Active Immunotherapy Research Articles

Expression, purification and characterization of a novel triple fusion protein developed for the immunotherapy of survivin positive cancers

Survivin is an inhibitor of apoptosis, and expressed in a large number of cancers. As Survivin expression is very low in normal tissues, it assumes significance as a prominent target for tumor diagnosis, prognosis and developing anti-cancer therapies. We report development of a novel triple fusion protein for a prospective vaccine against Survivin in targeted cancer immunotherapy. A gene was synthesized by combining the nucleotides encoding human origin Survivin and heat-labile enterotoxin of Escherichia coli (LTB). Further, nucleotides corresponding to single chain variable fragment (scFv) of a monoclonal having affinity for DEC205 receptor present on dendritic cells, were also incorporated into the gene sequence. This complete gene was expressed to a triple fusion recombinant protein using a bacterial expression vector under the control of robust bacteriophage T7 promoter. The recombinant DCSurvivin-LTB protein, with a size of approximately 60 kDa, was purified from the inclusion bodies using affinity based Ni-NTA columns. The purified protein was confirmed by the Western blot, and further characterized with circular dichroism, fluorescence spectroscopy and mass spectroscopy. This molecularly adjuvanted Survivin fusion protein designed to deliver to the dendritic cells for better antigen processing, elicited a stronger anti-Survivin immune response compared to Survivin protein alone. It can be an effective vaccine in active and passive immunotherapies for Survivin expressing cancer cells.

Passive Anti-amyloid Beta Monoclonal Antibodies: Lessons Learned over Past 20 Years.

Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impairs cognitive and functional abilities, placing a substantial burden on both patients and caregivers. Current symptomatic treatments fail to halt the progression of AD, highlighting the urgent need for more effective disease-modifying therapies (DMTs). DMTs under development are classified as either passive or active on the basis of their mechanisms of eliciting an immune response. While this review will touch on active immunotherapies, we primarily focus on anti-amyloid beta monoclonal antibodies (mAbs), a form of passive immunotherapy, discussing their multifaceted role in AD treatment and the critical factors influencing their therapeutic efficacy. With two mAbs now approved and prescribed in the clinical setting, it is crucial to reflect on the lessons learned from trials of earlier mAbs that have shaped their development and contributed to their current success. These insights can then guide the creation of even more effective mAbs, ultimately enhancing therapeutic outcomes for patients with AD while minimizing adverse events.

Anti-Tumor Immunity to Patient-Derived Breast Cancer Cells by Vaccination with Interferon-Alpha-Conditioned Dendritic Cells (IFN-DC).

Breast cancer represents one of the leading causes of death among women. Surgery can be effective, but once breast cancer has metastasized, it becomes extremely difficult to treat. Conventional therapies are associated with substantial toxicity and poor efficacy due to tumor heterogeneity, treatment resistance and disease relapse. Moreover, immune checkpoint blockade appears to offer limited benefit in breast cancer. The poor tumor immunogenicity and the immunosuppressive tumor microenvironment result in scarce T-cell infiltration, leading to a low response rate. Thus, there is considerable interest in the development of improved active immunotherapies capable of sensitizing a patient's immune system against tumor cells. We evaluated the in vitro anti-tumor activity of a personalized vaccine based on dendritic cells generated in the presence of interferon (IFN)-α and granulocyte-macrophage colony-stimulating factor (IFN-DC) and loaded with an oxidized lysate from autologous tumor cells expanded as 3D organoid culture maintaining faithful tumor antigenic profiles. Our findings demonstrate that stimulation of breast cancer patients' lymphocytes with autologous IFN-DC led to efficient Th1-biased response and the generation in vitro of potent cytotoxic activity toward the patients' own tumor cells. This approach can be potentially applied in association with checkpoint blockade and chemotherapy in the design of new combinatorial therapies for breast cancer.

Active Immunotherapy for the Prevention of Alzheimer's and Parkinson's Disease.

