PLGA-Astragalus Polysaccharide Nanovaccines Exert Therapeutic Effect in Colorectal Cancer.

Background: Tumor vaccines have achieved remarkable progress in treating patients with various tumors in clinical studies. Nevertheless, extensive research has also revealed that tumor vaccines are not up to expectations for the treatment of solid tumors due to their low immunogenicity. Therefore, there is an urgent need to design a tumor vaccine that can stimulate a broad anti-tumor immune response. Methods: In this work, we developed a nanovaccine (NP-TCL@APS), which includes nanoparticles loaded with colorectal cancer tumor cell lysates (TCL) and Astragalus polysaccharides (APS) into poly (lactic-co-glycolic acid) to induce a robust innate immune response. The NP-TCL@APS was identified by transmission electron microscopy and Malvern laser particle size analyzer. The killing and immune activation effects of NP-TCL@APS were evaluated in vitro. Finally, safety and anti-tumor efficacy were evaluated in the colorectal cancer tumor-bearing mouse model. Results: We found that NP-TCL@APS was preferentially uptaken by DC and further promoted the activation of DC in vitro. Additionally, nanoparticles codelivery of TCL and APS enhanced the antigen-specific CD8+ T cell response and suppressed the growth of tumors in mouse models with good biocompatibility. Conclusion: We successfully prepared a nanovaccine termed NP-TCL@APS, which can promote the maturation of DC and induce strong responses by T lymphocytes to exert anti-tumor effects. The strategy proposed here is promising for generating a tumor vaccine and can be extended to various types of cancers.

Tuning the fluidity and protein corona of ultrasound-responsive liposomal nanovaccines to program T cell immunity in mice.

Inducing high levels of antigen-specific CD8α+ T cells in the tumor is beneficial for cancer immunotherapy, but achieving this in a safe and effective manner remains challenging. Here, we have developed a designer liposomal nanovaccine containing a sonosensitizer (LNVS) to efficiently program T cell immunity in mice. Following intravenous injection, LNVS accumulates in the spleen in a protein corona and fluidity-dependent manner, leading to greater frequencies of antigen-specific CD8α+ T cells than soluble vaccines (the mixture of antigens and adjuvants). Meanwhile, some LNVS passively accumulates in the tumor, where it responds to ultrasound (US) to increase the levels of chemokines and adhesion molecules that are beneficial for recruiting CD8α+ T cells to the tumor. LNVS + US induces higher levels of intratumoral antitumor T cells than traditional sonodynamic therapy, regresses established mouse MC38 tumors and orthotopic cervical cancer, and protects cured mice from relapse. Our platform sheds light on the importance of tuning the fluidity and protein corona of naovaccines to program T cell immunity in mice and may inspire new strategies for cancer immunotherapy.

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.

Mitochondrial rewiring with small-molecule drug-free nanoassemblies unleashes anticancer immunity.

The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.

Biomaterials-assisted cancer vaccine delivery: preclinical landscape, challenges, and opportunities.

INTRODUCTION: Cancer vaccines (protein and peptide, DNA, mRNA, and tumor cell) have achieved remarkable success in the treatment of cancer. In particular, advances in the design and manufacture of biomaterials have made it possible to control the presentation and delivery of vaccine components to immune cells. AREAS COVERED: This review summarizes findings from major databases, including PubMed, Scopus, and Web of Science, focusing on articles published between 2005 and 2024 that discuss biomaterials in cancer vaccine delivery. EXPERT OPINION: The development of cancer vaccines is hindered by several bottlenecks, including low immunogenicity, instability of vaccine components, and challenges in evaluating their clinical efficacy. To transform preclinical successes into viable treatments, it is essential to pursue continued innovation, collaborative research, and address issues related to scalability, regulatory pathways, and clinical validation, ultimately improving outcomes against cancer.

Low-Dose Mildronate-Derived Lipidoids for Efficient mRNA Vaccine Delivery with Minimal Inflammation Side Effects.

mRNA vaccines have been revolutionizing disease prevention and treatment. However, their further application is hindered by inflammatory side effects, primarily caused by delivery systems such as lipid nanoparticles (LNPs). In response to this issue, we prepared cationic lipids (mLPs) derived from mildronate, a small-molecule drug, and subsequently developed the LNP (mLNP-69) comprising a low dose of mLP. Compared with the LNP (sLNP) based on SM-102, a commercially available ionizable lipid, mLNP-69 ensures effective mRNA delivery while significantly reducing local inflammation. In preclinical prophylactic and therapeutic B16-OVA melanoma models, mLNP-69 demonstrated successful mRNA cancer vaccine delivery in vivo, effectively preventing tumor occurrence or impeding tumor progression. The results suggest that the cationic lipids derived from mildronate, which exhibit efficient delivery capabilities and minimal inflammatory side effects, hold great promise for clinical application.

