Peptide-based Cancer Vaccines Research Articles

A comprehensive bibliometric analysis (2000–2022) on the mapping of knowledge regarding immunotherapeutic treatments for advanced, recurrent, or metastatic cervical cancer

BackgroundDespite extensive literature on therapeutic strategies for cervical cancer, a bibliometric analysis specifically focused on immunotherapy for advanced, recurrent, or metastatic (A/R/M) cervical malignancies remains unexplored. This study aims to address this gap by presenting a comprehensive overview that includes general characteristics, research focal points, the trajectory of evolution, and current emerging trends in this under-researched area.MethodsA systematic search was conducted using the Web of Science Core Collection (WOSCC) to identify articles related to A/R/M cervical cancer published between 2000 and 2022. Citespace and VOS viewer were the primary tools used to identify research focal points, intriguing future patterns, and to evaluate contributions and co-occurrences among authors, institutions, countries, and journals.ResultsA total of 1,001 original articles were identified, involving 6,387 authors from 66 countries and 1,474 institutions, and published across 366 academic journals. The United States contributed most significantly. The most productive researcher was Van der Burg SH from Leiden University Medical Center. The International Journal of Cancer and Cancer Research were identified as the most productive and influential journals, respectively. Analysis of co-citation clusters highlighted 25 clusters, primarily focusing on potential predictive biomarkers, dendritic cell-based tumor vaccines, therapeutic HPV vaccinations, peptide-based cancer vaccines, tumor immune microenvironments, and adoptive cell transfer (ACT). The latest significant trends in A/R/M cervical cancer immunotherapy research included ACT, CAR-T, and immune checkpoint inhibitors (ICIs), as revealed by keyword and reference burst detection.ConclusionThis pioneering study provides a detailed landscape of immunotherapy research in A/R/M cervical cancer. It underscores the importance of global collaboration, enriches our understanding of the immunology of A/R/M cervical cancer, expands on potential beneficiaries of immunotherapy, and explores clinical applications of various therapies, including therapeutic vaccines, adoptive cell transfer, and ICIs, particularly in combination with established treatments such as chemotherapy, radiotherapy, and targeted therapy.

Tumor-Derived Antigenic Peptides as Potential Cancer Vaccines.

Peptide antigens derived from tumors have been observed to elicit protective immune responses, categorized as either tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs). Subunit cancer vaccines incorporating these antigens have shown promise in inducing protective immune responses, leading to cancer prevention or eradication. Over recent years, peptide-based cancer vaccines have gained popularity as a treatment modality and are often combined with other forms of cancer therapy. Several clinical trials have explored the safety and efficacy of peptide-based cancer vaccines, with promising outcomes. Advancements in techniques such as whole-exome sequencing, next-generation sequencing, and in silico methods have facilitated the identification of antigens, making it increasingly feasible. Furthermore, the development of novel delivery methods and a deeper understanding of tumor immune evasion mechanisms have heightened the interest in these vaccines among researchers. This article provides an overview of novel insights regarding advancements in the field of peptide-based vaccines as a promising therapeutic avenue for cancer treatment. It summarizes existing computational methods for tumor neoantigen prediction, ongoing clinical trials involving peptide-based cancer vaccines, and recent studies on human vaccination experiments.

Orchestrated codelivery of peptide antigen and adjuvant to antigen-presenting cells by using an engineered chimeric peptide enhances antitumor T-cell immunity.

The intrinsic pharmacokinetic limitations of traditional peptide-based cancer vaccines hamper effective cross-presentation and codelivery of antigens and adjuvants, which are crucial for inducing robust antitumor CD8+ T-cell responses. Here, we report the development of a versatile strategy that simultaneously addresses the different pharmacokinetic challenges of soluble subunit vaccines composed of antigens and CpG to modulate vaccine efficacy via translating an engineered chimeric peptide, eTAT, as an intramolecular adjuvant. Linking antigens to eTAT enhanced cytosolic delivery of the antigens. This, in turn, led to improved activation and lymph node-trafficking of antigen-presenting cells and antigen cross-presentation, thus promoting antigen-specific T-cell immune responses. Simple mixing of eTAT-linked antigens and CpG significantly enhanced codelivery of antigens and CpG to the antigen-presenting cells, and this substantially augmented the adjuvant effect of CpG, maximized vaccine immunogenicity and elicited robust and durable CD8+ T-cell responses. Vaccination with this formulation altered the tumor microenvironment and exhibited potent antitumor effects, with generally further enhanced therapeutic efficacy when used in combination with anti-PD1. Altogether, the engineered chimeric peptide-based orchestrated codelivery of antigen and adjuvant may serve as a promising but simple strategy to improve the efficacy of peptide-based cancer vaccines.