Neurodegenerative diseases (ND) give rise to significant declines in motor, autonomic, behavioral, and cognitive functions. Of these conditions, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent, impacting over 55 million people worldwide. Given the staggering financial toll on the global economy and their widespread manifestation, NDs represent a critical issue for healthcare systems worldwide. Current treatment options merely seek to provide symptomatic relief or slow the rate of functional decline and remain financially inaccessible to many patients. Indeed, no therapy has yet demonstrated the potential to halt the trajectory of NDs, let alone reverse them. It is now recognized that brain accumulation of pathological variants of AD- or PD-associated proteins (i.e., amyloid-β, Tau, α-synuclein) begins years to decades before the onset of clinical symptoms. Accordingly, there is an urgent need to pursue therapies that prevent the neurodegenerative processes associated with pathological protein aggregation long before a clinical diagnosis can be made. These therapies must be safe, convenient, and affordable to ensure broad coverage in at-risk populations. Based on the need to intervene long before clinical symptoms appear, in this review, we present a rationale for greater investment to support the development of active immunotherapy for the prevention of the two most common NDs based on their safety profile, ability to specifically target pathological proteins, as well as the significantly lower costs associated with manufacturing and distribution, which stands to expand accessibility to millions of people globally.

Mechanistic Approach to Immunity and Immunotherapy of Alzheimer's Disease: A Review.

Alzheimer's disease (AD) is a debilitating neurodegenerative condition characterized by progressive cognitive decline and memory loss, affecting millions of people worldwide. Traditional treatments, such as cholinesterase inhibitors and NMDA receptor antagonists, offer limited symptomatic relief without addressing the underlying disease mechanisms. These limitations have driven the development of more potent and effective therapies. Recent advances in immunotherapy present promising avenues for AD treatment. Immunotherapy strategies, including both active and passive approaches, harness the immune system to target and mitigate AD-related pathology. Active immunotherapy stimulates the patient's immune response to produce antibodies against AD-specific antigens, while passive immunotherapy involves administering preformed antibodies or immune cells that specifically target amyloid-β (Aβ) or tau proteins. Monoclonal antibodies, such as aducanumab and lecanemab, have shown potential in reducing Aβ plaques and slowing cognitive decline in clinical trials, despite challenges related to adverse immune responses and the need for precise targeting. This comprehensive review explores the role of the immune system in AD, evaluates the current successes and limitations of immunotherapeutic approaches, and discusses future directions for enhancing the treatment efficacy.

A pentavalent peptide vaccine elicits Aβ and tau antibodies with prophylactic activity in an Alzheimer’s disease mouse model

Amyloid-β (Aβ) and hyperphosphorylated tau protein are targets for Alzheimer’s Disease (AD) immunotherapies, which are generally focused on single epitopes within Aβ or tau. However, due to the complexity of both Aβ and tau in AD pathogenesis, a multipronged approach simultaneously targeting multiple epitopes of both proteins could overcome limitations of monotherapies. Herein, we propose an active AD immunotherapy based on a nanoparticle vaccine comprising two Aβ peptides (1–14 and pyroglutamate pE3-14) and three tau peptides (centered on phosphorylated pT181, pT217 and pS396/404). These correspond to both soluble and aggregated targets and are displayed on the surface of immunogenic liposomes in an orientation that maintains reactivity with epitope-specific monoclonal antibodies. Intramuscular immunization of mice with individual epitopes resulted in minimally cross-reactive antibody induction, while simultaneous co-display of 5 antigens (“5-plex”) induced antibodies against all epitopes without immune interference. Post-immune sera recognized plaques and neurofibrillary tangles from human AD brain tissue. Vaccine administration to 3xTg-AD mice using a prophylactic dosing schedule inhibited tau and amyloid pathologies and resulted in improved cognitive function. Immunization was well tolerated and did not induce antigen-specific cellular responses or persistent inflammatory responses in the peripheral or central nervous system. Antibody levels could be reversed by halting monthly vaccinations. Altogether, these results indicate that active immune therapies based on nanoparticle formulations of multiple Aβ and tau epitopes warrant further study for treating early-stage AD.