First step results from a phase II study of a dendritic cell vaccine in glioblastoma patients (CombiG-vax).

Background: Glioblastoma (GBM) is a poor prognosis grade 4 glioma. After surgical resection, the standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Our previous data on melanoma patients showed that Dendritic Cell vaccination (DCvax) could increase the amount of intratumoral-activated cytotoxic T lymphocytes. Methods: This is a single-arm, monocentric, phase II trial in two steps according to Simon's design. The trial aims to evaluate progression-free survival (PFS) at three months and the safety of a DCvax integrated with standard therapy in resected GBM patients. DCvax administration begins after completion of RT-CTwith weekly administrations for 4 weeks, then is alternated monthly with TMZ cycles. The primary endpoints are PFS at three months and safety. One of the secondary objectives is to evaluate the immune response both in vitro and in vivo (DTH skin test). Results: By December 2022, the first pre-planned step of the study was concluded with the enrollment, treatment and follow up of 9 evaluable patients. Two patients had progressed within three months after leukapheresis, but none had experienced DCvax-related G3-4 toxicities Five patients experienced a positive DTH test towards KLH and one of these also towards autologous tumor homogenate. The median PFS from leukapheresis was 11.3 months and 12.2 months from surgery. Conclusions: This combination therapy is well-tolerated, and the two endpoints required for the first step have been achieved. Therefore, the study will proceed to enroll the remaining 19 patients. (Eudract number: 2020-003755-15 https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003755-15/IT).

Bibliometric analysis of dendritic cell-based vaccines over the past 15 years.

Dendritic cells, which are crucial for inducing T-cell responses, are pivotal in current immunotherapy strategies aiming to replenish depleted T cells within the tumor microenvironment to combat tumors. Consequently, dendritic cell vaccine-based cancer therapies have garnered significant attention. Through bibliometric analysis, we examined research trends in this field. We searched the Web of Science core database and identified 16,476 articles on dendritic cell-based vaccines published from January 1, 2009, to December 30, 2023. The United States leads in this research domain, with Emory University being a prominent collaborator. The Journal of Immunology is the primary publication outlet, and Banchereau, J emerges as the most influential author. Recent hot keywords include nanoparticle, delivery, cancer vaccine, and clinical trial, indicating that cancer immunotherapy research, especially dendritic cell-based vaccines, is poised to become a future trend and hotspot.

Nanovaccines: Immunogenic tumor antigens, targeted delivery, and combination therapy to enhance cancer immunotherapy.

Nanovaccines have been designed to overcome the limitations associated with conventional vaccines. Effective delivery methods such as engineered carriers or smart nanoparticles (NPs) are critical requisites for inducing self-tolerance and optimizing vaccine immunogenicity with minimum side effects. NPs can be used as adjuvants, immunogens, or nanocarriers to develop nanovaccines for efficient antigen delivery. Multiloaded nanovaccines carrying multiple tumor antigens along with immunostimulants can effectively increase immunity against tumor cells. They can be biologically engineered to boost interactions with dendritic cells and to allow a gradual and constant antigen release. Modifying NPs surface properties, using high-density lipoprotein-mimicking nanodiscs, and developing nano-based artificial antigen-presenting cells such as dendritic cell-derived-exosomes are amongst the new developed technologies to enhance antigen-presentation and immune reactions against tumor cells. The present review provides an overview on the different perspectives, improvements, and barriers of successful clinical application of current cancer therapeutic and vaccination options. The immunomodulatory effects of different types of nanovaccines and the nanoparticles incorporated into their structure are described. The advantages of using nanovaccines to prevent and treat common illnesses such as AIDS, malaria, cancer and tuberculosis are discussed. Further, potential paths to develop optimal cancer vaccines are described. Given the immunosuppressive characteristics of both cancer cells and the tumor microenvironment, applying immunomodulators and immune checkpoint inhibitors in combination with other conventional anticancer therapies are necessary to boost the effectiveness of the immune response.