Exploring the development prospects of TNBC and HER2+ BC treatment based on targeted therapy

Breast cancer (BC) is one of the most common cancers in women, and the number of patients is increasing year by year. TNBC (triple-negative breast cancer) and HER2+ BC, as the two most common subtypes, deserve more in-depth research. At present, there are many targeted therapies and immunotherapies for these two subtypes, using inhibitors or cancer vaccines to treat breast cancer more efficiently, and some research has achieved phased results. However, there are still many research gaps, such as the safety and immune mechanism of the vaccine are unclear, and only a few number of epitopes trigger an immune response. In this paper, three targeted therapies for TNBC (PARA inhibitors, CDK inhibitors and PI3K/AKT/mTOR signaling pathway inhibitors) were analyzed. Two types of immunotherapy (ICIs and CAR-T therapy), And four cancer vaccines for HER2+ BC (Peptide-based cancer vaccines, Protein-based cancer vaccines,DNA Based Anti-HER2 Vaccines and Dendritic Cell Vaccines), and summarized their respective advantages and disadvantages to provide more theories and case references for future studies. There are still many unanswered questions about drug resistance, and future research can focus on the immune microenvironment and drug resistance

Decade-long WT1-specific CTLs induced by WT1 peptide vaccination.

The peptide-based cancer vaccine targeting Wilms' tumor 1 (WT1) is a promising immunotherapeutic strategy for hematological malignancies. It remains unclear how long and to what extent the WT1-specific CD8 + cytotoxic T cell (CTL) persist after WT1 peptide vaccination. The WT1 peptide vaccine was administered with written consent to a patient with CML in the chronic phase who did not respond well to imatinib, and the patient was followed for 12 years after vaccination. Immune monitoring was performed by specific amplification of WT1-specific CTLs using a mixed lymphocyte peptide culture. T-cell receptors (TCRs) of amplified WT1-specific CTLs were analyzed using next-generation sequencing. This study was approved by the Institutional Review Board of our institution. WT1-specific CTLs, which were initially detected during WT1 peptide vaccination, persisted at a frequency of less than 5 cells per 1,000,000 CD8 + T cells for more than 10 years. TCR repertoire analysis confirmed the diversity of WT1-specific CTLs 11 years after vaccination. CTLs exhibited WT1 peptide-specific cytotoxicity in vitro. The WT1 peptide vaccine induced an immune response that persists for more than 10 years, even after cessation of vaccination in the CML patient.

PLGA-PEI nanoparticle covered with poly(I:C) for personalised cancer immunotherapy.

Melanoma is the main cause of death among skin cancers and its incidence worldwide has been experiencing an appalling increase. However, traditional treatments lack effectiveness in advanced or metastatic patients. Immunotherapy, meanwhile, has been shown to be an effective treatment option, but the rate of cancers responding remains far from ideal. Here we have developed a personalized neoantigen peptide-based cancer vaccine by encapsulating patient derived melanoma neoantigens in polyethylenimine (PEI)-functionalised poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and coating them with polyinosinic:polycytidylic acid (poly(I:C)). We found that PLGA NPs can be effectively modified to be coated with the immunoadjuvant poly(I:C), as well as to encapsulate neoantigens. In addition, we found that both dendritic cells (DCs) and lymphocytes were effectively stimulated. Moreover, the developed NP was found to have a better immune activation profile than NP without poly(I:C) or without antigen. Our results demonstrate that the developed vaccine has a high capacity to activate the immune system, efficiently maturing DCs to present the antigen of choice and promoting the activity of lymphocytes to exert their cytotoxic function. Therefore, the immune response generated is optimal and specific for the elimination of melanoma tumour cells.