Anti-Cytokine Active Immunotherapy Based on Supramolecular Peptides for Alleviating IL-1β-Mediated Inflammation.

IL-1β is a principal proinflammatory cytokine underlying multiple local and systemic chronic inflammatory conditions including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and type 2 diabetes. Passive immunotherapies and biologic drugs targeting IL-1β, while offering significant clinical benefit, nevertheless have limitations such as significant non-response rates, induction of anti-drug antibodies, and high costs. Here, an active immunotherapy raising antibody responses against IL-1β employing self-assembling peptide nanofibers is described. The nanofibers contain defined quantities of B-cell epitopes from IL-1β and exogenous T helper epitopes and employ the Q11 self-assembling peptide platform. Without adjuvant, the nanofibers raised durable anti-IL-1β antibody responses that inhibit IL-1β activity in vitro and in vivo. In a mouse model of imiquimod-induced psoriasis, prophylactic immunizations with the nanofibers diminished symptoms of epidermal thickening. This therapeutic effect is associated with biasing the immune response toward an anti-inflammatory IgG1/Th2 phenotype and a lowered expression of proinflammatory genes in the skin. Further, anti-IL-1β nanofibers induced therapeutic immunosuppressive CD62L+ Treg cells. This technology represents a potential alternative for passive immunotherapies and other biologics for treating chronic inflammatory conditions.

The current therapeutic cancer vaccines landscape in non-small cell lung cancer.

Currently, conventional immunotherapies for the treatment of non-small cell lung cancer (NSCLC) have low response rates and benefit only a minority of patients, particularly those with advanced disease, so novel therapeutic strategies are urgent deeded. Therapeutic cancer vaccines, a form of active immunotherapy, harness potential to activate the adaptive immune system against tumor cells via antigen cross-presentation. Cancer vaccines can establish enduring immune memory and guard against recurrences. Vaccine-induced tumor cell death prompts antigen epitope spreading, activating functional T cells and thereby sustaining a cancer-immunity cycle. The success of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rendered cancer vaccines a promising avenue, especially when combined with immunotherapy or chemoradiotherapy for NSCLC. This review delves into the intricate antitumor immune mechanisms underlying therapeutic cancer vaccines, enumerates the tumor antigen spectrum of NSCLC, discusses different cancer vaccines progress and summarizes relevant clinical trials. Additionally, we analyze the combination strategies, current limitations, and future prospects of cancer vaccines in NSCLC treatment, aiming to offer fresh insights for their clinical application in managing NSCLC. Overall, cancer vaccines offer promising potential for NSCLC treatment, particularly combining with chemoradiotherapy or immunotherapy could further improve survival in advanced patients. Exploring inhaled vaccines or prophylactic vaccines represents a crucial research avenue.

A First-in-Human Phase I Clinical Study with MVX-ONCO-1, a Personalized Active Immunotherapy, in Patients with Advanced Solid Tumors.

This first-in-human phase I study introduces a groundbreaking approach to personalized cancer immunotherapy, addressing limitations of traditional strategies. By combining autologous irradiated tumor cells as a source of patient-specific antigens and utilizing encapsulated cell technology for localized, sustained delivery of granulocyte-macrophage colony-stimulating factor as an adjuvant, the study shows a very good safety and feasibility profile. This innovative approach holds the promise of addressing tumor heterogeneity by taking advantage of each patient's antigenic repertoire.

