues, we propose a novel nanoplatform integrating photothermal material gold nanorods (GNRs) with polyphenols for enhanced immunotherapy efficacy via photothermal therapy. Polyphenols, natural compounds with phenolic hydroxyl groups, are known for their ability to bind tightly to various molecules, making them ideal for antigen capture. We synthesized GNRs modified with polyphenols (GNR-PA and GNR-GA) and demonstrated their ability to induce immunogenic cell death upon laser irradiation, releasing tumor-associated antigens (TAAs). The surface polyphenols on GNRs effectively captured released TAAs to shield them from clearance. In vivo studies confirmed increased accumulation of GNR-GA in lymph nodes and enhanced dendritic cell maturation, leading to promoted effector T cell infiltration into tumors. Furthermore, treatment combined with PD-1/PD-L1 pathway blockade demonstrated potent tumor regression and systemic immunotherapy efficacy. Our findings highlight the potential of this photothermal nanoplatform as a promising strategy to overcome the limitations of current cancer immunotherapy approaches and improve therapeutic outcomes.