Design and Evaluation of Synthetic Delivery Formulations for Peptide-Based Cancer Vaccines.

With the recent advances in neoantigen identification, peptide-based cancer vaccines offer substantial potential in the field of immunotherapy. However, rapid clearance, low immunogenicity, and insufficient antigen-presenting cell (APC) uptake limit the efficacy of peptide-based cancer vaccines. This review explores the barriers hindering vaccine efficiency, highlights recent advancements in synthetic delivery systems, and features strategies for the key delivery steps of lymph node (LN) drainage, APC delivery, cross-presentation strategies, and adjuvant incorporation. This paper also discusses the design of preclinical studies evaluating vaccine efficiency, including vaccine administration routes and murine tumor models.

Peptide-Based Therapeutics in Cancer Therapy.

A monster called cancer is still one of the most challenging human problems and one of the leading causes of death in the world. Different types of treatment methods are used for cancer therapy; however, there are challenges such as high cost and harmful side effects in using these methods. Recent years have witnessed a surge in the development of therapeutic peptides for a wide range of diseases, notably cancer. Peptides are preferred over antibiotics, radiation therapy, and chemotherapy in the treatment of cancer due to a number of aspects, including flexibility, easy modification, low immunogenicity, and inexpensive cost of production. The use of therapeutic peptides in cancer treatment is a novel and intriguing strategy. These peptides provide excellent prospects for targeted drug delivery because of their high selectivity, specificity, small dimensions, good biocompatibility, and simplicity of modification. Target specificity and minimal toxicity are benefits of therapeutic peptides. Additionally, peptides can be used to design antigens or adjuvants for vaccine development. Here, types of therapeutic peptides for cancer therapy will be discussed, such as peptide-based cancer vaccines and tumor-targeting peptides (TTP) and cell-penetrating peptides (CPP).

Optimized dithranol-imiquimod-based transcutaneous immunization enables tumor rejection.

Transcutaneous immunization (TCI) is a non-invasive vaccination method promoting strong cellular immune responses, crucial for the immunological rejection of cancer. Previously, we reported on the combined application of the TLR7 agonist imiquimod (IMQ) together with the anti-psoriatic drug dithranol as novel TCI platform DIVA (dithranol/IMQ based vaccination). In extension of this work, we further optimized DIVA in terms of drug dose, application pattern and established a new IMQ formulation. C57BL/6 mice were treated on the ear skin with dithranol and IMQ-containing ointments together with ovalbumin-derived peptides. T cell responses were determined by flow cytometry and IFN-ɤ ELISpot assay, local skin inflammation was characterized by ear swelling. Applying the adjuvants on separate skin sites, a reduced number of specific CD8+ T cells with effector function was detectable, indicating that the local concurrence of adjuvants and peptide antigens is required for optimal vaccination. Likewise, changing the order of dithranol and IMQ resulted in an increased skin inflammatory reaction, but lower frequencies of antigen-specific CD8+ T cells indicating that dithranol is essential for superior T cell priming upon DIVA. Dispersing nanocrystalline IMQ in a spreadable formulation (IMI-Sol+) facilitated storage and application rendering comparable immune responses. DIVA applied one or two weeks after the first immunization resulted in a massive increase in antigen-specific T cells and up to a ten-fold increased memory response. Finally, in a prophylactic tumor setting, double but no single DIVA treatment enabled complete control of tumor growth, resulting in full tumor protection. Taken together, the described optimized transcutaneous vaccination method leads to the generation of a strong cellular immune response enabling the effective control of tumor growth and has the potential for clinical development as a novel non-invasive vaccination method for peptide-based cancer vaccines in humans.

A Universal Cyclodextrin-Based Nanovaccine Platform Delivers Epitope Peptides for Enhanced Antitumor Immunity.