A bibliometric analysis of vaccination against atherosclerosis

ABSTRACT A growing body of research indicates the promising potential of vaccines in both preventing and treating atherosclerosis (AS). To gain a comprehensive understanding of the current research landscape and emerging trends in this field, this study conducted a bibliometric analysis of publications on AS vaccines using the Web of Science Core Collection (WoSCC) database, based on the “bibliometric” R package and VOSviewer software. From 1991 to 2024, a total of 462 publications were identified in the WoSCC. The United States appeared as the leading contributor in terms of both total publications and citations. The Vaccine journal exhibited the highest publications output. Nilsson J from the Lund University in Sweden was the author with the most published articles, total citations and Hirsch index (H-index). Keywords analysis and thematic maps analysis revealed the passive immunotherapy (AS protective antibodies vaccines) was a hot mature theme, the active immunotherapy (AS antigens vaccines) was an emerging and booming theme, while the efficacy and safety of AS vaccines was a niche and well-developed theme. These findings offered valuable insights into the AS vaccination and provided guidance for future research in this domain.

MRNA Vaccine for Alzheimer's Disease: Pilot Study.

The escalating global healthcare challenge posed by Alzheimer's Disease (AD) and compounded by the lack of effective treatments emphasizes the urgent need for innovative approaches to combat this devastating disease. Currently, passive and active immunotherapies remain the most promising strategy for AD. FDA-approved lecanemab significantly reduces Aβ aggregates from the brains of early AD patients administered biweekly with this humanized monoclonal antibody. Although the clinical benefits noted in these trials have been modest, researchers have emphasized the importance of preventive immunotherapy. Importantly, data from immunotherapy studies have shown that antibody concentrations in the periphery of vaccinated people should be sufficient for targeting Aβ in the CNS. To generate relatively high concentrations of antibodies in vaccinated people at risk of AD, we generated a universal vaccine platform, MultiTEP, and, based on it, developed a DNA vaccine, AV-1959D, targeting pathological Aβ, completed IND enabling studies, and initiated a Phase I clinical trial with early AD volunteers. Our current pilot study combined our advanced MultiTEP technology with a novel mRNA approach to develop an mRNA vaccine encapsulated in lipid-based nanoparticles (LNPs), AV-1959LR. Here, we report our initial findings on the immunogenicity of 1959LR in mice and non-human primates, comparing it with the immunogenicity of its DNA counterpart, AV-1959D.

Effect of probiotics on quality of life for patients with cancer undergoing immunotherapy.

e24148 Background: Probiotics are crucial in oncology for enhancing gut health, boosting immune response, potentially improving immunotherapy efficacy, and reducing side effects of cancer treatments. Research links a healthy gut microbiome with better immunotherapy outcomes, however, more studies in this area are required to validate this hypothesis. Methods: Oncological patients at Hospital Ángeles Puebla's Comprehensive Cancer Center undergoing immunotherapy were invited to participate and provided their consent to receive a daily probiotic and prebiotic mix (including Lactobacillus rhamnosus, Bifidobacterium longum, Pediococcus pentosaceus, and others) for three months. Their health was closely monitored, and quality of life assessed using the EORTC-QLQ-C30 questionnaire at the start, day 45, and day 90. A Kruskal-Wallis H-test was conducted to correlate the EORTC-QLQ-C30 scores with their diagnosis, clinical stage, presence of comorbidities, and use of ancillary treatments, as well as a Spearman's test to associate these scores with their age. Results: 22 patients were included. Average age was 64.5 years, with 77% being male and 23% female. 68.18% were in stage IV, 4.55% in stage III, 18.18% in stage II, and 9.09% in stage I. Comorbidities included: diabetes in 31.82%, hypertension in 40.91%, and other diseases in 22.73%. Treatment regimens involved 81.81% receiving Anti-PD-L1 and 18.18% receiving Anti-PD-1. Additionally, 40.91% were on corticosteroids and another 40.91% on proton pump inhibitors as ancillary treatments. Median follow-up was 3.13 months, during which 23% of the patients experienced adverse events. Of these, 9.09% were grade 4 according to the CTCAE v.5, and 13.63% were grade 1. Significant differences were found between patients with hepatocellular carcinoma versus renal carcinoma in the overall score on day 1 (KW: 4.47, p-value: 0.0344), with no differences in the rest of the scores. Significant differences were also identified between patients with advanced-stage versus early or locally advanced-stage cancer in terms of pain (KWS: 4.091, p-value: 0.043), dyspnea (KWS: 4.355, p-value: 0.037), loss of appetite (KWS: 4.091, p-value: 0.043), constipation (KWS: 3.971, p-value: 0.046), and diarrhea (KWS: 4.355, p-value: 0.037). A negative correlation was found between age and social functioning (Spearman: -0.73, p-value: 0.03), as well as with the presence of pain (Spearman: -0.73, p-value: 0.04). Conclusions: In this study, we observed a decrease in symptoms and an increase in functionality and overall quality of life scores among the patients. This suggests that patients undergoing active immunotherapy treatment may benefit from the use of probiotics and prebiotics as an ancillary treatment. However, further extended studies with larger populations are necessary to corroborate our findings.