Uniform Polymeric Nanovaccine Platform for Improving the Availability and Efficacy of Neoantigen Peptides.

Personalized cancer vaccines targeting specific neoantigens have been envisioned as one of the most promising approaches in cancer immunotherapy. However, the physicochemical variability of the identified neoantigens limits their efficacy as well as vaccine manufacturing in a uniform format. Herein, we developed a uniform nanovaccine platform based on poly(2-oxazoline)s (POx) to chemically conjugate neoantigen peptides, regardless of their physicochemical properties. This vaccine system could self-assemble into nanoparticles with uniform size (around 50 nm) and improve antigen accumulation as well as infiltration in the lymph node to increase antigen presentation. In vivo vaccination using this system conjugated with three predicted peptide neoantigen peptides from the MC38 tumor cell line induced 100% robust CD8+ T cell responses and superior tumor clearance compared to free peptides. This POx-based vaccine carrier represents a generalizable approach to increase the availability and efficacy of screened neoantigen peptides for a personalized cancer vaccine.

Glucosylated Nanovaccines for Dendritic Cell-Targeted Antigen Delivery and Amplified Cancer Immunotherapy.

Engineering nanovaccines capable of targeting dendritic cells (DCs) is desperately required to maximize antigen cross-presentation to effector immune cells, elicit strong immune responses, and avoid adverse reactions. Here, we showed that glucose transporter 1 (Glut-1) on DCs is a reliable target for delivering antigens to DCs, and thus, a versatile antigen delivery strategy using glucosylated nanovaccines was developed for DC-targeted antigen delivery and tumor immunotherapy. The developed glucosylated ovalbumin-loaded nanovaccines highly accumulated in lymph nodes and efficiently engaged with Glut-1 on DCs to accelerate intracellular antigen delivery and promote DC maturation and antigen presentation, which elicited potent antitumor immunity to prevent and inhibit ovalbumin-expressing melanoma. Moreover, immunotherapeutic experiments in DC- and macrophage-depleted animal models confirmed that the glucosylated nanovaccines functioned mainly through DCs. In addition, the neoantigen-delivering glucosylated nanovaccines were further engineered to elicit tumor-specific immune responses against MC38 tumors. This study offers a DC-targeted antigen delivery strategy for cancer immunotherapy.

Generation of the therapeutic monoclonal antibody NEO-201, derived from a cancer vaccine, which targets human malignancies and immune suppressor cells.

INTRODUCTION: Cancer vaccines stimulate the activation of specific humoral and cellular adaptive responses against cancer cells.Antibodies generated post vaccination can be isolated and further selected to develop highly specific and potent monoclonal antibodies (mAbs) against tumor-associated antigens. AREAS COVERED: This review describes different types of cancer vaccines, the process of the generation of the mAb NEO-201 from the Hollinshead cancer vaccine platform, the characterization of the antigen recognized by NEO-201, the ability of NEO-201 to bind and mediate the killing of cancer cells and immunosuppressive cells (gMDSCs and Tregs) through ADCC and CDC, NEO-201 preclinical and clinical toxicity and efficacy. EXPERT OPINION: To overcome the problem of poor clinical efficacy of cancer vaccines, due to the activity of immunosuppressive cells, cancer vaccines could be combined with other immunotherapeutics able to deplete immunosuppressive cells. Results from clinical trials, employing NEO-201 alone or in combination with pembrolizumab, showed that durable stabilization of disease after treatment was due to the ability of NEO-201 to target and reduce the percentage of circulating Tregs and gMDSCs.These findings provide compelling support to combine NEO-201 with cancer vaccines to reintegrate their ability to elicit a robust and durable immune adaptive response against cancer.

Nutrition's checkpoint inhibition: The impact of nutrition on immunotherapy outcomes.