Currently, there is still an intense demand for a simple and scalable delivery platform for peptide-based cancer vaccines. Herein, a cyclodextrin-based polymer nanovaccine platform (CDNP) is designed for the codelivery of peptides with two immune adjuvants [the Toll-like receptor (TLR)7/8 agonist R848 and the TLR9 agonist CpG] that is broadly applicable to epitope peptides with diverse sequences. Specifically, the cyclodextrin-based polymers are covalently linked to epitope peptides via a bioreactive bond-containing cross-linker (PNC-DTDE-PNC) and then physically load with R848 and CpG to obtain CDNP. The CDNP efficiently accumulats in the lymph nodes (LNs), greatly facilitating antigen capture and cross-presentation by antigen-presenting cells. The immunogenicity of the epitope peptides is significantly enhanced by the codelivery and synergy of the adjuvants, and the CDNP shows the ability to inhibit tumor progression in diverse tumor-bearing mouse models. It is concluded that CDNP holds promise as an optimized peptide-based cancer vaccine platform.

Peptide-based vaccine for cancer therapies.

Different strategies based on peptides are available for cancer treatment, in particular to counter-act the progression of tumor growth and disease relapse. In the last decade, in the context of therapeutic strategies against cancer, peptide-based vaccines have been evaluated in different tumor models. The peptides selected for cancer vaccine development can be classified in two main type: tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs), which are captured, internalized, processed and presented by antigen-presenting cells (APCs) to cell-mediated immunity. Peptides loaded onto MHC class I are recognized by a specific TCR of CD8+ T cells, which are activated to exert their cytotoxic activity against tumor cells presenting the same peptide-MHC-I complex. This process is defined as active immunotherapy as the host's immune system is either de novo activated or restimulated to mount an effective, tumor-specific immune reaction that may ultimately lead to tu-mor regression. However, while the preclinical data have frequently shown encouraging results, therapeutic cancer vaccines clinical trials, including those based on peptides have not provided satisfactory data to date. The limited efficacy of peptide-based cancer vaccines is the consequence of several factors, including the identification of specific target tumor antigens, the limited immunogenicity of peptides and the highly immunosuppressive tumor microenvironment (TME). An effective cancer vaccine can be developed only by addressing all such different aspects. The present review describes the state of the art for each of such factors.

Peptide-Based Therapeutic HPV Cancer Vaccine Synthesized via Bacterial Outer Membrane Vesicles.

Peptide-based vaccines have broad application prospects because of their safety, simple preparation, and effectiveness, especially in the development of personalized cancer vaccines, which have shown great advantages. However, the current peptide-based vaccines often require artificial synthesis and intricate delivery technology, which increases the cost and complexity of preparation. Here, we developed a simple technique for combining a peptide and a delivery system using the natural secretion system of bacteria. Specifically, we biosynthesized an antigenic peptide in bacteria, which was then extracellularly released through the bacterial secretory vesicles, thus simultaneously achieving the biosynthesis and delivery of the peptide. The system utilizes the natural properties of bacterial vesicles to promote antigen uptake and dendritic cell (DC) maturation. Therefore, tumor-specific CD4+ Th1 and CD8+ cytotoxic T lymphocyte (CTL) responses were induced in TC-1 tumor-bearing mice, thereby efficiently suppressing tumor growth. This research promotes innovation and extends the application of peptide-based vaccine biosynthesis technology. Importantly, it provides a new method for personalized cancer immunotherapy that uses screened peptides as antigens in the future.

Design and In Silico Validation of a Novel MZF-1-Based Multi-Epitope Vaccine to Combat Metastatic Triple Negative Breast Cancer.

Immunotherapy is emerging as a potential therapeutic strategy for triple negative breast cancer (TNBC) owing to the immunogenic landscape of its tumor microenvironment. Interestingly, peptide-based cancer vaccines have garnered a lot of attention as one of the most promising cancer immunotherapy regimens. Thus, the present study intended to design a novel, efficacious peptide-based vaccine against TNBC targeting myeloid zinc finger 1 (MZF1), a transcription factor that has been described as an oncogenic inducer of TNBC metastasis. Initially, the antigenic peptides from MZF1 were identified and evaluated based on their likelihood to induce immunological responses. The promiscuous epitopes were then combined using a suitable adjuvant (50S ribosomal L7/L12 protein) and linkers (AAY, GPGPG, KK, and EAAAK) to reduce junctional immunogenicity. Furthermore, docking and dynamics analyses against TLR-4 and TLR-9 were carried out to understand more about their structural stability and integrity. Finally, the constructed vaccine was subjected to in silico cloning and immune simulation studies. Overall, the findings imply that the designed chimeric vaccine could induce strong humoral and cellular immune responses in the desired organism. In light of these findings, the final multi-epitope vaccine could be used as an effective prophylactic treatment for TNBC and may pave the way for future research.