Abstract CT126: A Phase 0 Study of EGF-Depleting Therapy CIMAvax-EGF in Combination With Standard Therapy for RAS- and BRAF Wild-Type Metastatic Colorectal Cancer

Abstract Background: Colorectal Cancer (CRC) is the 3rd most common cancer in the US and a leading cause of cancer-related death. The epidermal growth factor receptor (EGFR) is overexpressed by immunohistochemistry (IHC) in up to 60% of CRC and is a relevant target for treatment. Monoclonal antibodies targeting the EGFR (cetuximab, panitumumab) have been in clinical use since 2004 as single agents as well as in combination with chemotherapeutics for patients with metastatic CRC, however primary and secondary resistance is very common. CIMAvax-EGF® (CIMAvax) vaccinates against one of the main EGFR ligands: the epidermal growth factor (EGF) protein. The vaccine is based on active immunotherapy where an individual’s immune response is manipulated to release its own effector antibodies against circulating EGF. We hypothesize that adding CIMAvax-EGF to standard chemotherapy has the potential to elicit an immune response against EGF for RAS- and BRAF wild-type metastatic CRC. Methods: This is a phase 0 study to evaluate CIMAvax in combination with standard therapy for RAS- and BRAF wild-type metastatic CRC. Patients will be treated with chemotherapy/biologic agent plus CIMAvax 2.4 mg (DL 1); DL -1 is 1.2 mg. The starting dose is the dose currently established as recommended dose in combination with immunotherapy in patients with non-small cell lung cancer. Cohorts A, B1 and B2 will enroll each 6-12 patients. Based on the known CIMAvax safety profile, we expect to enroll 18-20 patients in these cohorts. Cohort C will enroll 4-6 patients. Cohort A will enroll patients who have not received prior therapy for advanced disease. Patients in Cohort A will be treated with mFOLFOX6/Bevacizumab/CIMAvax at present. Cohort B will enroll patients who have received at least one but no more than 2 prior therapies for advanced disease. Cohort B is comprised of 2 sub-Cohorts. The standard therapy backbone in Cohort B1 will be FOLFIRI/anti-EGFR therapy, and in Cohort B2 mFOLFOX6/anti-EGFR therapy. Cohort C will enroll patients who have not received prior therapy for advanced disease and are candidates for liver metastasectomy. Cohort C will start accruing after the safety run-in phase in Cohorts A, and B2 are completed. The primary objective of this study is to determine the immunogenicity of CIMAvax in the 1st and 2nd/3rd line setting. Secondary objectives include determining the safety and efficacy of these combinations in this patient population and PFS. Exploratory objectives include evaluation of immunomodulation in the tumor microenvironment in patients undergoing metastasectomy of liver metastases, predictive/prognostic role of EGFR ligands (such as EGF, epiregulin, and amphiregulin), somatic mutation profile, EGFR expression by IHC and EGFR copy number alterations/mRNA expression. This trial is currently open for accrual. Clinicaltrials.gov number NCT06011772 Citation Format: Deepak Vadehra, Cayla Janes, Rachel Frascati, Mary Reid, Tania C. Ramos, Sarbajit Mukherjee, Kalet L. Monzón, Patricia L. Alvárez, Orestes S. Morales, Circe M. Pardillo, Christos Fountzilas. A Phase 0 Study of EGF-Depleting Therapy CIMAvax-EGF in Combination With Standard Therapy for RAS- and BRAF Wild-Type Metastatic Colorectal Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT126.