OBJECTIVES: To determine if nutritional status effects response to immunotherapy in women with gynecologic malignancies. METHODS: A retrospective chart review was conducted on gynecologic cancer patients who received immunotherapy at a single institution between 2015 and 2022. Immunotherapy included checkpoint inhibitors and tumor vaccines. The prognostic nutritional index (PNI) was calculated from serum albumin levels and total lymphocyte count. PNI values were determined at the beginning of treatment for each patient and assessed for their association with immunotherapy response. Disease control response (DCR) as an outcome of immunotherapy was defined as complete response, partial response, or stable disease. RESULTS: One hundred and ninety-eight patients received immunotherapy (IT) between 2015 and 2022. The gynecological cancers treated were uterine (38%), cervix (32%), ovarian (25%), and vulvar or vaginal (4%) cancers. The mean PNI for responders was higher than the non-responder group (p < 0.05). The AUC value for PNI as a predictor of response was 49. A PNI value of 49 was 43% sensitive and 85% specific for predicting a DCR. In Cox proportional hazards analysis, after adjusting for ECOG score and the number of prior chemotherapy lines, severe malnutrition was associated with progression-free survival (PFS) (HR = 1.85, p = 0.08) and overall survival (OS) (HR = 3.82, p < 0.001). Patients with PNI < 49 were at a higher risk of IT failure (HR = 2.24, p = 0.0001) and subsequent death (HR = 2.84, p = 9 × 10-5). CONCLUSIONS: PNI can be a prognostic marker to predict response rates of patients with gynecologic cancers treated with immunotherapy. Additional studies needed to understand the mechanistic role of malnutrition in immunotherapy response.

Current status and future directions of nanovaccine for cancer: a bibliometric analysis during 2004-2023.

Background: Nanovaccine treatment is an exciting area of research in immunology and personalized medicine, holding great promise for enhancing immune responses and targeting specific diseases. Their small size allows efficient uptake by immune cells, leading to robust immune activation. They can incorporate immune-stimulating molecules to boost vaccine efficacy. Therefore, nanovaccine can be personalized to target tumor-specific antigens, activating the immune system against cancer cells. Currently, there have been ample evidence showing the effectiveness and potential of nanovaccine as a treatment for cancer. However, there was rare bibliometric analysis of nanovaccine for cancer. Here we performed a bibliometric and visual analysis of published studies related to nanovaccine treatment for cancer, providing the trend of future development of nanovaccine. Methods: We collected the literatures based on the Web of Science Core Collection SCI-Expanded database. The bibliometric analysis was performed via utilizing visualization analysis tools VOSviewer, Co-Occurrence (COOC), Citespace, Bibliometrix (R-Tool of R-Studio), and HitCite. Results: A total of 517 literatures were included in this study. China is the country with the most publications and the highest total local citation score (TLCS). The Chinese Academy of Sciences holds the largest research count in this field and the most prolific author is Deling Kong from Nankai University. The most prominent journal for publishing in this area is Biomaterials. The researches mainly focus on the therapeutic process of tumor nanovaccines, the particle composition and the application of nanovaccines, suggesting the potential hotspots and trends of nanovaccine. Conclusion: In this study, we summarized the characteristics and variation trends of publications involved in nanovaccine, and categorized the most influential countries, institutions, authors, journals, hotspots and trends regarding the nanovaccine for cancer. With the continuous development of nanomaterials and tumor immunotherapy, nanovaccine for cancer provides a research field of significant clinical value and potential application.

Personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma: a non-randomized phase 1 trial.

Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.

Tetradecanol-wrapped, CpG-loaded porous Prussian blue nanoimmunomodulator for photothermal-responsive in situ anti-tumor vaccine-like immunotherapy.

Therapeutic vaccine becomes a promising strategy to fight cancer by enhancing and sustaining specific anti-tumor immune responses. However, its efficacy is often impeded by low immunogenicity, the immunosuppressive tumor microenvironment (TME), and immune-related adverse events. Herein, we introduce 1-tetradecanol (TD)-wrapped, CpG-loaded porous Prussian blue nanoparticles (pPBNPs-CpG@TD) as a nanoimmunomodulator to initiate photothermal-induced immunogenic cell death (ICD) and photothermal-responsive release of CpG for augmenting the ICD effect. It was revealed that the dual-photothermal action significantly potentiated the in situ anti-tumor vaccine-like immunotherapy in terms of enhanced immunogenicity, promoted dendritic cell maturation, and increased T lymphocyte infiltration, consequently eliciting a robust immune response for inhibiting both primary and rechallenge tumors on a subcutaneous 4T1 tumor-bearing mouse model. The development and use of photoactive nanoimmunomodulators represents a novel and effective strategy to boost immunogenicity and counteract immunosuppressive TME, marking a significant advancement in the realm of ICD-driven in situ anti-tumor vaccine-like immunotherapy.

Long-term follow up of patients treated with a DNA vaccine (pTVG-hp) for PSA-recurrent prostate cancer.