Supramolecular assembly of a trivalent peptide hydrogel vaccine for cancer immunotherapy.

Vaccination shows great promise in cancer immunotherapy. However, the induction of robust and broad therapeutic CD8 T cell immunity against tumors is challenging due to the essential heterogenicity of tumor antigen expression. Recently, bioinspired materials have reshaped the field of cancer nanomedicine. Herein, a bioinspired nanofibrous trivalent peptide hydrogel vaccine was constructed using the spontaneous supramolecular co-assembly of three antigenic epitope-conjugated peptides, which could mimic the fibrillar structure and biological function of the extracellular matrix and naturally occurring protein assembly. The hydrogel vaccine could be accurately and flexibly adjusted to load each antigenic peptide at a defined ratio, which facilitated the antigen presentation of dendritic cells and significantly improved the initiation of CD8 T cell response and the secretion of interferon-γ (IFN-γ). C57BL/6 mice were immunized with the trivalent peptide hydrogel vaccine, where it elicited a high broad-spectrum antitumor CD8 T cell response that significantly inhibited the growth of B16 tumors in the absence of additional immunoadjuvants or delivery systems. In summary, the supramolecular assembly of triple antigenic epitope-conjugated peptides offers a simple, customizable, and versatile approach for the development of cancer vaccines with remarkable therapeutic efficacy, thereby providing a highly versatile platform for the application of personalized multivalent tumor vaccines. STATEMENT OF SIGNIFICANCE: (1) We report a feasible, versatile and bioinspired approach to manufacture a multivalent peptide-based hydrogel cancer vaccine in the absence of additional adjuvants, which closely mimics immune niches, co-delivers antigen epitopes, greatly promotes antigen presentation to DCs and their subsequent homing to dLNs and elicits a broad-spectrum antitumor CD8 T cell response, resulting in significant inhibition of B16 tumor growth. (2) This feasible and efficient co-assembly strategy provides an attractive platform for engineering a range of multivalent vaccines at defined ratios to further enhance antigen-specific T cell responses. This approach may also be used for personalized immunotherapy with neo-epitopes.

Design of a potential Sema4A-based multi-epitope vaccine to combat triple-negative breast cancer: an immunoinformatic approach.

Immunotherapy is revamping the therapeutic strategies for TNBC owing to its higher mutational burden and tumour-associated antigens. One of the most intriguing developments in cancer immunotherapy is the focus on peptide-based cancer vaccines. Thus, the current work aims to develop an efficient peptide-based vaccine against TNBC that targets Sema4A, which has recently been identified as a major regulator of TNBC progression. Initially, the antigenic peptides derivedfrom Sema4A were determined and evaluated based on their capability to provoke immunological responses. The assessed epitopes were then linked with a suitable adjuvant (RpfB and RpfE) and appropriate linkers (AAY, GPGPG, KK and EAAAK) to preclude junctional immunogenicity. Eventually, docking and dynamics simulations are performed against TLR-2, TLR-4, TLR-7 and TLR-9 to assess the interaction between the vaccine construct and TLR receptors, as the TLR signalling pathway is critical in the host immune response. The developed vaccine was then exposed to in silico cloning and immune simulation analysis. The findings suggest that the designedvaccine could potentially evoke significant humoral and cellular immune responses in the intended organism. Considering these outcomes, the final multi-epitope vaccine could be employed to serve as an effective choice for TNBC management and may open new avenues for further studies.

Fluorescence labeling of anchor-modified Mart-1 peptide for increasing its affinity for HLA-A*0201: Hit two targets with one arrow.