Alzheimer's Disease Immunotherapy: Current Strategies and Future Prospects.

Alzheimer's disease (AD) is an extremely complex and heterogeneous pathology influenced by many factors contributing to its onset and progression, including aging, amyloid-beta (Aβ) plaques, tau fibril accumulation, inflammation, etc. Despite promising advances in drug development, there is no cure for AD. Although there have been substantial advancements in understanding the pathogenesis of AD, there have been over 200 unsuccessful clinical trials in the past decade. In recent years, immunotherapies have been at the forefront of these efforts. Immunotherapy alludes to the immunological field that strives to identify disease treatments via the enhancement, suppression, or induction of immune responses. Interestingly, immunotherapy in AD is a relatively new approach for non-infectious disease. At present, antibody therapy (passive immunotherapy) that targets anti-Aβ aimed to prevent the fibrillization of Aβ peptides and disrupt pre-existing fibrils is a predominant AD immunotherapy due to the continuous failure of active immunotherapy for AD. The most rational and safe strategies will be those targeting the toxic molecule without triggering an abnormal immune response, offering therapeutic advantages, thus making clinical trial design more efficient. This review offers a concise overview of immunotherapeutic strategies, including active and passive immunotherapy for AD. Our review encompasses approved methods and those presently under investigation in clinical trials, while elucidating the recent challenges, complications, successes, and potential treatments. Thus, immunotherapies targeting Aβ throughout the disease progression using a mutant oligomer-Aβ stimulated dendritic cell vaccine may offer a promising therapy in AD.

Abstract 4106: A novel synthetic long peptide vaccine composition targeting multiple PD-L1 T-cell epitopes exhibits anti-tumor efficacy in a syngeneic mouse colorectal cancer model

Abstract Background Cancer immunotherapy targeting immune checkpoints has shown promising clinical anti-tumor efficacy over the past decades. Monoclonal antibodies against PD-1 or PD-L1 have demonstrated clinical efficacy in a wide spectrum of cancer types. Despite the clinical success of therapies using immune checkpoint inhibitors (ICI), only a subset of patients shows long-lasting tumor remission, while resistance and toxicities to these agents remain to be addressed. This supports the need to explore alternative immunotherapeutic approaches or additional therapies for synergistic combinations to augment the anti-tumor efficacy for cancer patients receiving ICI therapies. Methods As an active immunotherapy approach, we developed a blend of four novel synthetic peptide vaccines each containing one PD-L1 T-cell epitope with individual covalent conjugation of the carrier protein, keyhole limpet haemocyanin (KLH), which is to break immune tolerance towards self-molecules. The four PD-L1 epitopes range from 30 to 40 amino acids in length, which target different domains of mouse PD-L1 protein. The PD-L1 peptides were synthesized using the technique of solid-phase peptide synthesis and purified by high performance liquid chromatography. All naked peptides were conjugated to KLH protein by thiol-maleimide reaction, followed by dialysis for purification. The peptide vaccines were formulated with a Toll-like receptor 9 agonist CpG ODN 1826 and aluminum hydroxide gel for animal immunization. Results These synthetic long PD-L1 peptide vaccines are highly immunogenic in a syngeneic BALB/c mouse model for a cell-mediated immune response when admixed and formulated with adjuvants. The vaccine composition is well tolerated by the mice with no evidence of toxicity and autoimmunity. In vivo administration of the vaccine formulation can elicit a positive PD-L1-specific T cell response in splenocytes with an IFN-γ ELISPOT assay. Moreover, in vivo vaccination of these PD-L1 peptide vaccines in a CT26 syngeneic mouse preventive colorectal cancer model exhibits a potent anti-tumor activity, with a 54% tumor growth inhibition (p<0.001) in tumor volume compared to that of the adjuvant-control group at the end of the study. Conclusions Taken together, our data demonstrate a proof-of-concept that T cell-based PD-L1 peptide vaccines are a promising therapeutic strategy for inducing anti-tumor immunity to combat cancers. Citation Format: Kenneth Nansheng Lin, Melvin Toh. A novel synthetic long peptide vaccine composition targeting multiple PD-L1 T-cell epitopes exhibits anti-tumor efficacy in a syngeneic mouse colorectal cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4106.