We have previously reported two single-agent phase I trials, evaluating the dose or schedule, of a DNA vaccine (pTVG-HP) encoding prostatic acid phosphatase (PAP) administered with GM-CSF as the adjuvant. These were in patients with PSA-recurrent, radiographically non-metastatic, prostate cancer (PCa). We report here the long-term safety and overall survival of these patients. Specifically, 22 patients with non-metastatic, castration-sensitive PCa (nmCSPC) were treated with pTVG-HP, 100-1500 µg, administered over 12 weeks and followed for 15 y. 17 patients with non-metastatic castration-resistant PCa (nmCRPC) were treated with 100 µg pTVG-HP with different schedules of administration over 1 y and followed for 5 y. No adverse events were detected in long-term follow-up from either trial that were deemed possibly related to vaccination. Patients with nmCSPC had a median overall survival of 12.3 y, with 5/22 (23%) alive at 15 y. 8/22 (36%) died due to prostate cancer with a median survival of 11.0 y, and 9/22 (41%) died of other causes. Patients with nmCRPC had a median overall survival of 4.5 y, with 8/17 (47%) alive at 5 y. The presence of T-cells specific for the PAP target antigen was detectable in 6/10 (60%) individuals with nmCSPC, and 3/5 (60%) individuals with nmCRPC, many years after immunization. The detection of immune responses to the vaccine target years after immunization suggests durable immunity can be elicited in patients using a DNA vaccine encoding a tumor-associated antigen.Trial Registration: NCT00582140 and NCT00849121.

Screening of tumor antigens and immunogenic cell death landscapes of prostate adenocarcinoma for exploration of mRNA vaccine.

BACKGROUND: In this study, effective antigens of mRNA vaccine were excavated from the perspective of ICD, and ICD subtypes of PRAD were further distinguished to establish an ICD landscape, thereby determining suitable vaccine recipients. RESEARCH DESIGN AND METHODS: TCGA and MSKCC databases were applied to acquire RNA-seq data and corresponding clinical data of 554 and 131 patients, respectively. GEPIA was employed to measure prognostic indices. Then, a comparison of genetic alterations was performed utilizing cBioPortal, and correlation of identified ICD antigens with immune infiltrating cells was analyzed employing TIMER. Moreover, ICD subtypes were identified by means of consensus cluster, and ICD landscape of PRAD was depicted utilizing graph learning-based dimensional reduction. RESULTS: In total, 4 PRAD antigens were identified in PRAD, including FUS, LMNB2, RNPC3, and ZNF700, which had association with adverse prognosis and infiltration of APCs. PRAD patients were classified as two ICD subtypes based on their differences in molecular, cellular, and clinical features. Furthermore, ICD modulators and immune checkpoints were also differentially expressed between two ICD subtype tumors. Finally, the ICD landscape of PRAD showed substantial heterogeneity among individual patients. CONCLUSIONS: In summary, the research may provide a theoretical foundation for developing mRNA vaccine against PRAD as well as determining appropriate vaccine recipients.

Novel mRNA adjuvant ImmunER enhances prostate cancer tumor-associated antigen mRNA therapy via augmenting T cell activity.

Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8+T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.

Personalized dendritic cell vaccine in multimodal individualized combination therapy improves survival in high-risk pediatric cancer patients.

A lot of hope for high-risk cancers is being pinned on immunotherapy but the evidence in children is lacking due to the rarity and limited efficacy of single-agent approaches. Here, we aim to assess the effectiveness of multimodal therapy comprising a personalized dendritic cell (DC) vaccine in children with relapsed and/or high-risk solid tumors using the N-of-1 approach in real-world scenario. A total of 160 evaluable events occurred in 48 patients during the 4-year follow-up. Overall survival of the cohort was 7.03 years. Disease control after vaccination was achieved in 53.8% patients. Comparative survival analysis showed the beneficial effect of DC vaccine beyond 2 years from initial diagnosis (HR = 0.53, P = .048) or in patients with disease control (HR = 0.16, P = .00053). A trend for synergistic effect with metronomic cyclophosphamide and/or vinblastine was indicated (HR = 0.60 P = .225). A strong synergistic effect was found for immune check-point inhibitors (ICIs) after priming with the DC vaccine (HR = 0.40, P = .0047). In conclusion, the personalized DC vaccine was an effective component in the multimodal individualized treatment. Personalized DC vaccine was effective in less burdened or more indolent diseases with a favorable safety profile and synergized with metronomic and/or immunomodulating agents.