One of the most successful strategies in designing peptide-based cancer vaccines is modifying natural epitope peptides to increase their binding strength to human leukocyte antigens (HLAs). Anchor-modified Mart-1 peptide (ELAGIGILTV) is among the artificial epitope peptides with the highest binding affinity for HLA-A*0201. In this study, by fluorescence labeling of its either C- or N-terminus with Nε -(5-carboxyfluorescein)-l-lysine, we not only made it traceable but also drastically increased its binding strength to HLA-A*0201. HLA streptamer, for the first time, is introduced for measuring the binding constants (Ka ) of the labeled peptides. The affinity of the labeled peptides for the HLA-A*201 of the MCF-7 cells was extraordinarily high and co-incubating them with the highest possible amount of the unlabeled peptide, as a competitor, did not significantly prohibit them from binding to the HLA. The reproducibility of the obtained results was confirmed by using the T2 cell line. The HLA-deficient K562 cell line was used as the negative control. With in silico simulations, we found two hydrophobic pockets on both sides of HLA-A*0201 for anchoring the C- or N-terminal 5-carboxyfluorescein probe, which can explain the extraordinary affinity of the labeled peptides for the HLA-A*0201.

WT1 Trio Peptide-Based Cancer Vaccine for Rare Cancers Expressing Shared Target WT1.

No standard treatment has been established for most rare cancers. Here, we report a clinical trial of a biweekly WT1 tri-peptide-based vaccine for recurrent or advanced rare cancers. Due to the insufficient number of patients available for a traditional clinical trial, the trial was designed for rare cancers expressing shared target molecule WT1. The recruitment criteria included WT1-expressing tumors as well as HLA-A*24:02 or 02:01. The primary endpoints were immunoglobulin G (IgG) antibody (Ab) production against the WT1-235 cytotoxic T lymphocyte (CTL) epitope and delayed-type hypersensitivity (DTH) skin reactions to targeted WT1 CTL epitopes. The secondary endpoints were safety and clinical efficacy. Forty-five patients received WT1 Trio, and 25 (55.6%) completed the 3-month protocol treatment. WT1-235 IgG Ab was positive in 88.0% of patients treated with WT1 Trio at 3 months, significantly higher than 62.5% of the weekly WT1-235 CTL peptide vaccine. The DTH positivity rate in WT1 Trio was 62.9%, which was not significantly different from 60.7% in the WT1-235 CTL peptide vaccine. The WT1 Trio safety was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer. Fifteen (33.3%) patients achieved stable disease after 3 months of treatment. In conclusion, the biweekly WT1 Trio vaccine containing the WT1-332 helper T lymphocyte peptide induced more robust immune responses targeting WT1 than the weekly WT1-235 CTL peptide vaccine. Therefore, WT1-targeted immunotherapy may be a potential therapeutic strategy for rare cancers.

Mechanism of action of DSP-7888 (adegramotide/nelatimotide) Emulsion, a peptide-based therapeutic cancer vaccine with the potential to turn up the heat on non-immunoreactive tumors

BackgroundWilms’ tumor 1 (WT1) is highly expressed in various solid tumors and hematologic malignancies. DSP-7888 (adegramotide/nelatimotide) Emulsion is an investigational therapeutic cancer vaccine comprising three synthetic epitopes derived from WT1. We evaluated the mechanism of action of DSP-7888 Emulsion, which is hypothesized to induce WT1-specific cytotoxic T lymphocytes (CTLs) and helper T lymphocytes (HTLs).MethodsThe ability of nelatimotide and adegramotide to induce WT1-specific CD8+ T cells and CD4+ T cells was assessed in human peripheral blood mononuclear cells (PBMCs). The ability of DSP-7888 Emulsion to induce WT1-specific CTLs in vivo was assessed using human leukocyte antigen-I (HLA-I) transgenic mice. To assess how adegramotide, the helper peptide in DSP-7888 Emulsion, enhances WT1-specific CTLs, HLA-I transgenic mice were administered DSP-7888 or nelatimotide-only Emulsion. Interferon-gamma secretion under antigen stimulation by splenocytes co-cultured with or without tumor cells was then quantified. The effects of combination treatment with DSP-7888 Emulsion and an anti–programmed cell death protein 1 (PD-1) antibody on tumor volume and the frequency of tumor-infiltrating WT1-specific T cells were assessed in HLA-I transgenic mice implanted with WT1 antigen-positive tumors.ResultsThe peptides in DSP-7888 Emulsion were shown to induce WT1-specific CTLs and HTLs in both human PBMCs and HLA-I transgenic mice. Unlike splenocytes from nelatimotide-only Emulsion-treated mice, splenocytes from DSP-7888 Emulsion-treated mice exhibited high levels of interferon-gamma secretion, including when co-cultured with tumor cells; interferon-gamma secretion was further enhanced by concomitant treatment with anti-PD-1. HLA-I transgenic mice administered DSP-7888 Emulsion plus anti-PD-1 experienced significantly greater reductions in tumor size than mice treated with either agent alone. This reduction in tumor volume was accompanied by increased numbers of tumor-infiltrating WT1-specific CTLs.ConclusionsDSP-7888 Emulsion can promote both cytotoxic and helper T-cell-mediated immune responses against WT1-positive tumors. Adegramotide enhances CTL numbers, and the CTLs induced by treatment with both nelatimotide and adegramotide are capable of functioning within the immunosuppressive tumor microenvironment. The ability of anti-PD-1 to enhance the antitumor activity of DSP-7888 Emulsion in mice implanted with WT1-positive tumors suggests the potential for synergy.