Active immunotherapy for C5a-mediated inflammation using adjuvant-free self-assembled peptide nanofibers

The terminal protein in the complement cascade C5a is a potent inflammatory molecule and chemoattractant that is involved in the pathology of multiple inflammatory diseases including sepsis and arthritis, making it a promising protein to target with immunotherapies. Active immunotherapies, in which patients are immunized against problematic self-molecules and generate therapeutic antibodies as a result, have received increasing interest as an alternative to traditional monoclonal antibody treatments. In previous work, we have designed supramolecular self-assembling peptide nanofibers as active immunotherapies with defined combinations of B- and T-cell epitopes. Herein, the self-assembling peptide Q11 platform was employed to generate a C5a-targeting active immunotherapy. Two of three predicted B-cell epitope peptides from C5a were found to be immunogenic when displayed within Q11 nanofibers, and the nanofibers were capable of reducing C5a serum concentrations following immunization. Contrastingly, C5a's precursor protein C5 maintained its original concentration, promising to minimize side effects heretofore associated with C5-targeted therapies. Immunization protected mice against an LPS-challenge model of sepsis, and it reduced clinical severity in a model of collagen-antibody induced arthritis. Together, this work indicates the potential for targeting terminal complement proteins with active immunotherapies by leveraging the immunogenicity of self-assembled peptide nanomaterials. Statement of significanceChronic inflammatory diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease are currently treated primarily with monoclonal antibodies against key inflammatory mediators. While helpful for many patients, they have high non-response rates, are costly, and commonly fail as anti-drug antibodies are raised by the patient. The approach we describe here explores a fundamentally different treatment paradigm: raising therapeutic antibody responses with an active immunotherapy.We employ innovative supramolecular peptide nanomaterials to elicit neutralizing antibody responses against complement component C5a and demonstrate therapeutic efficacy in preclinical mouse models of sepsis and rheumatoid arthritis. The strategy reported may represent a potential alternative to monoclonal antibody therapies.

Analysis and Validation of Tyrosine Metabolism-related Prognostic Features for Liver Hepatocellular Carcinoma Therapy.