Cell-penetrating peptides enhance peptide vaccine accumulation and persistence in lymph nodes to drive immunogenicity

Peptide-based cancer vaccines are widely investigated in the clinic but exhibit modest immunogenicity. One approach that has been explored to enhance peptide vaccine potency is covalent conjugation of antigens with cell-penetrating peptides (CPPs), linear cationic and amphiphilic peptide sequences designed to promote intracellular delivery of associated cargos. Antigen-CPPs have been reported to exhibit enhanced immunogenicity compared to free peptides, but their mechanisms of action invivo are poorly understood. We tested eight previously described CPPs conjugated to antigens from multiple syngeneic murine tumor models and found that linkage to CPPs enhanced peptide vaccine potency invivo by as much as 25-fold. Linkage of antigens to CPPs did not impact dendritic cell activation but did promote uptake of linked antigens by dendritic cells both invitro and invivo. However, T cell priming invivo required Batf3-dependent dendritic cells, suggesting that antigens delivered by CPP peptides were predominantly presented via the process of cross-presentation and not through CPP-mediated cytosolic delivery of peptide to the classical MHC class I antigen processing pathway. Unexpectedly, we observed that many CPPs significantly enhanced antigen accumulation in draining lymph nodes. This effect was associated with the ability of CPPs to bind to lymph-trafficking lipoproteins and protection of CPP-antigens from proteolytic degradation in serum. These two effects resulted in prolonged presentation of CPP-peptides in draining lymph nodes, leading to robust T cell priming and expansion. Thus, CPPs can act through multiple unappreciated mechanisms to enhance T cell priming that can be exploited for cancer vaccines with enhanced potency.

Potential association factors for developing effective peptide-based cancer vaccines.

Peptide-based cancer vaccines have been shown to boost immune systems to kill tumor cells in cancer patients. However, designing an effective T cell epitope peptide-based cancer vaccine still remains a challenge and is a major hurdle for the application of cancer vaccines. In this study, we constructed for the first time a library of peptide-based cancer vaccines and their clinical attributes, named CancerVaccine (https://peptidecancervaccine.weebly.com/). To investigate the association factors that influence the effectiveness of cancer vaccines, these peptide-based cancer vaccines were classified into high (HCR) and low (LCR) clinical responses based on their clinical efficacy. Our study highlights that modified peptides derived from artificially modified proteins are suitable as cancer vaccines, especially for melanoma. It may be possible to advance cancer vaccines by screening for HLA class II affinity peptides may be an effective therapeutic strategy. In addition, the treatment regimen has the potential to influence the clinical response of a cancer vaccine, and Montanide ISA-51 might be an effective adjuvant. Finally, we constructed a high sensitivity and specificity machine learning model to assist in designing peptide-based cancer vaccines capable of providing high clinical responses. Together, our findings illustrate that a high clinical response following peptide-based cancer vaccination is correlated with the right type of peptide, the appropriate adjuvant, and a matched HLA allele, as well as an appropriate treatment regimen. This study would allow for enhanced development of cancer vaccines.