To explore tyrosine metabolism-related characteristics in liver hepatocellular carcinoma (LIHC) and to establish a risk signature for the prognostic prediction of LIHC. Novel prognostic signatures contribute to the mining of novel biomarkers, which are essential for the construction of a precision medicine system for LIHC and the improvement of survival. Tyrosine metabolism plays a critical role in the initiation and development of LIHC. Based on the tyrosine metabolism-related characteristics in LIHC, this study developed a risk signature to improve the prognostic prediction of patients with LIHC. To investigate the correlation between tyrosine metabolism and progression of LIHC and to develop a tyrosine metabolism-related prognostic model. Gene expression and clinicopathological information of LIHC were obtained from The Cancer Genome Atlas (TCGA) database. Distinct subtypes of LIHC were classified by performing consensus cluster analysis on the tyrosine metabolism-related genes. Univariate and Lasso Cox regression were used to develop a RiskScore prognosis model. Kaplan-Meier (KM) survival analysis with log-rank test and area under the curve (AUC) of receiver operating characteristic (ROC) were employed in the prognostic evaluation and prediction validation. Immune infiltration, tyrosine metabolism score, and pathway enrichment were evaluated using single-sample gene set enrichment analysis (ssGSEA). Finally, a nomogram model was developed with the RiskScore and other clinicopathological features. Based on the tyrosine metabolism genes in the TCGA cohort, we identified 3 tyrosine metabolism-related subtypes showing significant prognostic differences. Four candidate genes selected from the common differentially expressed genes (DEGs) between the 3 subtypes were used to develop a RiskScore model, which could effectively divide LIHC patients into high- and lowrisk groups. In both the training and validation sets, high-risk patients tended to have worse overall survival, less active immunotherapy response, higher immune infiltration and clinical grade, and higher oxidative, fatty, and xenobiotic metabolism pathways. Multivariate analysis confirmed that the RiskScore was an independent indicator for the prognosis of LIHC. The results from pan-- cancer analysis also supported that the RiskScore had a strong prognostic performance in other cancers. The nomogram demonstrated that the RiskScore contributed the most to the prediction of LIHC prognosis. Our study developed a tyrosine metabolism-related risk model that performed well in survival prediction, showing the potential to serve as an independent prognostic predictor for LIHC treatment.

Identification of an angiogenesis-related risk score model for survival prediction and immunosubtype screening in multiple myeloma.

Multiple myeloma (MM) is an incurable B-cell malignancy, but with the emergence of immunotherapy, a potential cure is hopeful. The individualized interaction between the tumor and bone marrow (BM) microenvironment determines the response to immunotherapy. Angiogenesis is a constant hallmark of the BM microenvironment in MM. However, little is known about the potency ability of angiogenesis-associated genes (AAGs) to regulate the immune microenvironment of MM patients. We comprehensively dissected the associations between angiogenesis and genomic landscapes, prognosis, and the immune microenvironment by integrating 36 AAGs. Immunohistochemistry was performed to verify the correlation between angiogenic factor expression and patient prognosis. Single-sample gene set enrichment analysis was applied to quantify the relative abundance of 28 infiltrating cells. The AAG score was constructed using the least absolute shrinkage and selection operator Cox regression model. Angiogenesis was closely correlated with MM patient prognosis, and the mutation intensity of the AAGs was low. Immunohistochemistry confirmed that high microvessel density predicted poor prognosis. Three AAG clusters and two gene clusters with distinct clinical outcomes and immune characteristics were identified. The established AAG_score model performed well in predicting patient prognosis and active immunotherapy response. The high-AAG_score subgroup was characterized by reduced immune cell infiltration, poor prognosis, and inactive immunotherapy response. Multivariate analyses indicated that the AAG_score was strongly robust and independent among the prognostic variables. This study revealed that angiogenesis is significantly related to MM patient prognosis and immune phenotype. Evaluating the AAG signature was conducive to predicting patient response to immunotherapy and guiding more efficacious immunotherapy strategies.

An Open-Label Study of Subcutaneous CpG Oligodeoxynucleotide (PF03512676) in Combination with Trastuzumab in Patients with Metastatic HER2+ Breast Cancer.

CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in utilizing CpG ODN as an adjuvant to improve clinical efficacy of current treatments and immunogenicity of breast cancers not traditionally responsive to active immunotherapy, such as those that are human epidermal growth factor receptor 2 (HER2)-positive. This study aimed to study the efficacy and safety of combination CpG ODN plus anti-HER2 antibody trastuzumab treatment in patients with advanced/metastatic breast cancer. This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response. Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment. CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored.

Safety and effectiveness of CIMAvax-EGF administered in community polyclinics.

https://rpcec.sld.cu/trials/RPCEC00000205-En, identifier RPCEC00000205.